bluuebunny/crossref_metadata_2025 huggingface dataset:
Carboplatin/Ifosfamide Window Therapy for Osteosarcoma: Results of the St Jude Children’s Research Hospital OS-91 Trial
Authors: Meyer William H. , Pratt Charles B. , Poquette Catherine A. , Rao Bhaskar N. , Parham David M. , Marina Neyssa M. , Pappo Alberto S. , Mahmoud Hazem H. , Jenkins Jesse J. , Harper James , Neel Michael , Fletcher Barry D.
Published: February 2017

PURPOSE: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin.

PATIENTS AND METHODS: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m2 × 1) and ifosfamide (2.65 g/m2/d × 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation.

RESULTS: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% ± 6.7% and 76.4% ± 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity.

CONCLUSION: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.
Tumor Variants by Hormone Receptor Expression in White Patients With Node-Negative Breast Cancer From the Surveillance, Epidemiology, and End Results Database
Authors: Anderson William F. , Chu Kenneth C. , Chatterjee Nilanjan , Brawley Otis , Brinton Louise A.
Published: February 2017

PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications.

METHODS: Breast cancer records were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER−), independent progesterone receptor (PR+ and PR−), and joint ERPR expression (ER+PR+, ER+PR−, ER−PR+, and ER−PR−).

RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER− and PR− breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR− to ER−PR+ to ER−PR−.

CONCLUSION: Variations of standard tumor cell characteristics and breast cancer–specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.
Neuroblastoma With Symptomatic Spinal Cord Compression at Diagnosis: Treatment and Results With 76 Cases
Authors: De Bernardi Bruno , Pianca Clotilde , Pistamiglio Paola , Veneselli Edvige , Viscardi Elisabetta , Pession Andrea , Alvisi Patrizia , Carli Modesto , Donfrancesco Alberto , Casale Fiorina , Giuliano Maria Grazia , di Montezemolo Luca Cordero , Di Cataldo Andrea , Lo Curto Margherita , Bagnulo Serenella , Schumacher Richard Fabian , Tamburini Angela , Garaventa Alberto , Clemente Luigi , Bruzzi Paolo
Published: February 2017

PURPOSE: To report on the treatment of patients with newly diagnosed neuroblastoma presenting with spinal cord compression (SCC).

PATIENTS AND METHODS: Of 1,462 children with neuroblastoma registered between 1979 and 1998, 76 (5.2%) presented with signs/symptoms of SCC, including motor deficit in 75 patients (mild in 43, moderate in 22, severe [ie, paraplegia] in 10), pain in 47, sphincteric deficit in 30, and sensory loss in 11. Treatment of SCC consisted of radiotherapy in 11 patients, laminectomy in 32, and chemotherapy in 33. Laminectomy was more frequently performed in cases with favorable disease stages and in those with severe motor deficit, whereas chemotherapy was preferred in patients with advanced disease.

RESULTS: Thirty-three patients achieved full neurologic recovery, 14 improved, 22 remained stable, and eight worsened, including three who become paraplegic. None of the 10 patients with grade 3 motor deficit, eight of whom were treated by laminectomy, recovered or improved. In the other 66 patients, the neurologic response to treatment was comparable for the three therapeutic modalities. All 11 patients treated by radiotherapy and 26 of 32 patients treated by laminectomy, but only two of 33 treated by chemotherapy, received additional therapy for SCC. Fifty-four of 76 patients are alive at time of the analysis, with follow-up of 4 to 209 months (median, 139 months). Twenty-six (44%) of 54 survivors have late sequelae, mainly scoliosis and sphincteric deficit.

CONCLUSION: Radiotherapy, laminectomy, and chemotherapy showed comparable ability to relieve or improve SCC. However, patients treated with chemotherapy usually did not require additional therapy, whereas patients treated either with radiotherapy or laminectomy commonly did. No patient presenting with (or developing) severe motor deficit recovered or improved. Sequelae were documented in 44% of surviving patients.
Why Academic Divisions of Hematology/Oncology Are in Trouble and Some Suggestions for Resolution
Authors: Smith Thomas J. , Girtman John , Riggins Jerry
Published: February 2017

PURPOSE: Academic divisions of hematology/oncology seem to have difficulty recruiting and retaining excellent productive clinicians. A major reason for this is that salaries do not compete with the private sector for similar work.

METHODS: We reviewed divisional finances productivity, and experiences from faculty members leaving.

RESULTS: The academic salaries are approximately one third of practice because the chemotherapy concession has been given to the academic hospital. In addition, there may be substantial problems in under-billing, lack of attention to detail in billing, and poor collection practices.

CONCLUSION: Academic practice still has much to offer, including opportunities for research and multidisciplinary team management, although the differences may narrow over the coming years. Attention to detail in the billing, collection for work performed, and increasing academic salaries to levels nearer to private practice are necessary components of the solution to recruit and retain quality pro-ductive clinicians.
Omission of Histologic Grading From Clinical Decision Making May Result in Overuse of Adjuvant Therapies in Breast Cancer: Results From a Nationwide Study
Authors: Lundin J. , Lundin M. , Holli K. , Kataja V. , Elomaa L. , Pylkkänen L. , Turpeenniemi-Hujanen T. , Joensuu H.
Published: February 2017

PURPOSE: To investigate the influence of routinely performed histologic grading on breast cancer outcome prediction and patient selection for adjuvant therapy.

PATIENTS AND METHODS: The analysis is based on a cohort of 2,842 women diagnosed with breast cancer and comprising 91% of all breast cancers diagnosed in five defined geographical regions in Finland in 1991 through 1992. Data on clinicopathologic factors and follow-up were collected from hospital case records and national registries. Histologic grade assessed at diagnosis and other clinicopathologic data were available for 1,554 operable unilateral invasive carcinomas. The relative value of grade with respect to competing prognostic factors was estimated with the Cox proportional hazards model and logistic regression. Interactions and nonlinearity of factors were accounted for by using an artificial neural network.

RESULTS: Histologic grade was correlated strongly with survival in the entire series and in all subgroups studied. Women with well-differentiated node-negative cancer had a 97% 5-year distant disease-free survival rate as compared with 78% for women with poorly differentiated cancer. Grade was an independent prognostic factor in multivariate models and increased the predictive accuracy of a neural network model. Inclusion of grade data in a Cox multivariate model based on tumor size and hormone receptor status in node-negative cancer increased the proportion of patients with 5% or less risk for distant recurrence at 5 years from 15% to 54%.

CONCLUSION: Even when assessed by pathologists who have no special training in breast cancer pathology, histologic grade has substantial and independent prognostic value in breast cancer. Omission of grading from clinical decision making may result in considerable overuse of adjuvant therapies.
Microsomal Epoxide Hydrolase Expression as a Predictor of Tamoxifen Response in Primary Breast Cancer: A Retrospective Exploratory Study With Long-Term Follow-Up
Authors: Fritz Peter , Mürdter Thomas E. , Eichelbaum Michel , Siegle Isabel , Weissert Matthias , Zanger Ulrich M.
Published: February 2017

PURPOSE: It has been suggested that estrogen receptor–independent high-affinity binding sites for antiestrogens could limit their local bioavailability and response. Microsomal epoxide hydrolase (mEH) was recently shown to be a component of the antiestrogen binding site complex. We investigated whether mEH expression in primary breast tumors is related to disease outcome and to the efficacy of tamoxifen treatment.

PATIENTS AND METHODS: Expression of mEH was semiquantitatively assessed by immunohistochemistry in sections prepared from archival paraffin blocks of primary breast cancers from 179 patients with a mean follow-up time of 81 months.

RESULTS: Expression of mEH was correlated with poor disease outcome in all patients (P < .01; n = 179) and in patients receiving tamoxifen (P < .01; n = 78), but not in patients not treated with tamoxifen. Moreover, mEH was an independent prognostic factor by Cox regression analysis.

CONCLUSION: The results of this first exploratory study suggest that mEH expression in primary breast cancer could be of predictive value for response to tamoxifen treatment and/or may be a novel independent prognostic factor for survival. The results are in agreement with the model that mEH participates in an estrogen receptor–independent tamoxifen- binding complex.
Equivalent Racial Outcome After Conformal Radiotherapy for Prostate Cancer: A Single Departmental Experience
Authors: Connell Philip P. , Ignacio Lani , Haraf Daniel , Awan Azhar M. , Halpern Howard , Abdalla Ibrahim , Nautiyal Jaishanker , Jani Ashesh B. , Weichselbaum Ralph R. , Vijayakumar Srinivasan
Published: February 2017

PURPOSE: African-American (AA) men with prostate cancer present with advanced disease, relative to white (W) men. This report summarizes our clinical and biochemical control (bNED) rates after conformal radiotherapy (RT). In particular, we aim to characterize any race-based outcome differences seen after comparable treatment.

PATIENTS AND METHODS: We reviewed 893 patients (418 AA and 475 W) with clinically localized prostate cancer treated between 1988 and 1997. Neoadjuvant hormonal blockade was used in 22.5% of cases, and all patients received conformal RT to a median dose of 68 Gy (range, 60 to 74.8 Gy). Biochemical failure was defined according to the American Society of Therapeutic Radiology and Oncology consensus definition. Median follow-up was 24 months (range, 1 to 114 months).

RESULTS: The 5-year actuarial survival, disease-free survival, and bNED rates for the entire population were 80.5%, 70.0%, and 57.6%, respectively. When classified by prognostic risk category, the 5-year actuarial bNED rates were 78.7% for favorable, 57.7% for intermediate, and 39.8% for unfavorable category patients. AA men presented at younger ages and with more advanced disease. Controlled for prognostic risk category, AA and W men had similar 5-year actuarial bNED rates in favorable (78% v 79%, P = .91), intermediate (52% v 62%, P = .44), and unfavorable categories (36% v 45%, P = .09). Race was not an independent prognostic factor (P = .36).

CONCLUSION: Conformal RT is equally effective for AA and W patients. More research is needed in order to understand and correct the advanced presentations in AA men. These data suggest a need for early screening in AA populations.
Transurethral Resection of Muscle-Invasive Bladder Cancer: 10-Year Outcome
Authors: Herr Harry W.
Published: February 2017

PURPOSE: To determine the 10-year outcome of patients with muscle-invasive bladder cancer treated by transurethral resection (TUR) alone.

PATIENTS AND METHODS: Of 432 newly evaluated patients with muscle-invasive bladder cancer, 151 were treated by standard radical cystectomy or by definitive TUR, if restaging TUR of the primary tumor site showed no (T0) or only non–muscle-invasive (T1) residual tumor. Patients were followed-up every 3 to 6 months thereafter for a minimum of 10 years and up to 20 years. Primary end points of the study were disease-specific survival, survival with a bladder, frequency of recurrent invasive tumors in the bladder, and survival after salvage cystectomy.

RESULTS: The 10-year disease-specific survival was 76% of 99 patients who received TUR as definitive therapy (57% with bladder preserved) compared with 71% of 52 patients who had immediate cystectomy (P = .3). Of the 99 patients treated with TUR, 82% of 73 who had T0 on restaging TUR survived versus 57% of the 26 patients who had residual T1 tumor on restaging TUR (P = .003). Thirty-four patients (34%) relapsed in the bladder with a new muscle-invasive tumor, 18 (53%) were successfully treated with salvage therapy via cystectomy, and 16 patients (16%) died of disease.

CONCLUSION: Radical TUR for muscle-invasive bladder cancer is a successful bladder-sparing therapeutic strategy in selected patients who have no residual tumor on a repeat vigorous resection of the primary tumor site.
Comparison of Positron Emission Tomography Scanning and Sentinel Node Biopsy in the Detection of Micrometastases of Primary Cutaneous Malignant Melanoma
Authors: Acland K.M. , Healy C. , Calonje E. , O’Doherty M. , Nunan T. , Page C. , Higgins E. , Russell-Jones R.
Published: February 2017

PURPOSE: Sentinel node biopsy (SNB) is a surgical technique for detecting micrometastatic disease in the regional draining nodes. 2-fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scanning is an imaging technique that can detect clinically undetectable metastases. This prospective study was undertaken to compare the sensitivity of FDG-PET scanning with SNB in the detection of micromatastatic malignant melanoma.

PATIENTS AND METHODS: Fifty consecutive patients (23 women, 27 men; mean age, 53 years) with primary melanoma >1 mm thick or lymphatic invasion were recruited (mean, 2.41 mm). Primary lesions had been narrowly excised (<1 cm). Patients underwent PET scanning followed by SNB, using a dual technique. Preoperative lymphoscintigraphy was used to identify the draining basin. Lymph nodes were examined histologically and immunostained for S100 and HMB 45.

RESULTS: The sentinel node (SN) was identified in all patients. Fourteen patients (28%) had positive SNBs, including eight patients with melanoma <1.5 mm thick. In none of these 14 patients did PET scans identify metastatic disease in the SN or draining basin. In seven patients, the PET scans were positive in other locations, and in four cases, this was suspicious of metastatic disease. However, no patient has developed recurrent melanoma (mean follow-up, 15 months). All patients with positive SNBs underwent therapeutic lymph node dissection. Further lymph node involvement was found in two patients (primary lesions, 1.3 mm and 3.5 mm thick).

CONCLUSION: This study demonstrates the limitations of FDG-PET scanning in staging patients with primary melanoma. SNB is the only reliable method for identifying micrometastatic disease in the regional draining node.
Definitive Results of a Phase II Trial of Cisplatin, Epirubicin, Continuous-Infusion Fluorouracil, and Gemcitabine in Stage IV Pancreatic Adenocarcinoma
Authors: Reni M. , Passoni P. , Panucci M. G. , Nicoletti R. , Galli L. , Balzano G. , Zerbi A. , Di Carlo V. , Villa E.
Published: February 2017

PURPOSE: To evaluate the efficacy and toxicity of a cisplatin, epirubicin, gemcitabine, and fluorouracil (PEF-G) schedule on stage IV pancreatic adenocarcinoma.

PATIENTS AND METHODS: Patients ≤ 70 years, with no prior chemotherapy and with bidimensionally measurable stage IV pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or Karnofsky performance status between 50 and 70. Treatment consisted of 40 mg/m2 each of cisplatin and epirubicin day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks, and fluorouracil 200 mg/m2/d as a protracted venous infusion.

RESULTS: Between April 1997 and April 1999, 49 patients from a single institution were eligible for the study. Altogether, 203 cycles (median, four cycles) of PEF-G were delivered. The objective response rate was 58% in 43 assessable patients and 51% in the intent-to-treat population. Fourteen patients had stable disease. Grade 3 or 4 World Health Organization neutropenia occurred in 51% of cycles, thrombocytopenia in 28%, anemia in 7%, stomatitis in 5%, and diarrhea, and nausea, and vomiting in 2%. The median duration of response was 8.5 months. The median time to tumor progression was 7.5 months. The median survival was 11 months in the assessable population and 10 months in the intent-to-treat population. Clinical benefit was achieved in 22 (78%) of 28 assessable patients.

CONCLUSION: PEF-G is a well-tolerated and safe regimen; it obtained a very high rate of durable responses and deserves further evaluation in a phase III trial.
Discrepancies in Clinical Laboratory Testing of Eligibility for Trastuzumab Therapy: Apparent Immunohistochemical False-Positives Do Not Get the Message
Authors: Tubbs R.R. , Pettay J.D. , Roche P.C. , Stoler M.H. , Jenkins R.B. , Grogan T.M.
Published: February 2017

BACKGROUND: Several studies have reported what seem to be false-positive results using the Food and Drug Administration (FDA)–approved HercepTest (Dako Corp, Carpinteria, CA) to profile Her-2/neu amplification and overproduction in breast carcinoma. False-positive status has been based on comparisons with gene copy enumeration by fluorescence in situ hybridization (FISH) and with comparisons to immunohistochemistry (IMH) results using a monoclonal antibody. However, simple overexpression by tumor cells that have normal gene copy has not been evaluated by profiling mRNA expression, ie, such cases could simply represent true-positive, transcriptionally upregulated overexpression.

MATERIALS AND METHODS: Four hundred infiltrating ductal carcinomas of breast were evaluated by IMH using monoclonal (CB11; Ventana Medical Systems, Inc, Tucson, AZ) and polyclonal (HercepTest; Dako) antibodies after antigen retrieval (AR). A polyclonal antibody sans AR (PCA/SAR) was also used. All IMH stains were evaluated and scored according to the guidelines for the FDA-approved HercepTest. A total of 145 of 400 carcinomas were subsequently evaluated by direct and digoxigenin-labeled (Dig) FISH, and 144 of 400 were evaluated by detection of mRNA overexpression via autoradiographic RNA:RNA in situ hybridization.

RESULTS: Overall HercepTest/CB11 IMH discordance was 12%. Expression of mRNA was highly concordant with FISH and DigFISH amplification and with CB11 and PCA/SAR immunohistology. IMH false-positive cases (no Her-2/neu gene amplification) occurred with both HercepTest (23%) and CB11 (17%), and the majority of false-positive results (34 of 44) were scored as 2+. All 2+ false-positive cases were mRNA-negative. Combined results of HercepTest and CB11 showed that 79% (38 of 48) of 3+ cases were Her-2/neu gene amplified, but only 17% (seven of 41) of 2+ cases had increased gene copy.

CONCLUSION: Discordant HercepTest/FISH results, and to a lesser extent discordance with CB11 IMH, are most commonly false-positive results with a score of 2+. The 2+ score as defined in the guidelines for the FDA-approved HercepTest should not be used as a criterion for trastuzumab therapy unless confirmed by FISH. Determination of Her-2 gene copy number by FISH may be a more accurate and reliable method for selecting patients eligible for trastuzumab therapy.
Effects of Epoetin Alfa on Hematologic Parameters and Quality of Life in Cancer Patients Receiving Nonplatinum Chemotherapy: Results of a Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Littlewood T. J. , Bajetta E. , Nortier J. W.R. , Vercammen E. , Rapoport B. ,   for the Epoetin Alfa Study Group
Published: February 2017

PURPOSE: This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival.

PATIENTS AND METHODS: Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels ≤ 10.5 g/dL, or greater than 10.5 g/dL but ≤ 12.0 g/dL after a hemoglobin decrease of ≥ 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study.

RESULTS: Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P = .0057) and increased hemoglobin (P < .001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P < .01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P = .13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P = .052) favoring epoetin alfa. Adverse events were comparable between groups.

CONCLUSION: Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.
Phase II Study of Paclitaxel and Valspodar (PSC 833) in Refractory Ovarian Carcinoma: A Gynecologic Oncology Group Study
Authors: Fracasso Paula M. , Brady Mark F. , Moore David H. , Walker Joan L. , Rose Peter G. , Letvak Laurie , Grogan Thomas M. , McGuire William P.
Published: February 2017

PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein–mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer.

PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid × 12 doses. Paclitaxel (70 mg/m2 intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein.

RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were ≥ 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients.

CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.
Carboplatin Skin Testing: A Skin-Testing Protocol for Predicting Hypersensitivity to Carboplatin Chemotherapy
Authors: Zanotti K. M. , Rybicki L. A. , Kennedy A. W. , Belinson J. L. , Webster K. D. , Kulp B. , Peterson G. , Markman M.
Published: February 2017

PURPOSE: A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy.

PATIENTS AND METHODS: Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study.

RESULTS: Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P = .89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P = .002).

CONCLUSION: An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.
Phase I and Pharmacokinetic Study of the Novel MDR1 and MRP1 Inhibitor Biricodar Administered Alone and in Combination With Doxorubicin
Authors: Peck Ronald A. , Hewett Jan , Harding Matthew W. , Wang Yow-Ming , Chaturvedi Pravin R. , Bhatnagar Anish , Ziessman Harvey , Atkins Frank , Hawkins Michael J.
Published: February 2017

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance–associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of 99mTc-sestamibi, a P-gp and MRP1 substrate, was also evaluated.

PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m2/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m2 was administered. Cycles were repeated every 21 to 28 days. 99mTc-sestamibi scans were performed before and during administration of VX-710 alone.

RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m2/h or less. Among seven patients receiving VX-710 160 mg/m2/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m2/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of 99mTc-sestamibi in all patients.

CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m2/h plus doxorubicin 45 mg/m2 has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.
Decreasing Late Mortality Among Five-Year Survivors of Cancer in Childhood and Adolescence: A Population-Based Study in the Nordic Countries
Authors: Möller Torgil R. , Garwicz Stanislaw , Barlow Lotti , Winther Jeanette Falck , Glattre Eystein , Olafsdottir Gudridur , Olsen Jörgen H. , Perfekt Roland , Ritvanen Annukka , Sankila Risto , Tulinius Hrafn ,   for the Association of the Nordic Cancer Registries and the Nordic Society for Pediatric Hematology and Oncology
Published: February 2017

PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases.

PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk.

RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment.

CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.
Treatment-Induced Pathologic Necrosis: A Predictor of Local Recurrence and Survival in Patients Receiving Neoadjuvant Therapy for High-Grade Extremity Soft Tissue Sarcomas
Authors: Eilber Fritz C. , Rosen Gerald , Eckardt Jeffery , Forscher Charles , Nelson Scott D. , Selch Michael , Dorey Frederick , Eilber Frederick R.
Published: February 2017

PURPOSE: To determine whether treatment-induced pathologic necrosis correlates with local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas.

PATIENTS AND METHODS: Four hundred ninety-six patients with intermediate- to high-grade extremity soft tissue sarcomas received protocol neoadjuvant therapy. All patients underwent surgical resection after neoadjuvant therapy and had pathologic assessment of tumor necrosis in the resected specimens.

RESULTS: The 5- and 10-year local recurrence rates for patients with ≥ 95% pathologic necrosis were significantly lower (6% and 11%, respectively) than the local recurrence rates for patients with less than 95% pathologic necrosis (17% and 23%, respectively). The 5- and 10-year survival rates for the patients with ≥ 95% pathologic necrosis were significantly higher (80% and 71%, respectively) than the survival rates for the patients with less than 95% pathologic necrosis (62% and 55%, respectively). Patients with less than 95% pathologic necrosis were 2.51 times more likely to develop a local recurrence and 1.86 times more likely to die of their disease as compared with patients with ≥ 95% pathologic necrosis. The percentage of patients who achieved ≥ 95% pathologic necrosis increased to 48% with the addition of ifosfamide as compared with 13% of the patients in all the other protocols combined.

CONCLUSION: Treatment-induced pathologic necrosis is an independent predictor of both local recurrence and overall survival in patients who receive neoadjuvant therapy for high-grade extremity soft tissue sarcomas. A complete pathologic response (≥ 95% pathologic necrosis) correlated with a significantly lower rate of local recurrence and improved overall survival.
Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse
Authors: Sievers Eric L. , Larson Richard A. , Stadtmauer Edward A. , Estey Elihu , Löwenberg Bob , Dombret Hervé , Karanes Chatchada , Theobald Matthias , Bennett John M. , Sherman Matthew L. , Berger Mark S. , Eten Catharine B. , Loken Michael R. , van Dongen Jacques J.M. , Bernstein Irwin D. , Appelbaum Frederick R. ,   for the Mylotarg Study Group
Published: February 2017

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse.

PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m2, at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events.

RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/μL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less.

CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.
Effective Dosing of Topotecan With Carboplatin in Relapsed Ovarian Cancer: A Phase I/II Study
Authors: Bowman A. , Rye T. , Ross G. , Wheatley A. , Smyth J. F.
Published: February 2017

PURPOSE: This phase I/II study was performed to evaluate the feasibility of administering the topoisomerase inhibitor topotecan in combination with carboplatin.

PATIENTS AND METHODS: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5.

RESULTS: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.

CONCLUSION: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.
Ovarian Failure After Adjuvant Chemotherapy Is Associated With Rapid Bone Loss in Women With Early-Stage Breast Cancer
Authors: Shapiro Charles L. , Manola Judith , Leboff Meryl
Published: February 2017

PURPOSE: We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in a prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy.

PATIENTS AND METHODS: Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starting chemotherapy (baseline), and 6 and 12 months after starting chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone ≥ 30 MIU/mL at the 12-month evaluation.

RESULTS: Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was −4.0 (range, −10.4 to +1.0; P = .0001) and −3.7 (range, −10.1 to 9.2; P = .0001), respectively. In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function. Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure.

CONCLUSION: Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine. This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated.
Variation in Delivery of Palliative Radiotherapy to Persons Dying of Cancer in Nova Scotia, 1994 to 1998
Authors: Johnston Grace M. , Boyd Christopher J. , Joseph Paul , MacIntyre Maureen
Published: February 2017

PURPOSE: To examine sociodemographic and clinical variables associated with provision of palliative radiotherapy (RT) to persons dying of cancer.

METHODS: The Nova Scotia Cancer Registry was used to identify 9,978 adults who were dying of cancer between 1994 and 1998 in the Canadian province of Nova Scotia. RT records from between April 1992 and December 1998 were obtained from the provincial treatment database. Multivariate analysis identified factors associated with two sequential decisions determining provision of palliative RT in the last 9 months of life: likelihood of receiving an RT consultation with a radiation oncologist and, given a consultation, likelihood of being treated with palliative RT.

RESULTS: The likelihood of having a consultation decreased with age (20 to 59 years v 80+ years: odds ratio [OR], 4.43 [95% confidence interval, 3.80 to 5.15]), increased with community median household income (> $50,000 v < $20,000: OR, 1.31 [1.02 to 1.70]), was higher for residents closer to the cancer center (< 25 km v 200+ km: OR, 2.47 [2.16 to 2.83]), increased between 1994 and 1998 (OR, 1.34 [1.16 to 1.56]), varied by cause of death (relative to thoracic cancers, head and neck: OR, 1.75 [1.31 to 2.33]; gynecologic: OR, 0.35 [0.27 to 0.44]), and was greater for those who had prior RT (OR, 2.20 [1.89 to 2.56]). Similar associations were observed when outcome was the provision of palliative RT given a consult, with one notable exception: prior RT was associated with a lower likelihood of receiving palliative RT (OR, 0.48 [0.40 to 0.58]).

CONCLUSION: Variations observed in delivery of palliative RT should prompt further investigation into equity of access to clinically appropriate, palliative radiation consultation and treatment.
Prospective, Multicenter Evaluation of Risk Factors Associated With Invasive Bacterial Infection in Children With Cancer, Neutropenia, and Fever
Authors: Santolaya M. E. , Alvarez A. M. , Becker A. , Cofré J. , Enríquez N. , O’Ryan M. , Payá E. , Pilorget J. , Salgado C. , Tordecilla J. , Varas M. , Villarroel M. , Viviani T. , Zubieta M.
Published: February 2017

PURPOSE: To identify clinical and laboratory parameters present at the time of a first evaluation that could help predict which children with cancer, fever, and neutropenia were at high risk or low risk for an invasive bacterial infection.

PATIENTS AND METHODS: Over a 17-month period, all children with cancer, fever, and neutropenia admitted to five hospitals in Santiago, Chile, were enrolled onto a prospective protocol. Associations between admission parameters and risk for invasive bacterial infection were assessed by univariate and logistic regression analyses.

RESULTS: A total of 447 febrile neutropenic episodes occurred in 257 children. Five parameters were statistically independent risk factors for an invasive bacterial infection. Ranked by order of significance, they were as follows: C-reactive protein levels of 90 mg/L or higher (relative risk [RR], 4.2; 95% confidence interval [CI], 3.6 to 4.8); presence of hypotension (RR, 2.7; 95% CI, 2.3 to 3.2); relapse of leukemia as cancer type (RR, 1.8, 95% CI, 1.7 to 2.3); platelet count less than or equal to 50,000/mm3 (RR, 1.7; 95% CI, 1.4 to 2.2); and recent (≤ 7 days) chemotherapy (RR, 1.3; 95% CI, 1.1 to 1.6). Other previously postulated risk factors (magnitude of fever, monocyte count) were not independent risk factors in this study population.

CONCLUSION: In a large population of children, common clinical and laboratory admission parameters were identified that can help predict the risk for an invasive bacterial infection. These results encourage the possibility of a more selective management strategy for these children.
Safety and Efficacy of Bisphosphonates Beyond 24 Months in Cancer Patients
Authors: Ali S. M. , Esteva F. J. , Hortobagyi G. , Harvey H. , Seaman J. , Knight R. , Costa L. , Lipton A.
Published: February 2017

PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months.

PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review.

RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy.

CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.