Summary Background Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of medically inoperable early stage non-small-cell lung cancer (NSCLC). Because patterns of late ...disease recurrence after SABR are not well characterised, we aimed to assess these outcomes in a cohort of patients with NSCLC. Methods Patients with18 F-fluorodeoxyglucose (18 F-FDG)-PET confirmed stage 1–2 NSCLC who were treated with SABR at the VU University Medical Center (Amsterdam, Netherlands) were identified from an institutional database. SABR doses were 54–60 Gy, delivered in three to eight once-daily fractions, depending on tumour size and location. Clinical follow-up and CT scans were done at 3, 6, and 12 months, then yearly thereafter.18 F-FDG-PET restaging was only done when clinically indicated. Initial sites of recurrence were classified as local, regional, and distant, and were differentiated from second primary tumours in the lung at multidisciplinary tumour board review. Findings Between April 4, 2003, and Dec 5, 2011, 676 patients were treated with SABR and were eligible for assessment of recurrence. The median follow-up was 32·9 months (IQR 14·9–50·9 months). 124 (18%) of 676 patients had disease recurrence. Actuarial 2-year rates of local, regional, and distant recurrence were 4·9% (95% CI 2·7–7·1), 7·8% (5·3–10·3), and 14·7% (11·4–18·0), respectively. Corresponding 5-year rates were 10·5% (95% CI 6·4–14·6), 12·7% (8·4–17·0), and 19·9% (14·9–24·6), respectively. Of the 124 recurrences, 82 (66%) were distant recurrences and 57 (46%) were isolated distant recurrences. Isolated locoregional recurrences occurred in the remaining 42 patients with disease recurrence (34%), 35 (83%) of whom did not develop subsequent distant recurrence. The median times to local, regional, and distant recurrence were 14·9 months (95% CI 11·4–18·4), 13·1 months (7·9–18·3), and 9·6 months (6·8–12·4), respectively. New pulmonary lesions characterised as second primary tumours in the lung developed in 42 (6%) of 676 patients at a median of 18·0 months (95% CI 12·5–23·5) after SABR. Interpretation Late recurrences after SABR are infrequent and two distinct patterns account for most cases. The predominant pattern is out-of-field, isolated distant recurrence presenting early, despite initial PET staging. A third of patients develop isolated locoregional recurrence; for these patients standardised follow-up is important to ensure that appropriate salvage treatments are considered. Funding None.
Automated and knowledge-based planning techniques aim to reduce variations in plan quality. RapidPlan uses a library consisting of different patient plans to make a model that can predict achievable ...dose-volume histograms (DVHs) for new patients and uses those models for setting optimization objectives. We benchmarked RapidPlan versus clinical plans for 2 patient groups, using 3 different libraries.
Volumetric modulated arc therapy plans of 60 recent head and neck cancer patients that included sparing of the salivary glands, swallowing muscles, and oral cavity were evenly divided between 2 models, Model(30A) and Model(30B), and were combined in a third model, Model60. Knowledge-based plans were created for 2 evaluation groups: evaluation group 1 (EG1), consisting of 15 recent patients, and evaluation group 2 (EG2), consisting of 15 older patients in whom only the salivary glands were spared. RapidPlan results were compared with clinical plans (CP) for boost and/or elective planning target volume homogeneity index, using HI(B)/HI(E) = 100 × (D2% - D98%)/D50%, and mean dose to composite salivary glands, swallowing muscles, and oral cavity (D(sal), D(swal), and D(oc), respectively).
For EG1, RapidPlan improved HI(B) and HI(E) values compared with CP by 1.0% to 1.3% and 1.0% to 0.6%, respectively. Comparable D(sal) and D(swal) values were seen in Model(30A), Model(30B), and Model60, decreasing by an average of 0.1, 1.0, and 0.8 Gy and 4.8, 3.7, and 4.4 Gy, respectively. However, differences were noted between individual organs at risk (OARs), with Model(30B) increasing D(oc) by 0.1, 3.2, and 2.8 Gy compared with CP, Model(30A), and Model60. Plan quality was less consistent when the patient was flagged as an outlier. For EG2, RapidPlan decreased D(sal) by 4.1 to 4.9 Gy on average, whereas HI(B) and HI(E) decreased by 1.1% to 1.5% and 2.3% to 1.9%, respectively.
RapidPlan knowledge-based treatment plans were comparable to CP if the patient's OAR-planning target volume geometry was within the range of those included in the models. EG2 results showed that a model including swallowing-muscle and oral-cavity sparing can be applied to patients with only salivary gland sparing. This may allow model library sharing between institutes. Optimal detection of inadequate plans and population of model libraries requires further investigation.
Spinal metastases are becoming increasingly common because patients with metastatic disease are living longer. The close proximity of the spinal cord to the vertebral column limits many conventional ...therapeutic options that can otherwise be used to treat cancer. In response to this problem, an innovative multidisciplinary approach has been developed for the management of spinal metastases, leveraging the capabilities of image-guided stereotactic radiosurgery, separation surgery, vertebroplasty, and minimally invasive local ablative approaches. In this Review, we discuss the variables that should be considered during the management of these patients and review the role of each discipline and their respective management options to provide optimal care. This work is synthesised into a practical algorithm to aid clinicians in the management of patients with spinal metastasis.
Summary Background Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We ...assessed thoracic radiotherapy for treatment of this patient group. Methods We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0–2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. Findings We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27–39) for the thoracic radiotherapy group versus 28% (95% CI 22–34) for the control group (hazard ratio HR 0·84, 95% CI 0·69–1·01; p=0·066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9–19) versus 3% (95% CI 2–8; p=0·004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0·73, 95% CI 0·61–0·87; p=0·001). At 6 months, progression-free survival was 24% (95% CI 19–30) versus 7% (95% CI 4–11; p=0·001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). Interpretation Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. Funding Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.
Stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) is associated with high local control rates. The impact of introducing SBRT in patients 75 years of age or older ...was studied using a population-based cancer registry.
The Amsterdam Cancer Registry was assessed in three eras: 1999 to 2001 (period A, pre-SBRT); 2002 to 2004 (period B, some availability of SBRT), and 2005 to 2007 (period C, full access to SBRT). χ(2), Kaplan-Meier, and Cox regression were used to compare treatment patterns and overall survival (OS) in three treatment groups: surgery, radiotherapy (RT), or neither.
A total of 875 elderly patients were diagnosed with stage I NSCLC in the study period. Median follow-up was 54 months. Primary treatment was surgery in 299 patients (34%), RT in 299 patients (34%), and neither in 277 patients (32%). RT use increased between periods A and C (26% v 42%, P < .01), corresponding to a decrease in untreated patients. The percentage of RT patients undergoing SBRT in periods B and C was 23% and 55%, respectively. Median survival for all patients increased from 16 months in period A to 21 months in period C (log-rank P < .01; hazard ratio HR = 0.65; 95% CI, 0.54 to 0.80). The improvement in OS was confined to RT patients (HR = 0.70; 95% CI, 0.49 to 0.99), whereas no significant survival improvements were seen in the other groups.
SBRT introduction was associated with a 16% absolute increase in RT use, a decline in the proportion of untreated elderly patients, and an improvement in OS.
High local control rates can be achieved using stereotactic radiotherapy in Stage I non-small-cell lung cancer (NSCLC), but reports have suggested that toxicity may be of concern. We evaluated early ...clinical outcomes of "risk-adapted" fractionation schemes in patients treated in a single institution.
Of 206 patients with Stage I NSCLC, 81% were unfit to undergo surgery and the rest refused surgery. Pathologic confirmation of malignancy was obtained in 31% of patients. All other patients had new or growing 18F-fluorodeoxyglucose positron emission tomography positive lesions with radiologic characteristics of malignancy. Planning four-dimensional computed tomography scans were performed and fractionation schemes used (3 x 20 Gy, 5 x 12 Gy, and 8 x 7.5 Gy) were determined by T stage and risk of normal tissue toxicity.
Median overall survival was 34 months, with 1- and 2-year survivals of 81% and 64%, respectively. Disease-free survival (DFS) at 1 and 2 years was 83% and 68%, respectively, and DFS correlated with T stage (p = 0.002). Local failure was observed in 7 patients (3%). The crude regional failure rate was 9%; isolated regional recurrence was observed in 4%. The distant progression-free survival at 1 and 2 years was 85% and 77%, respectively. SRT was well tolerated and severe late toxicity was observed in less than 3% of patients.
SRT is well tolerated in patients with extensive comorbidity with high local control rates and minimal toxicity. Early outcomes are not inferior to those reported for conventional radiotherapy. In view of patient convenience, such risk-adapted SRT schedules should be considered treatment of choice in patients presenting with medically inoperable Stage I NSCLC.
Volumetric intensity-modulated arc therapy (RA) allows for rapid delivery of highly conformal dose distributions. In this study, planning and dosimetry of RA were compared with conventional ...intensity-modulated radiation therapy (IMRT) plans of head-and-neck cancer patients.
Computed tomography scans of 12 patients who had completed IMRT for advanced tumors of the naso-, oro- and hypopharynx were replanned using RA using either one or two arcs. Calculated doses to planning target volume (PTV) and organs at risk (OAR) were compared between IMRT and RA plans. Dose distributions for single arc (n = 8) and double arc (n = 4) plans were verified using film dosimetry in three to five coronal planes using a quality assurance phantom.
RA plans allowed for a mean reduction in number of monitor units (MU) by nearly 60%, relative to seven field sliding window IMRT plans. RA plans achieved similar sparing of all OAR as IMRT. Double arc RA provided the best dose homogeneity to PTV with a lower standard deviation of PTV dose (1.4 Gy), vs. single arc plans (2.0 Gy) and IMRT (1.7 Gy). Film measurements showed good correspondence with calculated doses; the mean gamma value was 0.30 (double arc) and area of the film with a gamma exceeding 1 was 0.82%.
RA is a fast, safe, and accurate technique that uses lower MUs than conventional IMRT. Double arc plans provided at least similar sparing of OAR and better PTV dose homogeneity than single arc or IMRT.
RapidPlan, a commercial knowledge-based planning solution, uses a model library containing the geometry and associated dosimetry of existing plans. This model predicts achievable dosimetry for ...prospective patients that can be used to guide plan optimization. However, it is unknown how suboptimal model plans (outliers) influence the predictions or resulting plans. We investigated the effect of, first, removing outliers from the model (cleaning it) and subsequently adding deliberate dosimetric outliers.
Clinical plans from 70 head and neck cancer patients comprised the uncleaned (UC) ModelUC, from which outliers were cleaned (C) to create ModelC. The last 5 to 40 patients of ModelC were replanned with no attempt to spare the salivary glands. These substantial dosimetric outliers were reintroduced to the model in increments of 5, creating Model5 to Model40 (Model5-40). These models were used to create plans for a 10-patient evaluation group. Plans from ModelUC and ModelC, and ModelC and Model5-40 were compared on the basis of boost (B) and elective (E) target volume homogeneity indexes (HIB/HIE) and mean doses to oral cavity, composite salivary glands (compsal) and swallowing (compswal) structures.
On average, outlier removal (ModelC vs ModelUC) had minimal effects on HIB/HIE (0%-0.4%) and sparing of organs at risk (mean dose difference to oral cavity and compsal/compswal were ≤0.4 Gy). Model5-10 marginally improved compsal sparing, whereas adding a larger number of outliers (Model20-40) led to deteriorations in compsal up to 3.9 Gy, on average. These increases are modest compared to the 14.9 Gy dose increases in the added outlier plans, due to the placement of optimization objectives below the inferior boundary of the dose-volume histogram-predicted range.
Overall, dosimetric outlier removal from or addition of 5 to 10 outliers to a 70-patient model had marginal effects on resulting plan quality. Although the addition of >20 outliers deteriorated plan quality, the effect was modest. In this study, RapidPlan demonstrated robustness for moderate proportions of salivary gland dosimetric outliers.
Reducing dose to normal tissues is the advantage of protons versus photons. We aimed to describe a method for translating this reduction into a clinically relevant benefit.
Dutch scientific and ...health care governance bodies have recently issued landmark reports regarding generation of relevant evidence for new technologies in health care including proton therapy. An approach based on normal tissue complication probability (NTCP) models has been adopted to select patients who are most likely to experience fewer (serious) adverse events achievable by state-of-the-art proton treatment.
By analogy with biologically targeted therapies, the technology needs to be tested in enriched cohorts of patients exhibiting the decisive predictive marker: difference in normal tissue dosimetric signatures between proton and photon treatment plans. Expected clinical benefit is then estimated by virtue of multifactorial NTCP models. In this sense, high-tech radiation therapy falls under precision medicine. As a consequence, randomizing nonenriched populations between photons and protons is predictably inefficient and likely to produce confusing results.
Validating NTCP models in appropriately composed cohorts treated with protons should be the primary research agenda leading to urgently needed evidence for proton therapy.
Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell ...lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations. Methods The ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience. Recommendations For standard operative risk patients with stage I NSCLC, SBRT is not recommended outside of a clinical trial. Lobectomy with systematic lymph node evaluation remains the recommended treatment, although a sublobar resection may be considered in select clinical scenarios. Recommendations are provided regarding the use of SBRT in high operative risk patients and for inoperative patients, including in challenging scenarios where tumors are: centrally located, > 5 cm in diameter, lacking tissue diagnosis, synchronous primary or multifocal, second primary after pneumonectomy, proximal to or involved with mediastinal structures, abutting the chest wall, or recurring after previous treatment. Qualifying statements are included to provide further guidance for implementation, and the importance of a discussion of treatment options among members of the multidisciplinary cancer care team is emphasized. Additional information is available at: www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .
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