Study
Year
# patients
OS @ 2–3a (%)
LC @ 2–3a (%)
Nagata et al. [30]
2005
45
75
98
Baumann et al. [31]
2009
57
60
92
Fakiris et al. [32]
2009
70
43
88
Ricardi et al. [33]
2010
62
57
88
Timmerman et al. [34]
2010
55
56
98
Bral et al. [35]
2011
40
52
84
Prospective studies
329
56.2
91.2
Senthi et al. [70]
2012
676
55
95
Guckenberger et al. [38]
2013
582
47
80
164a
62a
93a
Grills
2013
859
51.5
94
Retrospective studies
2,049
51.3
91
Based on these findings, the 1.2013 version of the NCCN Guidelines [39] as well as the ESMO Clinical Practice Guidelines [40] consider SBRT as superior to conventionally fractionated radiotherapy and as the standard of care for medically inoperable patients.
SBRT in Medically Inoperable Patients Compared to Radiofrequency Ablation
Radiofrequency ablation (RFA) has been introduced as a minimally invasive option into the treatment of stage I NSCLC. No study performed a direct comparison between SBRT and RFA but a recent literature review reported improved local tumor control, cancer specific survival and overall survival after SBRT compared to RFA [41]. Additionally, toxicity and 30-day mortality [42] were lower after SBRT resulting in the conclusion, that SBRT should be proposed as the first non-surgical treatment to high-risk patients.
SBRT in Medically Operable Patients Compared to Surgery
Lobectomy is the evidence-based standard of care for operable stage I NSCLC patients: a randomized trial described improved local tumor control and OS after lobectomy compared to wedge resection [43]. Whether sublobar anatomical resection (segmentectomy) is equivalent to lobectomy is discussed controversially [44] but results of segmentectomy appear comparable especially in stage IA patients [45].
Based on the promising outcome of SBRT in medically inoperable patients, three randomized trials comparing SBRT with lobectomy (ROSEL, STAR) or sublobar resection (ACOSOG Z4099/RTOG 1021) have been started but all three studies closed early due to poor accrual: only 68/2,410 (2.8 %) patients were enrolled leaving us without level I evidence.
Because of this lack of level I evidence, several studies used statistical methods like matched pair analyses and propensity score matching were performed to correct for imbalances in patient characteristics between SBRT and surgery. Grills et al. performed a single-institution comparison between SBRT and wedge resection and reported improved local tumor control after SBRT with no differences in cancer specific survival; OS was better in the surgical cohort, which was explained by older age and increased comorbidities in the SBRT patients [46]. The previously cited US population based analysis showed no difference in OS and cancer specific survival for SBRT versus sublobar resection and SBRT versus lobectomy [20]. Puri et al. reported identical cancer specific survival between SBRT and surgery (lobectomy in 80 % of the patients) [47]. OS appeared better after surgery compared to SBRT but was not statistically significant and this potential difference was explained by increased pulmonary comorbidities in the SBRT cohort, which was not corrected in the propensity score matching. Verstegen et al. compared SBRT and VATS lobectomy in 128 patients after propensity score matching of gender, age, clinical tumor stage, tumor diameter, location of the tumor, pretreatment tumor histology, lung function (FEV1%), Charlson comorbidity score and WHO performance score [48]. Locoregional control was better after SBRT with no differences in freedom from progression and OS.
Few studies reported outcome after SBRT when patients were considered as suitable for surgical resection but surgery was refused. Two Japanese and Dutch studies described excellent OS of 70 % after 5 years (n = 87) [49] and 85 % at 3 years (n = 177) [50], respectively, results which compare well to OS after lobectomy.
Consequently, SBRT is a viable treatment option in the situation, when lobectomy is refused by the patients. Additionally, SBRT appears equivalent to sublobar resection and both options with their specific pros and cons should be discussed with the patient.
Toxicity and Quality of Live After Lung SBRT
The majority of patients are referred for SBRT because of severe pulmonary comorbidities and their poor pulmonary function does not allow surgical resection. Consequently, pulmonary toxicity is a concern in lung SBRT. The incidence of symptomatic radiation induced pneumonitis is consistently below 10 % in SBRT of lung tumors <5 cm in diameter and peripherally located. Higher mean lung doses and a larger low-dose spread have been reported to be correlated with the risk of radiation-induced pneumonitis [51, 52]. Additionally, pulmonary function is stable after SBRT with a loss of <10 % (FEV1, DLCO) within 24 months after treatment [25]. Pulmonary toxicity was not increased even in patients with very poor pre-SBRT pulmonary function [25] and with severe COPD GOLD III-IV [53]. Patients with pre-existent pulmonary fibrosis might be at increased risk for radiation induced pneumonitis
Chest wall toxicity (myositis, neuralgia, rip fracture, subcutaneous fibrosis, skin ulceration) has been reported when tumor are located close to the respective normal tissue structures. Doses >30 Gy to the chest wall haven been correlated with these toxicities and the volume of the chest wall exposed to these doses should be minimized by conformal treatment planning [54–56].
Severe toxicity to the brachial plexus (neuropathic pain, motor weakness, or sensory alteration), large bronchi (stenosis with pulmonary atelectasis) and esophagus (ulceration, perforation, fistula) has been reported but these toxicities are rare. Limiting the total dose to the plexus to <26 Gy in 3–4 fractions can minimize the risk of toxicity [57]. The issue of SBRT for centrally located tumors close to the esophagus and large bronchi is discussed below.
Clinical Practice of SBRT for Early Stage NSCLC
Lung SBRT is a multi-disciplinary task, involving all disciplines dealing with the diagnosis and treatment of lung cancer. Within the radiotherapy department, SBRT needs to be implemented and practiced by a multi-professional team consisting of the Radiation Oncologists, Medical Physicists and Radiation Technologists: all members of the team should have undergone dedicated training in SBRT. The development of written protocols is an essential component of the quality assurance.
Any treatment of NSCLC should be discussed within an interdisciplinary tumor board and this applies to SBRT as well. A careful assessment of the performance status is important to provide a sensible therapy concept. Perioperative morbidity is associated with older age and the presence of co-morbidities [4, 61]. Therefore, pulmonary function tests, cardiac assessment and performance status are recommended clinical assessments before estimating the operative risk and adjusting the treatment to the patient individual medical and personal situation.
In the following part, some clinical and technical issues of SBRT for stage I NSCLC will be discussed
SBRT Without Histopathological Confirmation of Disease
Histological confirmation of disease is recommended prior to any treatment for NSCLC. Transbronchial biopsy or transthoracic needle aspiration are primary methods. Nevertheless sometimes it is impossible or at high risk to prove malignancy because of the medical and/or pulmonary co-morbidities. In such cases radiological criteria of malignancy should be consulted. Swensen et al. [62] described a prediction model to estimate the probability of malignancy in solitary pulmonary nodules: clinical and radiographic characteristics are used to estimate the likelihood of malignant disease. Inclusion of FDG-PET imaging might further improve the accuracy of the prediction model [63, 64]. If malignancy is highly likely based on the described criteria, immediate SBRT without histopathological proof is justified [65], which is also standard practice in thoracic surgery [66]. Repeated imaging to evaluate the growth pattern is an option in boarderline risk-of-malignancy patients but might put the patient at risk for disease progression in the time interval [67].
Staging of Disease
In SBRT, only the primary tumor is treated with high irradiation doses and no elective nodal irradiation is performed. Consequently, a whole body FDG PET scan should be performed in all cases for exclusion of nodal metastases. The added value of FDG PET lies in the higher diagnostic accuracy for the detection of nodal metastases compared to CT-based staging (negative predictive value 90 %) [68, 69]. The FDG PET scan should be not older than 6 weeks to avoid disease progression in the interval between staging and treatment. In case of pathologic FDG uptake in mediastinal lymph nodes, further evaluation, e.g. by EBUS/EUS are mandatory. If the situation is still unclear, a mediastinoscopy may be necessary. After FDG PET based staging and exclusion of nodal disease, lymph node metastases are observed in about 10 % of the patients [70].
Technology of SBRT Planning and Delivery
Because lung tumors can move by several centimeters due to breathing of the patient, a motion management strategy is required for all patients [71]. This starts at treatment planning, where patient individual tumor motion is assessed by 4-dimensional CT (4D-CT), also known as respiration-correlated CT [72, 73]. Additionally, 4D-CT reduces motion artifacts and systematic errors introduced due to the non-representativeness of the captured breathing position [74, 75]. Various motion compensation techniques have been developed and are available in clinical practice – gating, tracking, breath-hold irradiation mid-ventilation concept, internal target volume concept – all with specific pros and cons [76]. It is of utmost importance, that breathing motion is consistently integrated into all steps of SBRT planning and delivery, especially into the image-guidance procedure. Though patient-specific motion management is strongly recommended, no benefit for advanced motion management strategies like gating or tracking has been found for patients with tumors moving <10–15 mm in amplitude, the majority of the patients [76, 77].
Treatment planning can be performed using 3D-conformal radiotherapy (3D-CRT), Intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). All published prospective trials have used 3D-CRT but IMRT and VMAT have the potential to increase dose conformity and homogeneity and reduce treatment delivery times [78]. Type B algorithms achieve accurate dose calculation especially at the interface of lung tissue and soft tissue and their use is highly recommended [79]. Monte Carlo dose calculation algorithms achieve most accurate results but differences to collapsed cone algorithms appear small.
The position of lung tumors within the patient varies from day to day and is different between the time of treatment planning and treatment delivery. This variation of the tumor position is not caused by patient misalignment but is rather a relative motion of the pulmonary tumor within the lung. The magnitude of this variability is 5–7 mm on average and up to several centimeters in individual patients [80, 81]. To avoid missing the tumor at the time of treatment delivery with the consequence of decreased local tumor control, daily pre-treatment image-guidance (IGRT) is mandatory [77]. Various IGRT technologies are available, which can be broadly categorized into planar and volumetric imaging. Major advantage of planar imaging is the possibility to perform repetitive verification during treatment delivery; however, implanted fiducial markers are required for visualization of the soft-tissue tumor with the associated risk of pneumothorax. Major advantage of volumetric imaging is the possibility not only to verify the tumor position but also the position of critical organs at risk close to the tumor, e.g. the spinal cord.
SBRT Irradiation Dose and Fractionation
Because of large differences in single-fraction doses between studies, comparison of physical doses is less meaningful but doses are converted to biological effective doses (BED) to account fractionation effects [82]. Independently, several groups demonstrated a clear dose-effect relationship for local tumor control [83–86]: a minimum PTV dose of >100 Gy BED (biological effective dose; α/β ratio 10 Gy) achieved local tumor control >90 %. It could be demonstrated that this dose-dependent increase in local control translates into improved OS [83, 87]. A recent meta-analysis reported best OS for medium-to-high SBRT doses of 83.2–146 Gy BED; OS was worse after SBRT with >146 Gy BED indicating a detrimental effect of excessively high SBRT doses [88].
This dose of minimum 100 Gy BED is usually delivered in 1–10 fractions but reimbursement rules have resulted in a widespread use of 5 or fewer fractions in the United States. The most frequently used fractionation scheme is 3 fractions of 18 Gy as PTV encompassing dose [89]. Whereas safety of such high single and total doses has been demonstrated for peripheral lung tumors of usually <5 cm size, high rates of severe toxicity have been reported in centrally located tumors with critical organs like the esophagus and large bronchi close by [90, 91]. In contrast, safety of SBRT for centrally located tumors has been reported if the total dose is delivered using a larger number (5–10) of treatment fractions of a lower single-fraction doses [92], a concept which is called risk adapted fractionation. Eight fractions of 7.5 Gy as PTV encompassing dose is the most frequently used and best-evaluated fractionation scheme for centrally located tumors [93].
Response Assessment and Follow-Up
Regular chest CT follow-up every 3–6 months for 2–3 years and annually thereafter is recommended for early detection of secondary primary lung tumors and local recurrences amendable for salvage therapy. Localized acute (asymptomatic) pneumonitis and late pulmonary fibrotic changes are regularly observed in the follow-up CT images and the radiological appearance of the fibrotic changes may remain dynamic for several years [94]. Anyone involved in the response assessment should be aware of these normal tissue reactions to SBRT doses to avoid misinterpretation as local recurrence. An algorithm for follow-up has been proposed, which identified high-risk CT morphological features of local recurrence: enlarging opacity at primary site, sequential enlarging opacity, enlarging opacity after 12-months, bulging margins of the opacity, loss of a linear margin, and loss of air bronchograms [95]. In the presence of such high-risk CT features, an FDG-PET should be acquired and a SUVmax ⩾5 is predictive for local recurrence.
Salvage treatment of isolated local recurrences has been performed very rarely and both salvage surgery and SBRT have been described. Salvage surgery was reported as safe in two studies with 5 [96] and 7 [97], where significant SBRT-related adhesions were found in none of the patients; re-SBRT should be restricted to peripherally located tumors [98].
Summary
SBRT is an evidence-based treatment option for patients with stage I NSLCLC. Prospective and retrospective studies reported consistent results of SBRT for stage I NSCLC: local tumor control exceeding 90 % and overall survival mainly limited by the comorbidities of the patients. Safe practice of SBRT requires, that it is performed by a multi-professional team experienced and trained in SBRT and image-guided radiotherapy. It is essential that patient selection to SBRT treatment is discussed in multi-disciplinary tumor boards considering the perioperative risk of the patient and patient preference.
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