Summary Background The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy ...(SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. Methods Eligible patients in the STARS and ROSEL studies were those with clinical T1–2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749 ; ROSEL: NCT00687986 ). Findings 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0–47·3) for the SABR group and 35·4 months (18·9–40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85–100) in the SABR group compared with 79% (64–97) in the surgery group (hazard ratio HR 0·14 95% CI 0·017–1·190, log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74–100) in the SABR group and 80% (65–97) in the surgery group (HR 0·69 95% CI 0·21–2·29, log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three 10% chest wall pain, two 6% dyspnoea or cough, and one 3% fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3–4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four 15% patients), chest pain (four 15% patients), and lung infections (two 7%). Interpretation SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. Funding Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.
Summary A randomised trial of screening for lung cancer using CT showed a survival benefit with screening, but issues surrounding risks arising from screening remain. The appropriate treatment of ...early-stage lung cancer detected in this way is receiving increasing attention. This Review discusses treatment-related issues for such tumours and explores the merits of surgery versus stereotactic ablative radiotherapy (SABR), both of which are effective treatments but have different risks for acute toxicity. Although surgery is widely deemed to be the preferred treatment for patients who are fit, growing evidence suggests that SABR achieves similar local control rates, but without the risks associated with surgery. Choice of local treatment should also be made with consideration of the high rates of disease recurrence and second primary lung tumours in patients after curative therapy for early-stage lung cancer. Careful collaborative evaluation by pulmonologists, interventional radiologists, thoracic surgeons, and radiation oncologists should guide decision making for each patient with a screen-detected early-stage lung cancer.
Approximately two-thirds of patients with early-stage non-small-cell lung cancer (NSCLC) in The Netherlands currently undergo surgical resection. As an increasing number of fit patients have elected ...to undergo stereotactic ablative radiotherapy (SABR) in recent years, we studied outcomes after SABR in patients with potentially operable stage I NSCLC.
In an institutional prospective database collected since 2003, 25% of lung SABR cases (n = 177 patients) were found to be potentially operable when the following patients were excluded: those with (1) synchronous lung tumors or other malignancy, (2) prior high-dose radiotherapy/pneumonectomy, (3) chronic obstructive pulmonary disease with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease classification. (4) a performance score of ≥3, and (5) other comorbidity precluding surgery. Study patients included 101 males and 76 females, with a median age of 76 years old, 60% of whom were staged as T1 and 40% of whom were T2. Median Charlson comorbidity score was 2 (range, 0-5). A SABR dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5, or 8 fractions, depending on tumor size and location. Follow-up chest computed tomography scans were obtained at 3, 6, and 12 months and yearly thereafter.
Median follow-up was 31.5 months; and median overall survival (OS) was 61.5 months, with 1- and 3-year survival rates of 94.7% and 84.7%, respectively. OS rates at 3 years in patients with (n = 59) and without (n = 118) histological diagnosis did not differ significantly (96% versus 81%, respectively, p = 0.39). Post-SABR 30-day mortality was 0%, while predicted 30-day mortality for a lobectomy, derived using the Thoracoscore predictive model (Falcoz PE et al. J Thorac Cardiovasc Surg 2007;133:325-332), would have been 2.6%. Local control rates at 1 and 3 years were 98% and 93%, respectively. Regional and distant failure rates at 3 years were each 9.7%. Toxicity was mild, with grade ≥3 radiation pneumonitis and rib fractures in 2% and 3%, respectively.
Patients with potentially operable disease who underwent primary SABR had a median OS that exceeded 5 years. This finding supports ongoing randomized clinical trials comparing surgery and SABR in cases of operable stage I NSCLC.
The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of ...diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.
We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.
We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.
Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.
These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness ...include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.
To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers.
We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance.
PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H
O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy.
Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.
Apart from clinical experience and theoretical considerations, there is a lack of evidence that the level of adherence to in-hospital mobilization protocols is related to functional recovery in ...patients after resection for lung cancer. The objectives of the study were to determine (1) the relationship between adherence to the in-hospital mobilization protocol and physical fitness at hospital discharge and (2) the value of physical fitness measures at discharge in predicting physical functioning 6 weeks and 3 months postoperatively.
This observational study included 62 patients who underwent surgical resection for lung cancer. Adherence to the in-hospital mobilization protocol was abstracted from patients' records. Physical fitness measures before the operation and at hospital discharge included handgrip strength, 30-second sit-to-stand test, and 6-minute walk test (6MWT). Self-reported physical functioning was assessed preoperatively and 6 weeks and 3 months postoperatively, using the Medical Outcome Study 36-Item Short Form (SF-36) Physical Function subscale (RAND Corp, Santa Monica, CA). Linear regression analyses were used to estimate the relationships of interest, adjusting for potential confounders.
Level of adherence to the mobilization protocol was significantly and independently related to handgrip strength, sit-to-stand test, and 6MWT at discharge. Handgrip strength and 6MWT at discharge significantly predicted SF-36 Physical Function at 6 weeks and 3 months postoperatively. The sit-to-stand test only predicted SF-36 Physical Function at 6 weeks.
Suboptimal postoperative mobilization after surgical resection for lung cancer negatively affects physical fitness at discharge. Our results underline the importance of adherence to early postoperative mobilization protocols. Measuring physical fitness at discharge may be useful to inform clinicians on elective referral of patients for postdischarge rehabilitation.
Abstract We report quality of life and indirect costs from patient reported outcomes from the ROSEL randomized control trial comparing stereotactic ablative radiotherapy (SABR, also known as ...stereotactic body radiotherapy or SBRT) versus surgical resection for medically operable stage IA non-small cell lung cancer. ROSEL closed prematurely after accruing and randomizing 22 patients. This exploratory analysis found the global health related quality of life and indirect costs to be significantly favorable and cheaper, with SABR.
Primary neuroendocrine tumors of the thymus (NETT) are rare tumors and represent a distinct category of tumors collectively displaying morphologic and biological neuroendocrine features. We sought to ...evaluate factors influencing long-term survival in patients with primary NETT.
From January 1990 to April 2011, 35 patients (27 male patients and 8 female patients) were surgically treated for primary NETT at 5 institutions.
No operative (30-day) mortality occurred. Morbidity was 37.14% (13/35 patients). All patients were followed for a total of 2,703 months. Fourteen patients had associated paraneoplastic syndrome. Twenty-four patients are alive, 19 of whom are free of disease and 5 of whom continue to have disease. The median overall survival was 153 months. The overall 5-year and 10-year actuarial survival rates were 84.34% and 60.82%, respectively. The 10-year survival was evaluated according to histologic type (typical carcinoid, 77.92%; atypical carcinoid, 54.55%; large-cell neuroendocrine carcinomas, 0%; Masaoka staging (stage I, 100%; stage II, 66.67%; stage III, 61.9%; stage Iva, 25%; stage IVb, 0%), presence of paraneoplastic syndrome (no = 70.67%; yes = 32.14%), postoperative radiotherapy (yes = 39.71%; no = 85.71.%), Surveillance, Epidemiology, and End Results (SEER) staging system (localized disease, 83.3%; regional disease, 53.3%; distant disease, 0%), tumor size (<7 cm = 90.9%; ≥7cm = 28.7%; p = 0.0007), and Ki67 expression, which was available in 23 patients (<10% = 85.71%; ≥10% = 0%; p = 0.0037).
The prognosis of primary NETT is statistically significantly related to tumor size >7 cm and to the proliferation index (evaluated by Ki67 expression >10%). The histologic type of the neoplasm, the presence of a paraneoplastic syndrome, the Masaoka staging, the evidence of distant disease, and postoperative radiotherapy also impact prognosis.
Right ventricular (RV) failure due to chronically abnormal loading is a main determinant of outcome in pulmonary hypertension (PH) and congenital heart disease. However, distinct types of RV loading ...have been associated with different outcomes. To determine whether the adaptive RV response depends on loading type, we compared hemodynamics, exercise, and hypertrophy in models of pressure overload due to pulmonary artery banding (PAB), pressure overload due to PH, combined pressure and volume overload, and isolated volume load. Ninety-four rats were subjected to either PAB, monocrotaline-induced PH (PH), aortocaval shunt (shunt), or combined monocrotaline and aortocaval shunt (PH + shunt). We performed pressure-volume analysis and voluntary exercise measurements at 4 wk. We compared PAB to PH (part I) and PH + shunt to either isolated PH or shunt (part II). In part I, enhanced contractility (end-systolic elastance and preload recruitable stroke work) was present in PH and PAB, but strongest in PAB. Frank-Starling mechanism was active in both PAB and PH. In PAB this was accompanied by diastolic dysfunction (increased end-diastolic elastance, relaxation constant), clinical signs of RV failure, and reduced exercise. These distinct responses were not attributable to differences in hypertrophy. In part II, in PH + shunt the contractility response was blunted compared with PH, which caused pseudonormalization of parameters. Additional volume overload strongly enhanced hypertrophy in PH. We conclude that different types of loading result in distinct patterns of RV adaptation. This is of importance for the approach to patients with chronically increased RV load and for experimental studies in various types of RV failure.
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