Summary Background Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this ...study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. Methods The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov ( NCT00433563 ) and is currently in follow-up. Findings Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 95% CI 0·95–1·45; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% 95% CI −3·2% to 13·7%). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 74% of 266 patients in the twice-daily group vs 170 65% of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 49% vs 101 38%; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 19% of 254 patients in the twice-daily group vs 47 19% of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 3% of 254 vs 4 2% of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Interpretation Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Funding Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).
Summary Background The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of ...soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities. Methods Consecutive patients who had had an operation at the Istituto Nazionale Tumori (Milan, Italy), from Jan 1, 1994, to Dec 31, 2013, formed the development cohort. Three cohorts of patient data from the Institut Gustave Roussy (Villejuif, France; from Jan 1, 1996, to May 15, 2012), Mount Sinai Hospital (Toronto, ON, Canada; from Jan 1, 1994, to Dec 31, 2013), and the Royal Marsden Hospital (London, UK; from Jan 1, 2006, to Dec 31, 2013) formed the external validation cohorts. We developed the nomogram for overall survival using a Cox multivariable model, and a Fine and Gray multivariable model for the distant metastases nomogram. We applied a backward procedure for variables selection for both nomograms. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plots and Hosmer–Lemeshow calibration test), and discrimination (Harrell C index). We plotted decision curves to evaluate the clinical usefulness of the two nomograms. Findings 1452 patients were included in the development cohort, with 420 patients included in the French validation cohort, 1436 patients in the Canadian validation cohort, and 444 patients in the UK validation cohort. In the development cohort, 10-year overall survival was 72·9% (95% CI 70·2–75·7) and 10-year crude cumulative incidence of distant metastases was 25·0% (95% CI 22·7–27·5). For the overall survival nomogram, the variables selected applying a backward procedure in the multivariable Cox model (patient's age, tumour size, Fédération Française des Centres de Lutte Contre le Cancer FNCLCC grade, and histological subtype) had a significant effect on overall survival. The same variables, except for patient age, were selected for the distant metastases nomogram. In the development cohort, the Harrell C index for overall survival was 0·767 (95% CI 0·743–0·789) and for distant metastases was 0·759 (0·736–0·781). In the validation cohorts, the Harrell C index for overall survival and distant metastases were 0·698 (0·638–0·754) and 0·652 (0·605–0·699; French), 0·775 (0·754–0·796) and 0·744 (0·720–0·768; Canadian), and 0·762 (0·720–0·806) and 0·749 (0·707–0·791; UK). The two nomograms both performed well in terms of discrimination (ability to distinguish between patients who have had an event from those who have not) and calibration (accuracy of nomogram prediction) when applied to the validation cohorts. Interpretation Our nomograms are reliable prognostic methods that can be used to predict overall survival and distant metastases in patients after surgical resection of soft-tissue sarcoma of the extremities. These nomograms can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic. Funding None.
Evidence for external beam radiation therapy (RT) as part of treatment for retroperitoneal sarcoma (RPS) is limited. Preoperative RT is the subject of a current randomized trial, but the results will ...not be available for many years. In the meantime, many practitioners use preoperative RT for RPS, and although this approach is used in practice, there are no radiation treatment guidelines. An international expert panel was convened to develop consensus treatment guidelines for preoperative RT for RPS.
An expert panel of 15 academic radiation oncologists who specialize in the treatment of sarcoma was assembled. A systematic review of reports related to RT for RPS, RT for extremity sarcoma, and RT-related toxicities for organs at risk was performed. Due to the paucity of high-quality published data on the subject of RT for RPS, consensus recommendations were based largely on expert opinion derived from clinical experience and extrapolation of relevant published reports. It is intended that these clinical practice guidelines be updated as pertinent data become available.
Treatment guidelines for preoperative RT for RPS are presented.
An international panel of radiation oncologists who specialize in sarcoma reached consensus guidelines for preoperative RT for RPS. Many of the recommendations are based on expert opinion because of the absence of higher level evidence and, thus, are best regarded as preliminary. We emphasize that the role of preoperative RT for RPS has not been proven, and we await data from the European Organization for Research and Treatment of Cancer (EORTC) study of preoperative radiotherapy plus surgery versus surgery alone for patients with RPS. Further data are also anticipated pertaining to normal tissue dose constraints, particularly for bowel tolerance. Nonetheless, as we await these data, the guidelines herein can be used to establish treatment uniformity to aid future assessments of efficacy and toxicity.
Summary As the prognosis of lung cancer patients improves, more patients are at risk of developing local recurrence or a new primary tumour in previously irradiated areas. Technological advances in ...radiotherapy and imaging have made treatment of patients with high-dose re-irradiation possible, with the aim of long-term disease-free survival and even cure. However, high-dose re-irradiation with overlapping volumes of previously irradiated tissues is not without risks. Late, irreversible, and potentially serious normal tissue damage may occur because of injury to surrounding thoracic structures and organs at risk. In this Review, we aimed to report the efficacy and toxic effects of high-dose re-irradiation for locoregional recurrent non-small-cell lung cancer. Our findings indicate that high-dose re-irradiation might be beneficial in selected patients; however, patients and physicians should be aware of the scarcity of high-quality data when considering this treatment.
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.
This critical review will focus on published data on the indications for radiotherapy in patients with extremity soft tissue sarcomas and its role in local control, survival, and treatment ...complications. The differences between pre- and postoperative radiotherapy will be discussed and consensus recommendations on target volume delineation proposed.
Summary Background The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes ...years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2 =0·83, 95% CI 0·83–0·83 in trials without radiotherapy, and 0·87, 0·87–0·87 in trials with radiotherapy) and excellent at trial level ( R2 =0·92, 95% CI 0·88–0·95 in trials without radiotherapy and 0·99, 0·98–1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77–0·85, dependent on the regimen being assessed) and trial level ( R2 range 0·89–0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2 =0·71, 95% CI 0·71–0·71 for concurrent chemotherapy and ρ2 =0·61, 0·61–0·61 for modified vs standard radiotherapy) and trial-level correlations very good ( R2 =0·85, 95% CI 0·77–0·92 for concurrent chemotherapy and R2 =0·95, 0·91–0·98 for modified vs standard radiotherapy). Interpretation We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.
The use of immune checkpoint inhibitors (ICIs) has drastically transformed the therapeutic landscape in lung cancer. Special focus has been put on immune-related toxicity; however, infections can ...also seem during ICI treatment. Although rare, tuberculosis (TB) has been increasingly identified after ICIs, and it seems that the programmed cell death protein 1 and programmed death-ligand 1 pathway is directly involved in its pathophysiology. Here, we describe the case of a patient with advanced NSCLC who developed abdominal TB after 32 months of pembrolizumab and who remains in tumor remission 10 months after discontinuation of this drug. Routine screening for latent TB before ICI treatment is advised, with closer collaboration between infectious disease specialists and oncologists.
Summary Background The optimum dose of prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC) is unknown. A meta-analysis suggested that the incidence of brain ...metastases might be reduced with higher PCI doses. This randomised clinical trial compared the effect of standard versus higher PCI doses on the incidence of brain metastases. Methods Between September, 1999, and December, 2005, 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2·5 Gy) or higher PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily sessions of 1·5 Gy separated by a minimum interval of 6 h) radiotherapy. All of the treatment schedules excluded weekends. Randomisation was stratified according to medical centre, age (≤60 and >60 years), and interval between the start of induction treatment and the date of randomisation (≤90, 91–180, and >180 days). Eligible patients were randomised blindly by the data centre of the Institut Gustave Roussy (PCI99-01 and IFCT) using minimisation, and by the data centres of EORTC (EORTC ROG and LG) and RTOG (for CALGB, ECOG, RTOG, and SWOG), both using block stratification. The primary endpoint was the incidence of brain metastases at 2 years. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov number NCT00005062. Findings Five patients in the standard-dose group and four in the higher-dose group did not receive PCI; nonetheless, all randomised patients were included in the effectiveness anlysis. After a median follow-up of 39 months (range 0–89 months), 145 patients had brain metastases; 82 in the standard-dose group and 63 in the higher-dose group. There was no significant difference in the 2-year incidence of brain metastases between the standard PCI dose group and the higher-dose group, at 29% (95% CI 24–35) and 23% (18–29), respectively (hazard ratio HR 0·80 95% CI 0·57–1·11, p=0·18). 226 patients in the standard-dose group and 252 in the higher-dose group died; 2-year overall survival was 42% (95% CI 37–48) in the standard-dose group and 37% (32–42) in the higher-dose group (HR 1·20 1·00–1·44; p=0·05). The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality: 189 patients in the standard group versus 218 in the higher-dose group died of progressive disease. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. The most common acute toxic events were fatigue (106 30% patients in the standard-dose group vs 121 34% in the higher-dose group), headache (85 24% vs 99 28%), and nausea or vomiting (80 23% vs 101 28%). Interpretation No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in limited-stage SCLC. Funding Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The European Organisation for Research and Treatment of Cancer (EORTC) contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the US National Cancer Institute.
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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