Patients with locally advanced resected non-small-cell lung cancer present a high risk of relapse. Although adjuvant platinum-based chemotherapy has become the standard of care, the role of ...postoperative radiation therapy (PORT) has been controversial for years. In patients with incomplete resection, PORT should be proposed, on the basis of a strong consensus, despite the absence of randomized evidence. In patients with completely resected (R0) non-small-cell lung cancer, a meta-analysis showed poorer outcomes after PORT in the absence of mediastinal involvement (pN0 and pN1). In patients with pN2, the role of PORT was less clear and required further research. The meta-analysis included trials using older radiation techniques and poorer quality of surgery according to today's standards, and selection of patients was not positron emission tomography-based. Newer retrospective and nonrandomized studies and subgroup analyses of randomized trials evaluating adjuvant chemotherapy suggested a survival benefit of PORT in patients with pN2 R0. Two recent randomized trials (Lung ART and PORT-C) evaluating conformal PORT versus no PORT retrieved no disease-free survival advantage for stage IIIA-N2 patients, even if mediastinal relapse was significantly decreased with PORT. PORT had no effect on survival, possibly given the high rate of distant relapse and risk of additional cardiopulmonary toxicity. Ongoing and future analyses are planned in Lung ART to identify patients for whom PORT could be recommended. Incorporation of newer systemic treatments (immune checkpoint inhibitors or targeted therapy in oncogene-addicted patients) is underway in the neoadjuvant and/or adjuvant setting. Better identification of patients at a high risk of disease recurrence, with analysis of circulating tumor DNA, on the basis of the detection of postsurgical minimal (or molecular) residual disease is warranted in future studies.
Learning Objectives
After completing this course, the reader will be able to:
Identify patients with non‐small cell lung cancer who may benefit from postoperative radiotherapy based upon current ...evidence.
Summarize the results of analyses of both older and more recent data regarding postoperative radiotherapy in NSCLC patients.
This article is available for continuing medical education credit at CME.TheOncologist.com
In completely resected non‐small cell lung cancer (NSCLC) patients with pathologically involved mediastinal lymph nodes (N2), administration of adjuvant platinum‐based chemotherapy is now considered the standard of care, based on level 1 evidence. The role of postoperative radiation therapy (PORT) in this group of patients remains controversial. The PORT meta‐analysis published in 1998 concluded that adjuvant radiotherapy was detrimental to patients with early‐stage completely resected NSCLC, but that the role of PORT in the treatment of tumors with N2 involvement was unclear, and that further research was warranted. Recent retrospective and nonrandomized studies, as well as subgroup analyses of recent randomized trials evaluating adjuvant chemotherapy, provide evidence of the possible benefit of PORT in patients with mediastinal nodal involvement. The role of PORT is also a valid question in patients with proven N2 disease who have undergone only induction chemotherapy followed by surgery, because the local recurrence rate for such patients varies in the range of 20%–60%. Based on the currently available data, PORT should be discussed for fit patients with completely resected NSCLC with N2 nodal involvement, preferably after completion of adjuvant chemotherapy. There is a need for new randomized evidence to evaluate PORT using the modern three‐dimensional conformal radiation technique, with attention paid to reducing the risk for, particularly, pulmonary and cardiac toxicity. A new large multi‐institutional randomized trial evaluating PORT in this patient population is needed and now under way.
摘要
目前，基于1级证据，在病理学显示纵隔淋巴结（N2）受累的非小细胞肺癌（NSCLC）完全性切除患者中，以铂类为基础的辅助化疗被认为是标准的治疗措施。而术后放疗（PORT）在这类患者中的作用仍有争论。1998年发表的PORT的meta分析断言，辅助放疗不利于完全性切除的早期NSCLC患者，但PORT在N2受累的患者治疗中的作用并未明确，需要进一步研究。近期回顾性和非随机研究以及近期评估辅助化疗的随机试验的亚组分析提供了PORT可能有益于纵隔淋巴结受累患者的证据。对于术前仅行诱导化疗的N2疾病确诊患者，PORT的作用也是一个实际问题，因为这类患者的局部复发率介于20%~60%。根据现有数据，对于状况良好的、N2淋巴结受累的NSCLC完全性切除患者行PORT值得探讨。需要新的随机证据来评价采用现代三维适形放疗技术的PORT，尤其要关注降低肺和心脏毒性风险。需要重新开展大样本、多中心的随机试验来评价该患者群体中PORT的作用，这样的试验目前正在进行中。
Randomized trials and a meta‐analysis of postoperative radiation therapy in non‐small cell lung cancer patients are discussed along with studies evaluating adjuvant chemoradiation in this patient population.
Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery ...versus surgery alone on abdominal recurrence-free survival.
EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018.
Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8–59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71–1·44; log rank p=0·95). The most common grade 3–4 adverse events were lymphopenia (98 77% of 127 patients in the radiotherapy plus surgery group vs one 1% of 128 patients in the surgery alone group), anaemia (15 12% vs ten 8%), and hypoalbuminaemia (15 12% vs five 4%). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events.
Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma.
European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
SummaryBackgroundPathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2–3 trial ...evaluated the safety and efficacy of the hafnium oxide (HfO 2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. MethodsAct.In.Sarc is a phase 2–3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0–2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FindingsBetween March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3–4 treatment-emergent adverse event was postoperative wound complication (eight 9% of 89 patients in the NBTXR3 group and eight 9% of 90 in the radiotherapy alone group). The most common grade 3–4 adverse events related to NBTXR3 administration were injection site pain (four 4% of 89) and hypotension (four 4%) and the most common grade 3–4 radiotherapy-related adverse event was radiation skin injury in both groups (five 6% of 89 in the NBTXR3 group and four 4% of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3–4 adverse event related to NBTXR3 was hypotension (six 7% of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. InterpretationThis trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FundingNanobiotix SA and PharmaEngine, Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To update literature-based recommendations for techniques used in high-precision thoracic radiotherapy for lung cancer, in both routine practice and clinical trials.
A literature search was performed ...to identify published articles that were considered clinically relevant and practical to use. Recommendations were categorised under the following headings: patient positioning and immobilisation, Tumour and nodal changes, CT and FDG-PET imaging, target volumes definition, radiotherapy treatment planning and treatment delivery. An adapted grading of evidence from the Infectious Disease Society of America, and for models the TRIPOD criteria, were used.
Recommendations were identified for each of the above categories.
Recommendations for the clinical implementation of high-precision conformal radiotherapy and stereotactic body radiotherapy for lung tumours were identified from the literature. Techniques that were considered investigational at present are highlighted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals.
The patterns of care, ...outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed.
The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis.
The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients ...with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio HR, 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.
Check the Reports and Check the Brain Le Péchoux, Cécile
International journal of radiation oncology, biology, physics,
07/2019, Volume:
104, Issue:
4
Journal Article
Peer reviewed
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Summary The incidence of brain metastases in patients with lung cancer has increased as a result of improved local and systemic control and better diagnosis from advances in brain imaging. Because ...brain metastases are responsible for life-threatening symptoms and serious impairment of quality of life, resulting in shortened survival, prophylactic cranial irradiation has been proposed in both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) to try to improve incidence of brain metastasis, survival, and eventually quality of life. Findings from randomised controlled trials and a meta-analysis have shown that prophylactic cranial irradiation not only reduces the incidence of brain metastases in patients with SCLC and with non-metastatic NSCLC, but also improves overall survival in patients with SCLC who respond to first-line treatment. Although prophylactic cranial irradiation is potentially associated with neurocognitive decline, this risk needs to be balanced against the potential benefit in terms of brain metastases incidence and survival. Several strategies to reduce neurotoxicity are being investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
The objective of this study was to evaluate the adequate margin in the local treatment of extremity soft tissue sarcomas (ESTS) and understand the relationship between local control and ...overall survival (OS).
Methods
All consecutive patients treated for a primary ESTS at a single center from 1993 to 2012 were reviewed.
Results
In all, 531 patients were included. Twelve (2 %) underwent a first-line amputation. The resections were R0/R1/not available in 434 (82 %), 92 (17 %), and 5 patients (1 %). The median tumor size was 8 cm, and the tumor grades were 1 (
n
= 132), 2 (
n
= 201), and 3 (
n
= 195). The median size of the minimal margin was 2 mm on fixed specimen. Preop or postop chemotherapy was administered to 222 patients, and 414 received radiotherapy. With a median follow-up period of 7 years, the 5-year actuarial local recurrence (LR) rate and OS were 8 % (95 % CI, 6–11 %) and 80 % (95 % CI, 76–83 %). Predictors of worse OS were grade 3, leiomyosarcoma, male gender, and age >60 years, whereas tumor size, margin status, and LR were not. Among patients requiring re-excision (
n
= 252), the presence of residual cells correlated with OS but not LR. After preoperative treatment, a percentage of residual cells ≥10 % correlated with OS but not LR. In the multivariate analysis, specific subtypes (epithelioid sarcoma and myxofibrosarcoma) and margin size <1 mm correlated with LR, whereas grade and the tissue constituting the surgical margins did not.
Conclusions
Specific subtypes and surgical margin size <1 mm were correlated with a higher LR. Neither the margin status nor LR affect OS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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