The impact of respiratory gating on lung dosimetry in stereotactic body radiotherapy for lung cancer

The purpose of this study was to evaluate the impacts of respiratory gating and different gating windows (GWs) on lung dosimetry in stereotactic body radiotherapy (SBRT) for lung cancer.Gated SBRT plans were developed using the four-dimensional computed tomography data from 17 lung cancer patients treated with SBRT. Using amplitude-based end-exhalation gating, we established 2 fixed GWs with approximate duty cycles of 50% (50% GW) and 25% (25% GW), respectively, for this study.For highly mobile tumors (3D mobility > 10 mm), additional benefits in lung-dose reductions were achieved with the 25% GW, as a result of inadequate mobility and planning target volume reductions obtained with the 50% GW. In these tumors, the absolute differences compared to the non-gated and 50% gated plans, were 0.5 Gy and 0.33 Gy for the mean lung dose and 1.11% and 0.71% for the V20, respectively. Dosimetric benefits were achieved with the 50% GW, compared with the non-gated plan, for tumors with both low mobility and small volume (gross tumor volume ≤ 10 cc). Among the identified predictive factors of dosimetric benefits, the lateral distance from midspinal canal and the motion range in anterior–posterior direction might be stronger factors because of their correlations with many of the lung-dose parameters and greater predictive capacity.The results of the present study might facilitate the selection of appropriate patients and the optimal GW according to the tumor characteristics for gated lung SBRT.     

Geometrical and dosimetrical uncertainties in hypofractionated radiotherapy of the lung: A review

The application of high precision hypofractionated regimes (a.k.a. stereotactic body radiotherapy (SBRT)) to the treatment of lung cancer is a ‘success story’ of radiotherapy. From the technical perspective, lung SBRT is a challenging technique as all aspects of the treatment workflow, from imaging to dose calculation to treatment delivery, should be carefully handled in order to ensure consistency between planned and delivered dose.In this review such technical aspects are presented and discussed, looking at what has been developed over the years.The use of imaging techniques such as slow-CT, breath-hold CT, four-dimensional CT and mid-ventilation is reviewed, presenting the main characteristics of each approach but not necessarily to single out ‘the best’ solution.Concerning dose calculation, a number of studies clearly separate dose algorithms that should be considered inadequate for lung SBRT (e.g. simple pencil beam algorithms) from approaches such as convolution algorithms, Monte Carlo, and solution of the transport equation, that are much better at handling the combination of small fields and heterogenenous geometries that make dose calculation not trivial.Patient positioning and management of intrafraction motion have been two areas of significant developments, to the point where it is difficult to identify which solution represents the best compromise between technical complexity and clinical effectiveness. The review analyses several of these methods, outlining the residual uncertainties associated with each of them.Last but not least, two subjects are discussed, adaptive therapy and particle therapy, that may represent in the near future additional tools for the technical improvement of lung SBRT.     

Predictive biochemical-markers for the development of brain metastases from lung cancer: Clinical evidence and future directions

BackgroundBrain metastases are a common complication of patients with lung cancer and lung cancer is one of the most common causes of brain metastases. The occurrence of brain metastases is associated with poor prognosis and high morbidity, even after intensive multimodal therapy. Therefore, identifying lung cancer patients with who are at high risk of developing brain metastases and applying effect intervention is important to reduce or delay the incidence of brain metastases. Biochemical-markers may meet an unmet need for following patients’ mechanisms of brain metastases.MethodsData for this review were identified by searches of Pubmed and Cochrane databases, and references from relevant articles using the search terms “lung cancer” and “brain metastasis”. Meeting abstracts, unpublished reports and review articles were not considered.ResultsClinical results for pathological and circulating markers including cancer molecular subtypes, miRNA, single nucleotide polymorphisms, and other markers are presented. However, these biochemical-markers are not yet established surrogate assessments for prediction of brain metastases.ConclusionsBiochemical-markers reported allowed physicians to identify which patients with lung cancer are at high risk for brain metastases. Prospective randomized clinical studies are needed to further assess the utility of these biochemical-markers.     

Lung cancer. Radiotherapy in lung cancer: Actual methods and future trends

This survey is performed to update knowledge about methods and trends in lung cancer radiotherapy. A significant development has been noticed in radiotherapeutic techniques, but also in the identification of clinical prognostic factors. The improvement in the therapeutic line includes: application of the four-dimensional computer tomography (4DCT), taking advantage of positron emission tomography (PET-CT), designing of new computational algorithms, allowing more precise irradiation planning, development of treatment precision verification systems and introducing IMRT techniques in chest radiotherapy. The treatment outcomes have improved with high dose radiotherapy, but other fractionation alternations have been investigated as well.     

Predictive value of vascular calcification identified in 4D planning CT of lung cancer patients treated with stereotactic body radiation therapy

PurposeThe aim was to identify vascular calcification in 4DCT scan of lung cancer patients and establish the association between overall survival (OS) and vascular calcification, as surrogate for vascular health.MethodsVascular calcification within the thoracic cavity were segmented in 334 lung cancer patients treated with stereotactic body radiation therapy (SBRT). This has been done automatically on 4D planning CT and average reconstruction scans. Correlation between cardiac comorbidity and calcification volumes was evaluated for patients with recorded Adult Co-Morbidity Evaluation (n = 303). Associations between the identified calcifications and OS were further investigated.ResultsThe volume of calcification from the average scan was significantly lower than from each phase (p < 0.001). The highest level of correlations between cardiac comorbidity and volume of the calcifications were found for one phase representing inhale and two phases representing exhale with the least motion blurring due to respiration (p < 0.005). The volume of the calcifications was subsequently averaged over these three phases. The average of calcification volumes over the three phases (denoted by inhale-exhale) showed the highest likelihood in univariate analysis and was chosen as vascular calcification measure. Cox-model suggested that tumor volume (Hazard Ratio [HR] = 1.46, p < 0.01) and inhale-exhale volume (HR = 1.05, p < 0.05) are independent factors predicting OS after adjusting for age, sex, and performance status.ConclusionIt was feasible to use. It 4DCT scan for identifying thoracic calcifications in lung cancer patients treated with SBRT. Calcification volumes from inhale-exhale phases had the highest correlation with overall cardiac comorbidity and the average of the calcification volume obtained from these phases was an independent predictive factor for OS.     

非小细胞肺癌体部寡转移的立体定向放射治疗

非小细胞肺癌(Non-small cell lung cancer, NSCLC)寡转移是NSCLC转移过程中的一种中间状态,是肿瘤生物侵袭过程中较温和的一个阶段,它介于原发灶与远处广泛转移之间,转移瘤数目≦5个,受累器官≦2个,此时肿瘤细胞尚不具备全身播散的倾向。晚期恶性肿瘤患者很大部分处于寡转移状态,而约30%的非小细胞肺癌(NSCLC)患者死于寡转移,目前对于寡转移的治疗以局部治疗为主(包括手术、放疗以及射频消融)。治疗隐匿性转移灶、寡转移灶及全身化学治疗结束后清除残留局部病灶成为治疗寡转移的关键,越来越得到专家共识。在无法手术或者拒绝手术的患者中,局部放放射治疗凸显巨大优势,尤其是体部立体定向放射治疗(Stereotactic Body Radiation Therapy, SBRT),大量临床研究结果显示体部立体定向放射治疗NSCLC寡转移是安全有效的,并能提高转移灶的局部控制率。本文旨在对SBRT治疗非小细胞肺癌寡转移的临床进展做一综述。     

Software simulation of tumour motion dose effects during flattened and unflattened ITV-based VMAT lung SBRT

PurposeRestricted studies comparing different dose rate parameters are available while ITV-based VMAT lung SBRT planning leads to perform the analysis of the most suitable parameters of the external beams used. The special emphasis was placed on the impact of dose rate on dose distribution variations in target volumes due to interplay effects.MethodsFour VMAT plans were calculated for 15 lung tumours using 6 MV photon beam quality (flattening filter FF vs. flattening filter free FFF beams) and maximum dose rate of 600 MU/min, 1000 MU/min and 1400 MU/min. Three kinds of motion simulations were performed finally giving 180 plans with perturbed dose distributions.Results6FFF-1400 MUs/min plans were characterized by the shortest beam on time (1.8 ± 0.2 min). Analysing the performed motion simulation results, the mean dose (Dmean) is not a sensitive parameter to related interplay effects. Looking for local maximum and local minimum doses, some discrepancies were found, but their significance was presented for individual patients, not for the whole cohort. The same was observed for other verified dose metrics.ConclusionsGenerally, the evaluation of VMAT robustness between FF and FFF concepts against interplay effect showed a negligible effect of simulated motion influence on tumour coverage among different photon beam quality parameters. Due to the lack of FFF beams, smaller radiotherapy centres are able to perform ITV-based VMAT lung SBRT treatment in a safe way. Radiotherapy department having FFF beams could perform safe, fast and efficient ITV-based VMAT lung SBRT without a concern about significance of interplay effects.     

Cardiac toxicity of lung cancer radiotherapy

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening.Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible.A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.     

Stereotactic ablative radiotherapy for oligometastatic prostate cancer

BackgroundThe present study assessed clinical outcomes of stereotactic body radiotherapy (SBRT) in oligometastatic prostate cancer patients.Materials and methodsBetween 2017 and 2020, 37 lesions (12 osseous and 25 nodal targets) detected with conventional and/or functional imaging, were treated in 29 patients (pts), in different clinical settings: de novo oligometastatic (2 pts), oligorecurrent castration-sensitive (19 pts), castration-resistant (6 pts) prostate cancers and oligoprogressive disease during systemic therapy (2 pts). SBRT was delivered with volumetric modulated arc therapy up to a total dose of 21 Gy given in 3 fractions for bone and 30 Gy in 5 fractions for nodal metastases. A total of 34% of pts received hormonal therapy. We evaluated biochemical control [prostate serum antigen (PSA) increase < 10%)], progression free-survival (PFS) (time from SBRT to biochemical progression), local control (LC) (time from SBRT to in-field radiologic progression), hormone/systemic therapy-free survival, acute and late toxicities.ResultsAt 3 months, biochemical response was observed in 20/29 pts (69%). At a median follow-up of 17 months (range 6–33), 8/20 (40%) of the 3-month responders remained free from progression. Two-year PFS and LC were 37% and 70%, respectively. In-field progression occurred in 3/37 (8%) lesions. Hormone/systemic therapy was delayed by an average of 11.6 months (range 3–28). No significant difference in PFS based on the type of lesion or concomitant endocrine therapy was observed and no toxicity > grade 2 was reported.ConclusionsSBRT for oligometastatic prostate cancer offers a good biochemical/local control and tangible delay of hormone/systemic therapy without major toxicities.     

Blood cadmium levels as a marker for early lung cancer detection

BackgroundWe assessed whether blood cadmium levels were associated with incident lung cancer and could be used in the context of a screening program for early-stage lung cancer.Material and methodsWe measured blood cadmium levels among 205 lung cancer patients and 205 matched controls. Cases and controls were matched for sex, age and smoking history (total pack-years, years since cessation for former smokers).ResultsThe odds ratio for those in the highest quartile of cadmium level (versus lowest) was four-fold (OR = 4.41, 95 % CI:2.01–9.67, p < 0.01). The association was present in former smokers (OR = 16.8, 95 % CI:3.96−71.2, p < 0.01), but not in current smokers (OR = 1.23, 95 % CI: 0.34–4.38) or in never smokers (OR not defined). Among former smokers, the association was present in both early- and late-stage lung cancer.ConclusionBlood cadmium levels may be a marker to help with the early detection of lung cancer among former smokers.     

Gene therapy for lung cancer

Lung cancer continues to be the largest killer of Americans due to cancer. Although progress has been made, with advances in chemotherapy, the majority of patients diagnosed with lung cancer ultimately succumb to the disease. A better understanding of the molecular pathogenesis of lung cancer is demonstrating how alterations in oncogenes and tumor suppressor genes control lung cancer initiation, growth, and survival. In this article, attempts to target molecular alterations in lung cancer using gene therapy techniques are reviewed. These include introducing suicide genes into tumor cells, replacement of defective tumor suppressor genes, inactivating oncogenes, and immunotherapy-based approaches using gene therapy technology. The major barrier for these techniques continues to be the inability to specifically target tumor cells while sparing normal cells. Nonetheless, these approaches are likely to yield important biologic and clinical data which will further the progress of lung cancer treatment.     

Stereotactic radiotherapy for brain metastases in patients with lung cancer; outcome and toxicity in clinical practice

BackgroundStereotactic radiotherapy (SRT) is an established modality for treating limited brain metastases (BMs). This study aimed to assess the real-life treatment outcome and associated prognostic factors for survival in a consecutive lung cancer cohort receiving SRT for BMs.Materials and methodsA retrospective review and analysis of patients with lung cancer with BMs treated with SRT in western Sweden between 2002 and 2017 were performed. Data were collected from patient charts and the radiotherapy dose planning system.ResultsOne hundred nine patients corresponding to 139 lesions were assessed; the majority were treated with single-fractionated SRT with 20 Gy. The median overall survival (OS) was 6.1 months, with a 12-month survival rate of 24%. The estimated overall disease control rate (DCR) was 84% at a median time of three months. On multivariate analysis, WHO performance status (PS) (p = 0.002) and smoking status (p = 0.005) were significant predictive factors for survival. Four percent of the patients experienced possible grade III–IV toxicity, and previously administered cranial radiation therapy was a significant independent factor (p = 0.03) associated with the risk of developing acute toxicity.ConclusionsSRT due to brain metastases from lung cancer is a well-tolerated treatment. When selecting patients suitable for treatment, PS and extracranial disease progression should be considered. Smoking cessation is probably of value even in this palliative setting. The goal of SRT for BMs is not only to improve survival but also to provide symptom relief, and future studies on SRT should assess patient-reported outcomes in addition to survival.     

Hypofractionated radiation therapy for early breast cancer: Follow up of a new treatment standard

AimTo assess the oncological outcomes of patients with early breast cancer treated with breast-conserving surgery and adjuvant hypofractionated radiation therapy.Methods and MaterialThis retrospective analysis included all patients ≥50 year of age with T1-2 N0 M0 breast cancer treated at our Radiation Oncology Unit between 2008 and 2011. Whole-breast radiation therapy was delivered to a dose of 42.5 Gy in 16 fractions, without boost. The primary outcome was local control.Results212 patients were identified. With a median follow up of 60 months, we found 3% local recurrence and 5.3% regional and/or distant recurrences. At the moment of data analysis, 17 patients had died. Out of 5 local recurrences, 2 had previously had a distant recurrence, both of them died. The other three were still alive at the last follow up. These results are comparable to those observed in Phase III trials that use this fractionation scheme.ConclusionsThe results obtained with this retrospective analysis are comparable to those obtained in large randomized trials. This data also supports the use of hypofractionated radiation therapy in Latin America. Hypofractionated radiation therapy for early breast cancer patients should be the standard adjuvant treatment.     

Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve

AimTo discuss current dosage for stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) patients and suggest alternative treatment strategies according to liver segmentation as defined by the Couinaud classification.BackgroundSBRT is a safe and effective alternative treatment for HCC patients who are unable to undergo liver ablation/resection. However, the SBRT fractionation schemes and treatment planning strategies are not well established.Materials and methodsIn this article, the latest developments and key findings from research studies exploring the efficacy of SBRT fractionation schemes for treatment of HCC are reviewed. Patients’ characteristics, fractionation schemes, treatment outcomes and toxicities were compiled. Special attention was focused on SBRT fractionation approaches that take into consideration liver segmentation according to the Couinaud classification and functional hepatic reserve based on Child–Pugh (CP) liver cirrhosis classification.ResultsThe most common SBRT fractionation schemes for HCC were 3 × 10–20 Gy, 4–6 × 8–10 Gy, and 10 × 5–5.5 Gy. Based on previous SBRT studies, and in consideration of tumor size and CP classification, we proposed 3 × 15–25 Gy for patients with tumor size <3 cm and adequate liver reserve (CP-A score 5), 5 × 10–12 Gy for patients with tumor sizes between 3 and 5 cm or inadequate liver reserve (CP-A score 6), and 10 × 5–5.5 Gy for patients with tumor size >5 cm or CP-B score.ConclusionsTreatment schemes in SBRT for HCC vary according to liver segmentation and functional hepatic reserve. Further prospective studies may be necessary to identify the optimal dose of SBRT for HCC.     

IGRT and motion management during lung SBRT delivery

Patient motion can cause misalignment of the tumour and toxicities to the healthy lung tissue during lung stereotactic body radiation therapy (SBRT). Any deviations from the reference setup can miss the target and have acute toxic effects on the patient with consequences onto its quality of life and survival outcomes. Correction for motion, either immediately prior to treatment or intra-treatment, can be realized with image-guided radiation therapy (IGRT) and motion management devices. The use of these techniques has demonstrated the feasibility of integrating complex technology with clinical linear accelerator to provide a higher standard of care for the patients and increase their quality of life.     

Stereotactic radiosurgery for patients with breast cancer brain oligometastases — molecular subtypes and clinical outcomes

BackgroundWe sought to determine the clinical outcomes of patients with breast cancer (BC) who had undergone stereotactic radiosurgery (SRS) for a limited number of brain metastases (BM) and to identify factors influencing overall survival (OS) and local control.Materials and methodsThe records of 45 patients who underwent SRS for 72 brain lesions were retrospectively evaluated. Statistics included the chi-squared test, Kaplan-Meier method, and the multivariate Cox model.ResultsThe median number of treated BM was 2 (range 1–10). Median OS from BM diagnosis and post-SRS were 27.6 [95% confidence interval (CI): 14.8–40.5) and 18.5 months (95% CI: 11.1–25.8), respectively. One-year and two-year survival rates after BM diagnosis were 55% and 41%, respectively. In a univariate analysis, the Luminal-B-human-epidermal-growth-receptor-positive (HER2+) subtype had the longest median OS at 39.1 months (95% CI: 34.1–44.1, p = 0.004). In an adjusted analysis, grade 2 [hazard ratio (HR): 0.1; 95% CI: 0.1–0.6, p = 0.005), craniotomy (HR: 0.3; 95% CI: 0.1–0.7; p = 0.006), and ≥ 2 systemic therapies received (HR: 0.3; 95% CI: 0.1–0.9, p = 0.028) were associated with improved OS. One-year and two-year intracranial progression-free survival rates were 85% and 63%, respectively. Four factors for a higher risk of any intracranial recurrence remained significant in the adjusted analysis, as follows: age < 50 years (HR: 4.2; 95% CI: 1.3–36.3; p = 0.014), grade 3 (HR: 3.7; 95% CI: 1.1–13.2; p = 0.038), HER2+ (HR: 6.9; 95% CI: 1.3–36.3; p = 0.023), and whether the brain was the first metastatic site (HR: 4.7; 95% CI: 1.6–14.5; p = 0.006).ConclusionIntrinsic BC characteristics are important determinants for both survival and intracranial control for patients undergoing SRS for oligometastatic brain disease.     

Normal tissue complication probability models for severe acute radiological lung injury after radiotherapy for lung cancer

PurposeTo derive Normal Tissue Complication Probability (NTCP) models for severe patterns of early radiological radiation-induced lung injury (RRLI) in patients treated with radiotherapy (RT) for lung tumors. Second, derive threshold doses and optimal doses for prediction of RRLI to be used in differential diagnosis of tumor recurrence from RRLI during follow-up.Methods and materialsLyman-EUD (LEUD), Logit-EUD (LogEUD), relative seriality (RS) and critical volume (CV) NTCP models, with DVH corrected for fraction size, were used to model the presence of severe early RRLI in follow-up CTs. The models parameters, including α/β, were determined by fitting data from forty-five patients treated with IMRT for lung cancer. Models were assessed using Akaike information criterion (AIC) and area under receiver operating characteristic curve (AUC). Threshold doses for risk of RRLI and doses corresponding to the optimal point of the receiver operating characteristic (ROC) curve were determined.ResultsThe α/βs obtained with different models were 2.7–3.2 Gy. The thresholds and optimal doses curves were EUDs of 3.2–7.8 Gy and 15.2–18.1 Gy with LEUD, LogEUD and RS models, and μ_d of 0.013 and 0.071 with the CV model. NTCP models had AUCs significantly higher than 0.5. Occurrence and severity of RRLI were correlated with patients’ values of EUD and μ_d.ConclusionsThe models and dose levels derived can be used in differential diagnosis of tumor recurrence from RRLI in patients treated with RT. Cross validation is needed to prove prediction performance of the model outside the dataset from which it was derived.