| 1. |
- Barlesi, Fabrice, et al.
(författare)
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Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer : AVAPERL (MO22089).
- 2013
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Ingår i: Journal of Clinical Oncology. - Alexandria, VA, USA : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 31:24, s. 3004-3011
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment.PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment.RESULTS: In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed.CONCLUSION: In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.
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| 2. |
- Bjorkholm, M., et al.
(författare)
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Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms
- 2011
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology: JCO. - 0732-183X .- 1527-7755. ; 29:17, s. 2410-2415
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). Methods: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. Results: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P32), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P32 greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. Conclusion: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P32 and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors. © 2011 by American Society of Clinical Oncology.
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| 3. |
- du Bois, Andreas, et al.
(författare)
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Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer.
- 2010
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Ingår i: Journal of Clinical Oncology. - : American society of clinical oncology. - 0732-183X .- 1527-7755. ; 28:27, s. 4162-4169
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: One attempt to improve long-term survival in patients with advanced ovarian cancer was thought to be the addition of more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Gemcitabine was among the candidates for a third drug.PATIENTS AND METHODS: We performed a prospective, randomized, phase III, intergroup trial to compare carboplatin plus paclitaxel (TC; area under the curve [AUC] 5 and 175 mg/m(2), respectively) with the same combination and additional gemcitabine 800 mg/m(2) on days 1 and 8 (TCG) in previously untreated patients with advanced epithelial ovarian cancer. TC was administered intravenously (IV) on day 1 every 21 days for a planned minimum of six courses. Gemcitabine was administered by IV on days 1 and 8 of each cycle in the TCG arm.RESULTS: Between 2002 and 2004, 1,742 patients were randomly assigned; 882 and 860 patients received TC and TCG, respectively. Grades 3 to 4 hematologic toxicity and fatigue occurred more frequently in the TCG arm. Accordingly, quality-of-life analysis during chemotherapy showed a disadvantage in the TCG arm. Although objective response was slightly higher in the TCG arm, this did not translate into improved progression-free survival (PFS) or overall survival (OS). Median PFS was 17.8 months for the TCG arm and 19.3 months for the TC arm (hazard ratio [HR], 1.18; 95% CI, 1.06 to 1.32; P = .0044). Median OS was 49.5 for the TCG arm and 51.5 months for the TC arm (HR, 1.05; 95% CI, 0.91 to 1.20; P = .5106).CONCLUSION: The addition of gemcitabine to carboplatin plus paclitaxel increased treatment burden, reduced PFS time, and did not improve OS in patients with advanced epithelial ovarian cancer. Therefore, we recommend no additional clinical use of TCG in this population.
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| 5. |
- Pujade-Lauraine, Eric, et al.
(författare)
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Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse.
- 2010
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 28:20, s. 3323-3329
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).PATIENTS AND METHODS: Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.RESULTS: Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.CONCLUSION: To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.
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| 7. |
- Schleiermacher, Gudrun, et al.
(författare)
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Emergence of New ALK Mutations at Relapse of Neuroblastoma
- 2014
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology: JCO. - 0732-183X .- 1527-7755. ; 32:25, s. 2727-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. Methods We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000 x deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. Results All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). Conclusion In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
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| 8. |
- Tveit, Kjell Magne, et al.
(författare)
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Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer : The NORDIC-VII Study
- 2012
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology: JCO. - 0732-183X .- 1527-7755. ; 30:15, s. 1755-1762
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. Patients and Methods: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. Results: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. Conclusion: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.
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| 9. |
- Wärnberg, Fredrik, et al.
(författare)
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Effect of Radiotherapy After Breast-Conserving Surgery for Ductal Carcinoma in Situ: 20 Years Follow-Up in the Randomized SweDCIS Trial
- 2014
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 32:32, s. 3613-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. Patients and Methods Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. Results There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, -3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer-specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. Conclusion Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated.
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