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- Breugom, A. J., et al.
(author)
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Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision : a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial
- 2015
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 26:4, s. 696-701
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Journal article (peer-reviewed)abstract
- Background: The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision (TME). Patients and methods: The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1: 1) to observation or adjuvant chemotherapy after preoperative (chemo) radiotherapy and TME. Radiotherapy consisted of 5 x 5 Gy. Chemoradiotherapy consisted of 25 x 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. Results: Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). Conclusion: The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo) radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual.
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- Kersting, J., et al.
(author)
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Effect of Radiotherapy Dose on Outcome in Nonmetastatic Sarcoma
- 2023
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In: Advances in Radiation Oncology. ; 8:4
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Journal article (peer-reviewed)abstract
- Purpose: Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS.Methods and Materials: The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S & RT group) and/or RT (RT group). EFS and OS were analyzed with uni-and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response.Results: S & RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose =53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose > 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S & RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age > 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S & RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40).Conclusions: In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.
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- Stacchiotti, S., et al.
(author)
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Epithelioid hemangioendothelioma, an ultra-rare cancer : a consensus paper from the community of experts
- 2021
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In: ESMO Open. - : Elsevier BV. - 2059-7029. ; 6:3
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Research review (peer-reviewed)abstract
- Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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- Reichardt, P., et al.
(author)
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Adjuvant therapy in primary GIST: state-of-the-art
- 2012
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In: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 23:11, s. 2776-2781
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Research review (peer-reviewed)abstract
- The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.
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- Hindi, N., et al.
(author)
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Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma : results from a retrospective worldwide registry
- 2023
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In: ESMO Open. - 2059-7029. ; 8:6
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Journal article (peer-reviewed)abstract
- Background: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. Materials and methods: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. Results: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. Conclusions: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.
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| 13. |
- Hooker, Andrew C, et al.
(author)
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Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function : incorporating cytochrome P4503A activity measurements
- 2008
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In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 84:1, s. 111-118
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Journal article (peer-reviewed)abstract
- The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.
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| 15. |
- Kazaks, A, et al.
(author)
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Stop codon insertion restores the particle formation ability of hepatitis B virus core-hantavirus nucleocapsid protein fusions
- 2002
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In: Intervirology. - : S. Karger AG. - 0300-5526 .- 1423-0100. ; 45:4-6, s. 340-349
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Journal article (peer-reviewed)abstract
- In recent years, epitopes of various origin have been inserted into the core protein of hepatitis B virus (HBc), allowing the formation of chimeric HBc particles. Although the C-terminus of a C-terminally truncated HBc (HBcΔ) tolerates the insertion of extended foreign sequences, the insertion capacity is still a limiting factor for the construction of multivalent vaccines. Previously, we described a new system to generate HBcΔ mosaic particles based on a read-through mechanism in an <i>Escherichia coli</i> suppressor strain [J Gen Virol 1997;78:2049–2053]. Those mosaic particles allowed the insertion of a 114-amino acid (aa)-long segment of a Puumala hantavirus (PUUV) nucleocapsid (N) protein. To study the value and the potential limitations of the mosaic approach in more detail, we investigated the assembly capacity of ‘non-mosaic’ HBcΔ fusion proteins and the corresponding mosaic constructs carrying 94, 213 and 433 aa of the hantaviral N protein. Whereas the fusion proteins carrying 94, 114, 213 or 433 aa were not assembled into HBcΔ particles, or only at a low yield, the insertion of a stop codon-bearing linker restored the ability to form particles with 94, 114 and 213 foreign aa. The mosaic particles formed exhibited PUUV-N protein antigenicity. Immunization of BALB/c mice with these mosaic particles carrying PUUV-N protein aa 1–114, aa 1–213 and aa 340–433, respectively, induced HBc-specific antibodies, whereas PUUV-N protein-specific antibodies were detected only in mice immunized with particles carrying N-terminal aa 1–114 or aa 1–213 of the N protein. Both the anti-HBc and anti-PUUV antibody responses were IgG1 dominated. In conclusion, stop codon suppression allows the formation of mosaic core particles carrying large-sized and ‘problematic’, e.g. hydrophobic, hantavirus sequences.
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