Study suggests married cancer patients may live longer than single ones.
The New York Times (9/1, D6, Rabin) reports in Vital Signs, "Married cancer patients live longer than single ones, presumably because they have a built-in support system, are more likely to stick to their treatment regimens, and may even be in better health to begin with," according to a study published in the journal Cancer. Data indicated that 65 percent "of married patients survived at least five years after a cancer diagnosis, compared with 57 percent of those who had never been married, 52 percent of the divorced patients and 47 percent of widowed patients."
Πέμπτη 3 Σεπτεμβρίου 2009
Τρίτη 1 Σεπτεμβρίου 2009
TASIGNA AND BCR-ABL MUTATIONS
Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase
From the Hanson Institute, Adelaide, Australia; University of Turin, San Luigi Gonzaga Hospital, Torino; and Institute of Hematology and Medical Oncology, Bologna, Italy; The Catholic University of Korea, Seoul, Korea; Universitätsmedizin Mannheim der Universität Heidelberg, Mannheim, Germany; M. D. Anderson Cancer Center, Houston, TX; Fred Hutchinson Cancer Research Center, Seattle, WA; and Novartis, East Hanover, NJ.
Corresponding author: Timothy Hughes, MD, MBBS, Institute of Medical and Veterinary Science, Hanson Center for Cancer Research, Department of Hematology, Frome Rd, Adelaide, 5000, Australia; e-mail: Timothy.hughes@imvs.sa.gov.au.
Purpose Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed.
Patients and Methods Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial.
Results Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] 
HIGH DOSE MIBG FOR METASTATIC PARAGAGLIOMA
Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma
From the Departments of Pediatrics, Nuclear Medicine, Medicine, and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, CA.
Corresponding author: Paul A. Fitzgerald, MD, Clinical Professor of Medicine, University of California, San Francisco, 350 Parnassus Ave, Suite 710, San Francisco, CA 94117; e-mail: paul.fitzgerald@ucsf.edu.
Purpose To evaluate the safety and efficacy of high-dose [131I]metaiodobenzylguanidine ([131I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL).
Methods Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [131I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [131I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [131I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [131I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [123I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A.
Results The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4).
Conclusion Although serious toxicity may occur, the survival and response rates achieved with high-dose [131I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.IDH1 MUTATION AND PROGNOSIS IN GBM
Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas
From the L'Institut National de la Santé et de la Recherche Médicale, U711, Biologie des Interactions Neurones&Glie; Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie Mazarin and Laboratoire de Neuropathologie R. Escourolle; and Université Pierre et Marie Curie, Faculté de Médecine, Paris, France.
Corresponding author: Marc Sanson, MD, PhD, L'Institut National de la Santé et de la Recherche Médicale U711, Fédération de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris cedex 13, France; e-mail: marc.sanson@psl.ap-hop-paris.fr.
Purpose Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas.
Patients and Methods IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome.
Results A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P <>–15). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P <>–14) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P <>–15) and loss of chromosome 10 (P <>–15). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021).
Conclusion This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.NO USE OF DOSE DENSE TEMOZOLAMIDE FOR GBM
Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma
From the Departments of Neurology, Epidemiology and Biostatistics, and Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Corresponding author: Lauren E. Abrey, MD, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, C-723, New York, NY 10065; e-mail: abreyl@mskcc.org.
Purpose Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM.
Patients and Methods Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m2 days 1 to 7 and 15 to 21) or metronomic (50 mg/m2 continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status.
Results Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm).
Conclusion Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.HIGH DOSE TORISEL FOR MANTLE CELL LYMPHOMA
Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma
From the Johannes Gutenberg-University, Mainz, Germany; Hôpital de Hautepierre, Strasbourg; Hôpital Saint-Louis, Paris; Hôpital Lyon Sud, Pierre Bénite, France; The University of Texas M. D. Anderson Cancer Center, Houston, TX; University Hospital Gasthuisberg, Leuven; University Hospital Gent, Gent, Belgium; Princess Margaret Hospital, Toronto, ON, Canada; University Hospital, Uppsala, Sweden; and Wyeth Research, Cambridge, MA.
Corresponding author: Georg Hess, MD, Department of Hematology/Oncology, Johannes Gutenberg-University, Langenbeckstr 1, Mainz, DE 55101; e-mail: g.hess@3-med.klinik.uni-mainz.de.
Purpose Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.
Patients and Methods In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.
Results Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.
Conclusion Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.BRCA MUTATION STATUS AND SENSITIVITY TO CHEMOTHERAPY
Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
From the Family Cancer Clinic, Departments of Medical Oncology, Oncological Surgery, and Clinical Genetics Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
Corresponding author: Mieke Kriege, PhD, Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; e-mail: a.kriege@erasmusmc.nl.
Purpose Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients.
Patients and Methods From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease.
Results The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HRmult] 0.64; P = .04) and a prolonged OS (HRmult, 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HRmult, 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS.
Conclusion BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.ABIRATERONE SUCCESS CONTINUES
Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer
From the Royal Marsden National Health Service Foundation Trust; The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and Cougar Biotechnology, Los Angeles, CA.
Corresponding author: Johann S. de Bono, MB ChB, FRCP, MSc, PhD, Section of Medicine, The Institute of Cancer Research, the Royal Marsden National Health Service Foundation Trust, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: johann.de-bono@icr.ac.uk.
Purpose It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.
Patients and Methods This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of 
Results A decline in PSA of
Conclusion CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.
Supported by Cougar Biotechnology. G.A., A.H.M.R., C.M., L.R.M., G.M., E.T., D.O., R.S., S.B.K., and J.S.d.B. are in the Section of Medicine, which is supported by a Cancer Research UK program grant and an Experimental Cancer Medicines Centre grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). G.A. and A.H.M.R. were also supported by the Royal Marsden Hospital Research Fund. G.A. is also supported by the Prostate Cancer Foundation, Santa Monica, CA. C.P. was supported by Cancer Research UK and the National Cancer Research Institute Prostate Cancer Collaborative. R.A. is in the Cancer Research UK Section of Clinical Trials at The Institute of Cancer Research, Surrey, UK. We also acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent.RISK OF BILATERAL RENAL CANCER
Risk of Bilateral Renal Cell Cancer
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Cancer Registry of Norway, Oslo, Norway; Dana-Farber Cancer Institute and Dana-Farber/Harvard Cancer Center; and Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Corresponding author: Hans-Olov Adami, MD, PhD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115; e-mail: adami@hsph.harvard.edu.
Purpose The risk of developing bilateral kidney cancer has not been adequately defined in any large, population-based study with long-term follow-up to our knowledge.
Patients and Methods We estimated the risk of metachronous bilateral renal cell cancer in patients diagnosed with unilateral kidney cancer, as recorded in the nationwide cancer registries of Norway and Sweden. Altogether 28,642 patients were followed for an average of 4.4 years. The standardized incidence ratio—the ratio of the observed number of bilateral cancers to the number expected on the basis of the incidence in the Norwegian and Swedish population at large—was used as a measure of relative risk. We used multivariate Poisson regression to separate the effects of the explanatory variables.
Results A synchronous bilateral renal cell cancer was reported in 86 patients. A total of 112 metachronous bilateral cancers were recorded during 126,493 person-years of follow-up compared with 35.8 expected, yielding an overall relative risk (RR) of 3.1 (95% CI, 2.6 to 3.8) and a cumulative incidence of 0.8% after 20 or more years of follow-up. In the multivariate analyses, risk increased monotonically with younger age at first diagnosis (P for trend < .001); compared with patients who were 60 years or older, those younger than 40 years were at a 17-fold higher risk (RR = 17.4; 95% CI, 10.1 to 29.8). We also found a modest but statistically significant decreasing trend with increasing duration of follow-up.
Conclusion The risk of metachronous bilateral renal cell cancer is drastically higher among patients first affected at a young age, suggesting a subset of early onset renal cell cancer with a strong genetic component.SOURCE OF STEM CELLS AND RELAPSE AFTER TRANSPLANTATION IN AML
Higher Incidence of Relapse With Peripheral Blood Rather Than Marrow As a Source of Stem Cells in Adults With Acute Myelocytic Leukemia Autografted During the First Remission
From the Hôpital Saint Antoine, Department of Hematology; Acute Leukemia Working Party, European Cooperative Group for Blood and Marrow Transplantation Paris Office; Faculté de Médecine, St Antoine Université Pierre et Marie Curie Paris 6 and Unité Ministerielle de Recherche (UMR) S-893; Hotel Dieu, Department of Hematology; Hôpital Saint Louis, Department of Hematology – Bone Marrow Transplantation (BMT) 1, Paris; Institut Paoli Calmettes, Unité de transplantation et de thérapie cellulaire; L'Institut National de la Santé et de la Recherche Médicale UMR 599, Marseille; Centre Hospitalier Universitaire (CHU), Bordeaux; Hôpital Haut-Leveque, Pessac; Hôpital Edouard Herriot, BMT Unit Pavillon E, Lyon; Hôpital Purpan CHU, Department of Hematology, Toulouse; Hôpital de Brabois, Hématologie et Médecine Interne, Nancy, France; University La Sapienza, Dipartimento di Biotecnologie Cellulari e Ematologia, Rome, Italy; University Medical Center Saint Radboud, Department of Haematology, Nijmegen; and the Leiden University Medical Center, Department of Hematology, Leiden, the Netherlands.
Corresponding author: Norbert Claude Gorin, MD, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France; email: norbert-claude.gorin@sat.aphp.fr.
Purpose The cell source for autologous stem cell transplantation has shifted from bone marrow (BM) to peripheral blood (PB). In acute myelocytic leukemia (AML), for patients who receive transplants during first complete remission (CR1), no prospective randomized study has compared relapse incidence (RI) to cell source.
Patients and Methods We analyzed 2,165 patients who received autografts (1,607 PB and 558 BM) from 1994 to 2006 and were reported to the European Cooperative Group for Blood and Marrow Transplantation with complete research data. Relative to the time of CR1, PB transplants were performed earlier than BM transplants. Because a poorer outcome was associated with a shorter interval from CR1 to transplantation, patients were divided into three groups: BM, early PB (
Results In a multivariate analysis adjusted for differences between groups and center, RI was higher with both early PB (56% ± 3%; hazard ratio [HR], 1.45; 95% CI, 1.11 to 1.9; P = .006) and late PB transplantation (46% ± 2%; HR, 1.3; 95% CI, 1.06 to 1.59; P = .01) as compared with BM transplantation (39% ± 2%). This translated into a significantly worse leukemia-free survival (LFS) for early PB transplantation (36% ± 3%; HR, 0.75; 95% CI, 0.58 to 0.96; P = .02) and a trend for a poorer LFS for late PB (46% ± 2%; HR, 0.84; 95% CI, 0.7 to 1.01; P = .06) as compared with BM (52% ± 2%).
Conclusion For patients with AML in CR1, risk of relapse is greater with PB transplantation rather than BM, independent of the interval from CR1 to transplantationGENE MARKERS FOR OUTCOME PREDICTION IN BLADDER CANCER
Generation of a Concise Gene Panel for Outcome Prediction in Urinary Bladder Cancer
From the Departments of Pathology, Preventive Medicine, and Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles; Departments of Laboratory Medicine and Urology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL; and Dipartimento Emergenza e Trapianti d'Organo, Sezione di Urologia, Università di Bari, Bari, Italy.
Corresponding author: Richard J. Cote, MD, FRCPath, Department of Pathology, Miller School of Medicine, University of Miami, 1611 NW 12th Ave, Miami, FL 33136; e-mail: rcote@med.miami.edu.
Purpose This study sought to determine if alterations in molecular pathways could supplement TNM staging to more accurately predict clinical outcome in patients with urothelial carcinoma (UC).
Patients and Methods Expressions of 69 genes involved in known cancer pathways were quantified on bladder specimens from 58 patients with UC (stages Ta-T4) and five normal urothelium controls. All tumor transcript values beyond two standard deviations from the normal mean expression were designated as over- or underexpressed. Univariate and multivariable analyses were conducted to obtain a predictive expression signature. A published external data set was used to confirm the potential of the prognostic gene panels.
Results In univariate analysis, six genes were significantly associated with time to recurrence, and 10 with overall survival. Recursive partitioning identified three genes as significant determinants for recurrence, and three for overall survival. Of all genes identified by either univariate or partitioning analysis, four were found to significantly predict both recurrence and survival (JUN, MAP2K6, STAT3, and ICAM1); overexpression was associated with worse outcome. Comparing the favorable (low or normal) expression of
PERITONEAL METASTASES FROM BREAST CANCER AND PROGNOSIS
"Such patients with advanced disease often require frequent admission for drainage of recurrent ascites," Dr. Justin Stebbing, from Imperial College Healthcare NHS Trust in London, and co-authors report.
Information on management and prognosis of these women has been "scarce," the researchers say, but on the basis of their findings they suggest that breast cancer with peritoneal metastases "represents a specific entity, with a very poor outcome."
As reported in the August issue of the European Journal of Cancer, the investigators reviewed outcomes of 44 women with confirmed peritoneal disease from breast cancer. In 34 women who had presented with early breast cancer, the median age at diagnosis was 50 years, and median age at diagnosis with peritoneal disease was 55 years. Ten women presented with stage IV breast cancer, with peritoneal disease already present in three.
Histology indicated 77% had invasive ductal carcinoma and 16% had invasive lobular carcinoma; for 7% the tumor type could not be determined.
Patients had a median of 3 chemotherapy treatments and 2 hormonal treatments prior to diagnosis of peritoneal disease. After diagnosis, 25 were treated with further chemotherapy, and 8 received second- or third-line hormonal treatments. Thirty-eight required paracentesis at least once.
Median survival once peritoneal disease was diagnosed was 1.56 months, the authors report. Hormone-receptor-positive disease had similarly poor survival.
The researchers believe that ultimately, identification of the molecular pathways that prevent the dissemination of breast cancer cells to the peritoneum will be required for the development of effective treatment.
In the meantime, the British team concludes, "The dismal outcome of these individuals, despite further active therapy, merits their inclusion into clinical trials designed specifically for this group of patients."
Eur J Cancer 2009;45:2146-2149.
AN INTERESTING FAILURE
- J Clin Oncol. 2009 Aug 17. [Epub ahead of print]
Pegylated Liposomal Doxorubicin Plus Docetaxel Significantly Improves Time to Progression Without Additive Cardiotoxicity Compared With Docetaxel Monotherapy in Patients With Advanced Breast Cancer Previously Treated With Neoadjuvant-Adjuvant Anthracycline Therapy: Results From a Randomized Phase III Study.
Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, Bogdanova NV, Manikhas GM, Oliynychenko GP, Chatikhine VA, Zhuang SH, Xiu L, Yuan Z, Rackoff WR.
Montefiore-Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY; City Oncology Hospital #62; N.N. Blokhin Cancer Research Center; and P.A. Herzen Oncology Research Institute, Moscow; N.N. Petrov Research Institute of Oncology and City Clinical Oncology Dispensary, Saint Petersburg, Russia; Regional Oncology Dispensary and State Medical Academy, Dnepropetrovsk; City Oncology Hospital, Kiev, Ukraine; and OrthoBiotech Oncology Research and Development, Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ.
PURPOSE: To determine whether the combination of pegylated liposomal doxorubicin (PLD) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy. PATIENTS AND METHODS: This international, phase III study randomly assigned 751 patients to receive either docetaxel 75 mg/m(2) (n = 373) or PLD 30 mg/m(2) followed by docetaxel 60 mg/m(2) every 21 days (n = 378) and continued until disease progression or prohibitive toxicity. The primary end point was time to progression (TTP). Secondary end points were overall survival (OS), objective response rate (ORR), cardiac toxicity, and safety. RESULTS: Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months (hazard ratio [HR] = 0.65; 95% CI, 0.55 to 0.77; P = .000001) and the ORR from 26% to 35% (P = .0085). OS was similar between the two groups (HR = 1.02; 95% CI, 0.86 to 1.22). The incidence of grade 3 or 4 adverse events were similar (78% v 72%), although a higher incidence of hand-foot syndrome (24% v 0%) and mucositis/stomatitis (12% v 1%) were observed in the PLD-docetaxel combination. Protocol-defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5% and 1% in both treatment arms, respectively. CONCLUSION: The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity, although mucocutaneous toxicity was more common.
TOPO2A DEBATE CONTINUES
From Journal of the National Cancer Institute
Topoisomerase II Alpha and Responsiveness of Breast Cancer to Adjuvant Chemotherapy
Published: 08/20/2009
Background: Amplification or deletion of the topoisomerase II alpha (TOP2A) gene in breast cancers has been postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than amplification of the human epidermal growth factor receptor type 2 (HER2) gene.
Methods: We studied 438 tumors from 710 premenopausal women with node-positive breast cancer who received cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy in the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. TOP2A alterations and HER2 amplification were quantified by fluorescence in situ hybridization. The association of TOP2A and HER2 status with recurrence-free survival (RFS) and overall survival (OS) in the two treatment groups was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard models. All statistical tests were two-sided.
Results: In patients whose tumors showed TOP2A alterations (either amplifications or deletions), treatment with CEF was statistically significantly superior to treatment with CMF in terms of RFS (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.17 to 0.73, P = .005) and OS (adjusted HR = 0.33, 95% CI = 0.15 to 0.75, P = .008). In patients without TOP2A amplification or deletion, the corresponding adjusted hazard ratios for RFS and OS were 0.90 (95% CI = 0.66 to 1.23, P = .49) and 1.09 (95% CI = 0.77 to 1.56, P = .62). Adjusted tests of interaction between treatment and TOP2A status were P = .09 for RFS and P = .02 for OS. Adjusted tests of interaction between treatment and HER2 status were P = .008 for RFS and P = .02 for OS.
Conclusion: TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.
SHIFT WORK AND BREAST CANCER RISK
The effect of shift work on cancer, particularly breast cancer, has received increasing interest from the lay media since a panel of the International Agency for Research on Cancer declared in 2007 that "shift work that involves circadian disruption is probably carcinogenic to humans."[1] This conclusion was based on sufficient evidence from animal studies and limited evidence from human studies. The evidence is strongest for breast cancer, although the risk of prostate and colorectal cancer may also be increased by shift work. Recently, 38 women with breast cancer who had previously worked night shifts for at least 20 years were compensated by the Danish national board of industrial injuries.[2] This has implications for employers, compensation boards, and employees internationally.
Two recent meta-analyses have suggested that the risk of breast cancer is increased by about 50% in night workers and by about 70% in flight personnel.[3,4] If this association is true, shift work might have its effect by several different mechanisms (Box).
[ CLOSE WINDOW ]
Box. Possible mechanisms by which shift work increases the risk of cancer
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All these mechanisms are biologically plausible and are supported by experimental evidence. However, the human evidence lags behind because of problems in accurately defining and assessing the relevant exposure and the difficulty in controlling for confounding factors, especially in cohort studies in one profession.
A range of health effects other than cancer may also be associated with shift work. Short term effects are relatively easy to study, and we have fairly consistent evidence that shift work increases fatigue, decreases quality of life, and increases the risk of injury. The possible longer term effects—which may include adverse pregnancy outcomes, coronary heart disease, gastrointestinal disturbances, and mental health disorders—are less clear.
We now have a 24 hour society, and about one in five people in the Western world work shifts of some sort. We have no alternative but to find ways to mitigate the short and long term health effects of shift work on workers. Considerable effort has been invested in finding "better" shift systems. To decrease injuries, recommendations suggest having shorter length shifts, fewer shifts before a rest day, stable rather than rotating shifts, and frequent rest breaks or scheduled napping within a shift.[10,11]
The aviation industry has an intense interest in research in this area, and the Aerospace Medical Association recommends frequent rests during shifts, including napping.[12] Unfortunately, it also concludes that the major differences in individual responses to sleep loss, sleep disruption, and time zone transitions make it impossible to develop a "one size fits all" shift schedule, and it is aiming to develop biomathematical models of fatigue to predict performance and alertness at an individual level.
Other researchers have concentrated on countermeasures that increase sleep duration, promote quick adaptation to night work, or improve subjective wellbeing at work. One possibility is to use our increasing understanding of the physiological control of the sleep-wake cycle to time our exposure to light and darkness for maximum adaptation. Using phototherapy lamps (especially those producing blue light, which is most efficient in resetting melatonin release time), wearing goggles, wearing sunglasses when driving home, and darkening bedrooms or wearing sleeping masks are being tried. Medications that are stimulants, hypnotics, or chronobiotics (substances that control the body clock) are also being used.[11] It may also be possible to screen workers to select those with factors that seem to be associated with better tolerance of shift work, such as being an "evening person," having better family support, and having fewer responsibilities at home.[11]
Most of this evidence on shift work relates to mitigating short term outcomes, and it is not known whether any of these measures help prevent the potential longer term effects of shift work. The only evidence on mitigation of long term effects is the suggestion that only longer term shift work (20-30 years) increases the risk of breast cancer.[3]
So where does that leave us in our attempt to answer the questions posed by workers, employees, and unions about shift work and breast cancer? Should employers warn longer term shift workers about the risks, offer mammogram screening programmes, or reorganise shift schedules to minimise short term effects? From a public health perspective we probably have enough evidence that shift work is harmful in the short term for us to make several recommendations. Shift lengths should be shorter; rest breaks should be included; and researchers should educate shift workers and employers as to how sleep-wake cycles are controlled and how this knowledge can be used to maximise sleep quality, sleep duration, and alertness at work.
FIRST LINE GEFITINIB THERAPY FOR NSCLC
- N Engl J Med. 2009 Aug 19. [Epub ahead of print]
Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M.
From the State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong (T.S.M.), Guangdong General Hospital, Guangzhou (Y-L.W., J.-J.Y.), Cancer Hospital, Chinese Academy of Medical Sciences, Beijing (D.-T.C.), and Shanghai Chest Hospital, Shanghai (B.H.) - all in China; Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Chiang Mai (S.T., B.C.), and Prince of Songkla University, Songkla (P.S.) - both in Thailand; National Taiwan University Hospital, Taipei, Taiwan (C.-H.Y.); National Cancer Center Hospital East, Chiba (N.S., Y.N.), National Kyushu Cancer Center, Fukuoka (Y.I.), National Cancer Center Hospital, Tokyo (Y.O.), AstraZeneca, Osaka (H.J.), and Kinki University School of Medicine, Osaka (M.F.) - all in Japan; Dr. Soetomo Hospital, Surabaya, Indonesia (B.M.); and AstraZeneca, Macclesfield, United Kingdom (E.L.D., C.L.W., A.A.A.). This article (10.1056/NEJMoa0810699) was published on August 19, 2009, at NEJM.org.
BACKGROUND: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. METHODS: In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001).>
C-TPF FOR HEAD AND NECK CANCER
- J Clin Oncol. 2009 Aug 24. [Epub ahead of print]
Phase I Study of C-TPF in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck.
Haddad RI, Tishler RB, Norris C, Goguen L, Balboni TA, Costello R, Wirth L, Lorch J, Andreozzi B, Annino D, Posner MR.
Department of Medical and Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School; and the Departments of Medicine, Radiation Oncology, and Head and Neck Surgery, Brigham and Women's Hospital, Boston, MA.
PURPOSE: Phase I study to determine the maximum tolerated dose (MTD) of fluorouracil (FU) in the docetaxel/cisplatin/FU (TPF) regimen when combined with cetuximab (C) for induction treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with previously untreated SCCHN were enrolled. FU cohorts were 700, 850, and 1,000 mg/m(2)/d for 4 days via continuous infusion. TPF given every 3 weeks for three cycles and C was given weekly for a total of 9 weeks, starting on day 1 of TPF. All patients received chemoradiotherapy after C-TPF. RESULTS: A total of 30 patients were enrolled and 28 were assessable. The median age was 57 years, 92% had stage 4 disease, 71% were oropharynx, and 100% had a performance status of 0. No dose-limiting toxicity (DLT) was encountered on dose levels 1 and 2. At dose level 3 of 1000 mg/m(2), one DLT was encountered and three more patients were enrolled with no DLTs. In the expansion cohort at the MTD, three DLT's were encountered. The decision was made to decrease the FU from 1,000 mg/m(2) to dose level 2 of 850 mg/m(2). A total of 13 patients were enrolled at the MTD of 850 mg/m(2). The number of average weeks that C was delivered was seven of nine planned. CONCLUSION: C-TPF appears to be safe and feasible as given in this study. GI toxicity (mucositis, enteritis, and diarrhea) appears to be the major combined DLT. Reducing the FU in TPF to 850 mg/m(2) reduces GI toxicity and is the recommended phase II dose.
LOW DOSE ESTRADIOL FOR BREAST CANCER TREATMENT
August 25, 2009 – Metastatic breast cancer that has become resistant to an aromatase inhibitor could benefit from treatment with estradiol.
In a new phase 2 randomized study of 66 patients, clinical benefit rates of 28% and 29% were found in patients treated with 6 mg and 30 mg daily doses of oral estradiol, respectively.
Because low-dose (6-mg) estradiol had less toxicity and fewer effects on quality of life, it was recommended for further study by the investigators, whose new paper is published in the August 19 issue of the Journal of the American Medical Association.
All of the patients had been treated with aromatase inhibitors, which reduce levels of estrogen, for at least 24 weeks, and all had acquired resistance to these agents.
Using estradiol, the most potent of the 3 estrogens naturally produced in the body, as a treatment is paradoxical because the study participants' breast cancers were hormone-receptor-positive and thus stimulated by estrogen.
"The women in the study had all experienced a relapse while on estrogen-lowering drugs, and their disease was progressing," said lead author Matthew J. Ellis, MD, PhD, in a press statement, "so they were faced with undergoing chemotherapy. We found that estrogen treatment stopped disease progression in many patients and was much better tolerated than chemotherapy would have been," added Dr. Ellis, who is an oncologist with the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital in St. Louis, Missouri.
Estradiol May Resensitize Some Tumors
Estrogens have been recommended as treatment for breast cancer since 1960 but have fallen out of favor clinically in recent years because of the emergence of a variety of antiestrogen agents and the use of chemotherapy, according to an editorial accompanying the study.
Nevertheless, this study and at least 1 other suggest that "sustained clinical benefit can be achieved by alternating between inhibitory and stimulatory estrogen-receptor modulation," write the editorialists, Pamela N. Munster, MD, from the University of California, San Francisco, and John T. Carpenter, MD, from the University of Alabama at Birmingham.
Indeed, in the current study, estradiol treatment not only stopped disease progression in about a third of patients, but in some patients, metastatic tumors became resensitized and again responded to antiestrogen treatments, say the editorialists.
About 40,000 women die of metastatic breast cancer each year, and estrogen therapy could potentially help thousands of women, said Dr. Ellis, noting that the therapy costs less than a dollar a day.
Study Details
Study participants, who had metastatic breast cancer that had been treated with an aromatase inhibitor and who had progression-free survival (≥24 weeks) or relapse (after ≥2 years), were randomized to either 6 mg (n = 34) or 30 mg (n = 32) of estradiol. Patients at high risk for estradiol-related adverse events were excluded.
Patients were examined after 1 and 2 weeks, and every 4 weeks thereafter, for clinical and laboratory toxicities and flare reactions. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion was evaluated for response.
The primary end point in the study, clinical benefit rate (defined as tumor response plus stable disease at 24 weeks), was achieved in 9 of 32 patients (28%; 95% confidence interval [CI], 18% - 41%) in the 30-mg group and in 10 of 34 patients (29%; 95% CI, 19% - 42%) in the 6-mg group.
An estradiol-stimulated increase in fluorodeoxyglucose F-18 uptake (≥12% prospectively defined), measured by positron emission tomography/computed tomography, was predictive of response (positive predictive value, 80%; 95% CI, 61% - 92%). However, it was possible to assess these estrogen-induced "flares" in only 46 patients (70%).
Seven patients with estradiol-sensitive disease were retreated with aromatase inhibitors at estradiol progression (2 of whom achieved partial response and 1 of whom achieved stable disease), suggesting resensitization to estrogen deprivation, report the authors.
The adverse-event rate (≥grade 3) was higher in the 30-mg group (11/32 [34%]; 95% CI, 23% - 47%) than in the 6-mg group (4/34 [18%]; 95% CI, 5% - 22%; P = .03).
The adverse effects associated with the 30-mg dose of estradiol led to treatment discontinuation in 4 of 32 patients; only 1 patient withdrew from therapy at the 6-mg dose, and that was for personal reasons.
Low Dose is Intriguing
Up until 1971, when tamoxifen was introduced, high doses of estrogens were one of the "few nonsurgical options for the breast cancer treatment," write the editorialists. Clinical trials at that time indicated that tamoxifen and high-dose estrogen in postmenopausal woman with advanced breast cancer had similar results, but that the adverse effects of estrogen were worse, they note.
The new study is "intriguing" because clinical benefits were observed at low doses, with reduced toxicities.
"These findings suggest that in contrast to the toxicities observed with the 30-mg dose in this study and reported in previous studies, a lower dose of 6 mg of estrogen can be administered with acceptable toxicities and fewer profound effects on quality of life," write the editorialists.
The editorialists also note that it is very likely that the resistance to aromatase inhibitors seen in the study was likely acquired rather than de novo. They believe that the likelihood stems from the long median time from initial diagnosis (82 months in the 30-mg group; 90 months in the 60-mg group).
The study was supported as individual cancer-center supplements from an Avon Foundation and National Cancer Institute Partners for Progress Award. The authors have disclosed no relevant financial relationships.
JAMA. 2009;302:774-780 and 797-798. Abstract
NEW THEORIES FOR LYMPHEDEMA AFTER BREAST CANCER SURGERY
August 14, 2009 — Slowly progressive weight lifting may be helpful in breast cancer survivors with lymphedema, according to the results of a randomized controlled trial reported in the August 13 issue of the New England Journal of Medicine.
"Weight lifting has generally been proscribed for women with breast-cancer–related lymphedema, preventing them from obtaining the well-established health benefits of weight lifting, including increases in bone density," write Kathryn H. Schmitz, PhD, MPH, from the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine and Abramson Cancer Center in Philadelphia, and colleagues.
"A program of controlled exercise through weight lifting may increase the physical-work capacity of the affected arm, thereby protecting it from injury sustained during common daily activities. Weight lifting offers additional benefits particularly relevant to breast-cancer survivors, including control of body fat and improved functional outcomes and bone health."
Weight-Lifting Improved Secondary Endpoints
In this study, 141 breast cancer survivors with stable lymphedema of the arm were randomly assigned to a group that received twice-weekly progressive weight lifting or to a control group. While weight lifting, participants were required to wear a well-fitted compression garment. The main study endpoint was the change in arm and hand swelling, measured by displaced water volume of the involved and uninvolved upper extremity, at 1 year. Secondary endpoints were the incidence of exacerbations of lymphedema, number and severity of lymphedema symptoms, and muscle strength.
Limb swelling increase of at least 5% occurred in 11% of the weight-lifting group and in 12% of the control group (cumulative incidence ratio, 1.00; 95% confidence interval, 0.88 – 1.13).
The weight-lifting group had greater improvements than the control group in self-reported severity of lymphedema symptoms (P = .03) and upper- and lower-body strength (P < .001 for both comparisons). In addition, the weight-lifting group had a lower incidence of lymphedema exacerbations, as determined by a certified lymphedema specialist (14% vs 29%; P = .04). Weight lifting was not associated with any serious adverse events.
"In breast-cancer survivors with lymphedema, slowly progressive weight lifting had no significant effect on limb swelling and resulted in a decreased incidence of exacerbations of lymphedema, reduced symptoms, and increased strength," the study authors write. "The results of this study reduce concerns that weight lifting will worsen arm and hand swelling associated with lymphedema in breast-cancer survivors."
Limitations of this study include incomplete blinding, that multiple therapists were used to evaluate for exacerbations, and possible reporting bias.
"The substantive treatment-related increases in strength, coupled with the lack of change in lean mass, indicate that the program was more focused on building muscle strength than on hypertrophy, as intended," the study authors conclude. "Further research is needed to determine the critical components of this intervention in order to facilitate its optimal use by breast-cancer survivors with lymphedema.... These findings support the potential benefits of a slowly progressive weight-lifting program in women with breast-cancer–related lymphedema, in conjunction with appropriate use of compression garments and close monitoring for arm and hand swelling."
Promising Results, More Research Needed
In an accompanying editorial, Wendy Demark-Wahnefried, PhD, RD, from M.D. Anderson Cancer Center in Houston, Texas, calls this intervention "promising" but recommends critical follow-up research, including detailed cost analysis and dissemination analyses.
"The report by Schmitz et al. provides strong reassurance regarding the safety of appropriately supervised weight training in women with a history of breast cancer and lymphedema," Dr. Demark-Wahnefried writes.
"A comprehensive strategy to improve the outcomes in these women should include dietary and exercise interventions aimed at weight management, since overweight, obesity, and weight gain after diagnosis are recognized as significant risk factors for lymphedema as well as for breast-cancer–associated death. Multifactor interventions that promote healthy eating, regular exercise (e.g., aerobic and progressive resistance training), and other lifestyle improvements (e.g., reducing smoking and alcohol use) have the potential to substantially improve overall health and survival among women with this common cancer."
The National Cancer Institute and the National Center for Research Resources supported this study. BSN Medical provided custom-fitted compression garments, and the fitness centers where the weight-lifting sessions took place (YMCA of Philadelphia and Vicinity, Sisters in Shape, and the Family YMCA of Burlington County, NJ) provided discounted membership fees for study participants. The study authors have disclosed no relevant financial relationships. Dr. Demark-Wahnefried has disclosed that she receives honoraria for consulting at the Livestrong Centers for Excellence at Ohio State University and at the University of Pennsylvania.
N Engl J Med. 2009;361:664–673; 710–711. Abstract
NO USE OF CONSOLIDATION PACLITAXEL FOR OVARIAN CANCER
- J Clin Oncol. 2009 Aug 24. [Epub ahead of print]
Phase III Trial of Observation Versus Six Courses of Paclitaxel in Patients With Advanced Epithelial Ovarian Cancer in Complete Response After Six Courses of Paclitaxel/Platinum-Based Chemotherapy: Final Results of the After-6 Protocol 1.
Pecorelli S, Favalli G, Gadducci A, Katsaros D, Panici PB, Carpi A, Scambia G, Ballardini M, Nanni O, Conte P.
University of Brescia, Brescia; University of Pisa, Pisa; University of Turin, Turin; La Sapienza University; and Sacro Cuore Catholic University, Rome; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola; University of Modena and Reggio Emilia, Modena; and Santa Maria Nuova Hospital, Reggio Emilia; Italy.
PURPOSE: To assess whether six courses of paclitaxel are effective as consolidation treatment in patients with advanced epithelial ovarian cancer who are in complete response after first-line paclitaxel/platinum-based chemotherapy. PATIENTS AND METHODS: Patients with stages IIb to IV disease in clinical or pathologic complete response after six courses of paclitaxel/platinum-based chemotherapy were randomly allocated to either observation (ie, control) or six courses of paclitaxel 175 mg/m(2) every 3 weeks (ie, maintenance). RESULTS: Two hundred patients were randomly assigned from March 1999 to July 2006. Because of the low accrual rate, an unplanned interim analysis of futility according to the Bayesian approach was performed. Grade 2 or greater motor neurotoxicity and sensory neurotoxicity were reported in 11.3% and 28.0% of the paclitaxel-arm patients, respectively. After a median follow-up of 43.5 months, 107 patients (53%) had experienced relapse, and 48 patients (24%) had died. Two-year progression-free survival rates were 54% (95% CI, 43% to 64%) and 59% (95% CI, 49% to 69%; P = not significant) in the control and maintenance arms, respectively. Corresponding 2-year overall survival rates were 90% (95% CI, 84% to 97%) and 87% (95% CI, 80% to 94%; P = not significant), respectively. The Cox model showed that residual disease after initial surgery (macroscopic v no macroscopic residuum; hazard ratio [HR], 1.91; 95%CI, 1.21 to 3.03) and stage (IIIc to IV v others; HR, 3.10; 95% CI, 1.13 to 8.48) were independent prognostic factors for progression-free survival, whereas the treatment arm (maintenance v control) had no prognostic relevance. CONCLUSION: A consolidation treatment with six cycles of paclitaxel does not prolong progression-free survival or overall survival in patients in complete response after first-line paclitaxel/platinum-based regimens.
GUIDLINESS FOR USE OF H1N1 VACCINE
August 24, 2009 — The US Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices (ACIP) has issued guidelines regarding the use of vaccine against infection with novel influenza A (H1N1) virus. The new recommendations were posted online August 21 in the Morbidity and Mortality Weekly Report.
"Because novel influenza A (H1N1) virus is continuing to cause illness in the United States and worldwide, the primary focus of vaccination efforts should be to vaccinate as many persons as possible in the recommended target groups as quickly as possible once vaccine becomes available," write Anne Schuchat, MD, and colleagues from the National Center for Immunization and Respiratory Diseases, CDC.
H1N1 Vaccine Use
"As vaccine availability increases, additional groups are recommended for vaccination.... These recommendations are intended to provide vaccination programs and providers with information to assist in planning and to alert providers and the public about target groups comprising an estimated 159 million persons who are recommended to be first to receive influenza A (H1N1) 2009 monovalent vaccine," write Dr. Schuchat and colleagues.
To assess which population groups should first be targeted for vaccination, the ACIP reviewed epidemiologic and clinical data on July 29, 2009. The ACIP also evaluated the projected supply likely to be available when the vaccine first becomes available, as well as the anticipated increase in vaccine availability during the following 6 months. By mid-October 2009, it is anticipated that licensed H1N1 vaccine will be available.
The guidelines recommend that vaccination efforts begin as soon as the vaccine is available. In accordance with state and local conditions, state and local health officials and vaccination providers should make decisions concerning vaccine administration and distribution.
Vaccination and healthcare providers should be vigilant about following announcements and other information forthcoming from state and local health departments and the CDC regarding vaccination against H1N1 virus infection. The CDC's influenza Web site and state and local health departments may provide additional information.
ACIP H1N1 Vaccine Recommendations
Key points of the ACIP recommendations include the following 3 items.
- First, 5 general population groups that should be targeted as an initial focus of vaccination efforts are pregnant women, household contacts or caregivers for infants younger than 6 months (such as parents, siblings, and daycare providers), healthcare and emergency medical services personnel, children and young adults 6 months to 24 years of age, and persons aged 25 to 64 years who are at greater risk for influenza-related complications because of underlying medical conditions. These medical conditions increasing risk for influenza-related complications include chronic pulmonary conditions, including asthma; cardiovascular conditions except for hypertension; renal, hepatic, cognitive, neurologic/neuromuscular, hematologic, or metabolic disorders, including diabetes mellitus; and immunosuppression caused by medications or by human immunodeficiency virus.
- Second, if initial vaccine availability is insufficient to meet demand, priority is established for a subset of persons within the initial target groups. These persons who are to receive priority for vaccination (order of target groups does not indicate priority) include pregnant women, household contacts or caregivers for infants younger than 6 months, healthcare and emergency medical services personnel in direct contact with patients or infectious material, children 6 months to 4 years of age, and children and adolescents aged 5 to 18 years who are at greater risk for influenza-related complications because of underlying medical conditions.
- Third, as vaccine availability increases, other adult population groups should receive H1N1 vaccine in accordance with the guidelines recommendations.
In addition, ACIP made additional recommendations concerning the use of influenza A (H1N1) 2009 monovalent vaccine, as follows:
- The number of doses of vaccine needed for immunization against H1N1 has not been determined. Vaccine should not be stockpiled for patients who already have received 1 dose but might require a second dose, because vaccine availability is expected to increase over time.
- If different anatomic sites are used, inactivated vaccines against seasonal and H1N1 viruses may be administered simultaneously. However, ACIP does not recommend simultaneous administration of live, attenuated vaccines against seasonal and H1N1 virus.
- All persons, including those older than 65 years of age, who are currently recommended for seasonal influenza vaccine should receive the seasonal vaccine as soon as it is available. Recommendations for use of the 2009 to 2010 seasonal influenza vaccine were previously published.
"The guiding principle of these recommendations is to vaccinate as many persons as possible as quickly as possible," the guidelines authors state. "ACIP will review new epidemiologic and clinical data as they become available and might revise these recommendations."
Morb Mortal Wkly Rep. Published online August 21, 2009.
MARIJUANA REDUCES HEAD AND NECK CANCER RISK
NEW YORK (Reuters Health) Aug 25 - Marijuana use for 10 to 20 years is associated with a 62% reduced risk of head and neck squamous cell carcinoma (HNSCC), the results of a population-based case-control study suggest.
However, further research from larger studies is needed to verify this association, the researchers emphasize. Moreover, even if marijuana use were found to protect against this malignancy, the risks of use may still outweigh this benefit.
"Marijuana is an entry-level drug and can be associated with later use of more serious addictive drugs, as well as other risk behaviors," Dr. Karl T. Kelsey, from Brown University, Providence, Rhode Island, and colleagues note. "Any policy regarding marijuana use should take these into consideration and should not be made based on one study's results."
The new study, reported in the August issue of Cancer Prevention Research, featured 434 patients with HNSCC and 547 matched controls seen in the Greater Boston area from December 1999 to December 2003. Lifetime marijuana use was assessed via questionnaire.
After adjusting for smoking, drinking, and other potential confounders, use of marijuana from 0.5 to 1.5 times per week was associated with a 48% reduced risk of HNSCC compared with less frequent use. This association was independent of human papillomavirus 16 antibody status.
Marijuana use starting at an older age appeared to confer greater protection against HNSCC than use beginning at a younger age. Relative to never users, those who began using marijuana between the ages of 15 and 19 years were 47% less likely to develop HNSCC, while users who began at age 20 or older had a 61% reduced risk (p trend <>
As to possible mechanisms for these associations, the authors note that cannabinoids have been shown to have antitumor effects and can influence cellular signaling.
Cancer Prev Res 2009;2:759-768.
CALCIUM CHANNEL BLOCKERS AND PLAVIX
- Heart. 2009 Aug 16. [Epub ahead of print]
Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition.
Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW.
Department of Internal Medicine II, Medical University of Vienna, Austria.
BACKGROUND: The extent of clopidogrel-mediated platelet inhibition varies considerably from one individual to the next. Numerous studies have shown that low responders suffer significantly more adverse events after coronary stenting than patients who respond well to antithrombotic treatment with clopidogrel. Dihydropyridine calcium-channel blockers (CCBs) inhibit the cytochrome P450 3A4 enzyme, which metabolizes clopidogrel to its active form. We therefore sought to investigate the influence of CCBs on clopidogrel-mediated platelet inhibition. METHODS: ADP-inducible platelet reactivity was assessed by light transmission aggregometry (LTA) and the VerifyNow P2Y12 assay in 162 patients after percutaneous intervention with stent implantation. Results in the fourth quartiles of both assays were considered as high-on treatment residual ADP-inducible platelet reactivity. RESULTS: Patients with concomitant CCB therapy showed a significantly higher on-treatment platelet reactivity than patients without CCB medication (p = 0.001 for both assays). Further, high on-treatment residual ADP-inducible platelet reactivity was significantly more common among patients currently taking CCBs (p = 0.001 for LTA and p = 0.004 for the VerifyNow P2Y12 assay). A multivariate regression analysis confirmed CCB treatment as an independent predictor of reduced clopidogrel-mediated platelet inhibition (p = 0.006 for LTA and p = 0.004 for the VerifyNow P2Y12 assay). CONCLUSION: CCBs decrease clopidogrel-mediated platelet inhibition in patients undergoing angioplasty and stenting for cardiovascular disease.
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