Lung cancer is the leading cause of cancer death in men and the second one in women worldwide (1). Recently, lung cancer diagnosis has greatly improved due to the wider use of total body computed tomography scan (CT scan) and metabolic diagnostic tools such as 18-F-fluodosossyglucose (18F-FDG) positron emission tomography. Recently, the role of the screening program in high risk patients for lung cancer has been well assessed (2), but concerns on resources, costs, and management of patients with abnormal screening, made its use difficult in the routine. Where the screening program has been correctly applied (3), the use of CT scan seemed to be able to anticipate stage I lung cancer if compared to chest radiography allowing a higher number of surgical radical treatment. This benefit in terms of clinical outcome was also showed in a recent update of the NELSON trial where the lung-cancer mortality for high risk persons was significantly lower among those who underwent volume CT scan screening than among those who did not (4). In the past, the American College of Chest Physicians (ACCP) clinical guidelines tried to identify different categories of lung nodules with different probabilities of malignancy suggesting that transthoracic biopsy or bronchoscopy should be performed even in patients with a high risk of surgical complications (5). However, taking into account the increasing number of new diagnoses of solitary pulmonary nodules, the real issue is to identify when an invasive procedure (such as a biopsy) that could be characterized by severe complications is really needed. Due to age, comorbidities, or poor lung functions, and considering that 2–3.5% of patients refused this procedure, almost 25% of patients with single pulmonary nodule will be deemed medically inoperable and consequently remain without pathological confirmation (6,7). Recently, the role of stereotactic body radiotherapy (SBRT) is becoming crucial, particularly in those patients at greater risk of surgical morbidity/mortality or candidate to sublobar resection. For this reason, the optimal therapeutic option (surgery vs. SBRT) should be offered after a multidisciplinary discussion. The role of empirical treatment with SBRT without a pathological confirmation have been increasing in this subset of patients, reaching almost 70% in some studies (8,9). Data from retrospective series showed that SBRT in patients without a histological confirmation have been encouraging (10-12). The aim of this narrative review is to evaluate the existing international literature about the role of ablative SBRT in treating solitary lung nodules without pathological confirmation.
We present the following article in accordance with the Narrative Review reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-21-39/rc).
A literature search in Medline was performed until April 2021 by one author (ED). Terms used were a combination of “solitary pulmonary nodule”, “radiotherapy”, “stereotactic body radiotherapy”, “pathological confirmation”, and “lung”. A total of 149 records were identified and screened. English language, full-text articles and presence of data about selection criteria in patients affected by solitary lung nodule not-histologically proven treated with radiation therapy, were inclusion criteria. No time limits were applied. Exclusion criteria were: case reports, abstracts, proceedings from scientific meetings, review and editorials. References listed in the screened articles were also evaluated and cross-referenced to ensure completeness. Studies including sub-cohort of patients treated with and without histological confirmation were included. At the end of the screening procedure, taking into account all the eligibility criteria, 8 studies were selected for the analysis and other 16 were retrieved from references of screened paper. Twenty-four studies were analyzed, and those more relevant will be discussed in our review (Table 1).
|Author||Year||Type||Nr Pts||Median Age||Nr Pts No Histology||Nr Pts Histology||PET (%)||Median Diam (mm)||Tot Dose [Gy] (Nr Fx)||Median BED||RT Techniques||3-yr LC (%)||3-yr OS (%)|
|No hystologically proven studies|
|Inoue (13)||2009||Retrospective||115||77||All||0||62||20||30–70 [2–10]||106||SBRT||–||100|
|Sakanaka (14)||2014||Retrospective||37||77||All||0||71||20||48 ||>100||SBRT, 3DcRT||94||74.2|
|Harkenrider (15)||2014||Retrospective||34||76||All||0||100||16||30–55 [3–10]||<100||SBRT||–||–|
|Wang (16)||2017||Retrospective||25||78||All||0||100||16||40–60 [2–5]||136||SBRT||78.8||70.2|
|Hasan (12)||2018||Retrospective||101||76||All||0||82||16||40–50 [4–5]||72–105.6||SBRT,3DcRT||94||45|
|Kowalchuk (17)||2020||Retrospective||91||78||All||0||100||20||20–60 [3–5]||132||SBRT, 3DcRT||–||–|
|Hystologically vs. No hystologically proven studies|
|Baumann (18)||2009||Phase II||57||75||19||38||14||45–66 ||113–211||SBRT||–||60|
|Verstegen (10)||2011||Retrospective||591||74||382||209||100||31||60 [5–8]||–||SBRT||–||–|
|Takeda (19)||2012||Retrospective||173||78||58||115||100||27||40 – 50 ||–||SBRT||87* 80§||74* 70§|
|Lagerwaard (9)||2008||Prospective||177||76||117||60||100||26||60 [3–5–8]||–||SBRT||93||84.7|
|Taremi (6)||2012||Retrospective||108||72||33||80||81||24||48–50–60 [4–10–3]||–||SBRT||–||–|
|Haidar (20)||2014||Retrospective||55||78||23||32||100||25||48–56 [4–5]||–||SBRT||94*° 91§°||30.2°|
|Fischer-Valuck (21)||2015||Retrospective||88||73||23||65||100||25||48–60 [10–12]||–||SBRT||–||59.9|
|Fujii (22)||2015||Retrospective||165||76||54||111||100||29* 19§||–||110* 112§||SBRT Proton||94*° 80§°||90* 73§|
|Murray (23)||2016||Retrospective||273||74||188||100||100||54–55–60 [3–5–8]||–||SBRT||95.7||38.6|
|Woody (24)||2017||Retrospective||740||–||223||517||100||22||50–60 [5–3]||105||SBRT||–||43|
|Wegner (11)||2018||Retrospective||196||76||100||96||100||16||48–50 [4–5]||100–105||SBRT,3DCRT||94||58|
|Zehentmayr (26)||2019||Retrospective||163||72||40||123||100||–||–||87–106||SBRT,3DCRT||n.r.||39.4°* 58.6° §|
|Fernandez (27)||2020||Retrospective||701||75||231||470||95||22||26–60 [1–10]||–||SBRT||–||83.6* 83.8§|
*, histologically proven; §, not histologically proven; °, median; n.r., not reached.
Characteristics of patients enrolled are reported in Table 1. All studies included but two (9,18), are retrospective. In six studies (12-17), only patients without pathological confirmation were included, while other 14 studies compared histologically proven and not populations in terms of clinical outcomes and safety (6,9-11,18,20-27). The studies included in the analysis were published between January 2009 and December 2019. Mean number of patients enrolled in the selected studies was 206 (range, 17–382). In nineteen of the 20 studies, authors declared to perform SBRT. Radiation therapy was delivered using proton or carbon ion just in a single study (22). Conversely, Temming et al. (25) and Wang et al. (16) delivered SBRT using CyberKnife. The median dimension of not histologically proven lesions was 20 (range, 16–28.4) mm. In all studies 18-F fluorodeoxyglucose CT-PET (18FDG) was used during the initial diagnostic assessment for the vast majority of patients (range, 62–100%). Main reasons for not proceeding to invasive hystopathological confirmation were: severe COPD, high risk of fatal bleeding, location of the primary tumor, patient’ refusal, cardiac comorbidities not suitable for anticoagulant suspension. Furthermore, peripheral lesions were treated more frequently than the central ones. A predictive model for the assessment of cancer probability was used only by Verstegen, Hasan, Sakanaka and Zehentmayr (10,12,14,26), while a combination of clinical and radiological characteristics was used in all the other analyses. Median follow up was 19.7 (range, 13–42) months. Doses delivered were very different, depending on several factors such as tumor dimension and localization, techniques, often also within the same cohort. Radiation therapy doses most frequently delivered were 40–60 Gy in 3–8 fractions using stereotactic techniques. In terms of efficacy, 3-year local control (reported in 55% of studies) was higher than 75%, while reported overall survival was more different ranging between 38.6% and 90% at three years. Overall toxicity reported was generally low, more than G3 were very rarely described (less than 2%) (23).
The present review focused on selection criteria in patients addressed to radiation therapy for solitary lung nodules in clinically diagnosed lung cancer.
Patel et al. (28) defined the solitary pulmonary nodule as a radiographic opacity up to 30 millimeters in diameter with at least two-thirds of its margins surrounded by lung parenchyma. As underlined in the evidence-based recommendations by the American College of Chest Physicians (ACCP) published in 2013 (5), the management of solitary lung nodules may strongly vary according to its dimension and radiological features. In the absence of a biopsy, performing adequate instrumental exams and collecting clinical information should help to estimate the probability of cancer. Notably, the recommendations stressed the importance of balancing benefits and harms of the different diagnostic procedures. Indeed, major complications appear to be very low after CT-guided transthoracic biopsy, accounting a risk of almost 5.7% (29), but the rate increases up to 40% (30-32) when considering all possible collateral effects. At the same time, the diagnostic yield of biopsies may vary widely (between 64% and 95%), thus exposing some patients to not justified risks without significant benefit.
For patients at high risk for complications (such as pneumothorax in severe COPD patients and fatal bleeding) secondary to diagnostic assessments, some quantitative models for the prediction of cancer probability have been developed. In the Swensen model (33) age, smoking status, history of extrathoracic cancers, nodule diameter, location, and presence of spiculations are combined. Furthermore, the Mayo Clinic model (34) is one of the most extensively validated model in the not-screened population, matching the Swensen model with the use of 18FDG-PET.
The use of those algorithms may help to select patients for SBRT without pathological diagnosis. However, a clear threshold of pre-test probability to treat patients with lung nodules without pathological confirmation using surgery or SBRT is not yet well defined. In the CHEST guidelines the authors stated that an active treatment approach could be reasonable when the pre-test probability of malignancy exceeded 65%. However, this finding is in contrast with the International Association for the Study of Lung Cancer (IALSC) recommendations that suggested a threshold of 85% (35).
Nowadays, merging information from anatomic and metabolic imaging yielded a higher diagnostic value (36). Louie et al. (37) and Senan et al. (38) added the 18-FDG-PET to the probability test and both identified a threshold of 85%. In our review we included also the study of Verstegen (10) that was the internal validation cohort of Louie model. In their report a comparative outcome analysis between proven and not proven patients was conducted. In patients without a pathological diagnosis the Swensen model for cancer probability assessment (33) was used resulting in a mean probability of malignancy equal to 92.5% (95% CI: 91.8–93.3%); furthermore 93.2% of these patients had a calculated probability of malignancy that exceeded 80%.
An interesting role of 18F-FDG-PET in the follow up was then suggested by Hasan et al. (12): indeed, its use may allow a radiologically confirmation of treated lesion, but also it may help the prediction of progression of disease. To date, this approach is not standardized being still under evaluation.
Actually, SBRT is recognized as an efficient and safe alternative to surgery showing high rates of local control in patients affected by early stage non-small cell lung cancer (NSCLC), comparable to surgery, but with a significant inferior morbidity (18).
In 2019, the Empiric Radiotherapy for Lung Cancer Collaborative Group published multi-institutional guidelines for the use of SBRT in patients with lung nodules without pathological confirmation (39). The authors focused on staging procedures, tools for predicting cancer probabilities and potential benefits of SBRT. They only analyzed the role of SBRT in treating peripheral lesions, because the central ones are usually candidate to surgery because of the high risk of severe toxicities. They suggested a pre-test threshold of 85% to candidate patients for local ablative treatment without having pathologically confirmed cancer; furthermore, they recommended moving for a local treatment based on size, radiological imaging and characteristics of the lesions. Authors also emphasized the need of biopsy prior SBRT whenever possible and strongly highlighted the crucial role of the multidisciplinary team in sharing a therapeutic choice in the context of “tailored” medicine.
The role of the multidisciplinary discussion on patients with suspicious early-lung cancer could be a point of strength requested by the main international guidelines, but the selection criteria are so variable between different Institutions, as observed in the studies collected in this review. Indeed, almost all studies reported not specific inclusion criteria for patients candidate to local “empiric” treatment. Moreover, no pre-test threshold was usually described. Only few authors (10,12,14,26) described the predictive model of cancer probability.
The role of predictive model and guidelines, as previously described, should help clinicians to weighting comorbidities and their life expectancy, in order to identify those patients candidate to invasive procedures for a pathological diagnosis and consequently, to local ablative treatment (surgery or SBRT).
In the comparative studies, patients without histological confirmation had smaller tumor diameter than those with pathological specimen (10,11,22). In Verstegen et al. (10), 591 patients were treated with SBRT with significant results in terms of local control (LC). No differences between both cohorts and no factors significantly correlate to overall survival (OS) after multivariate analysis. A subgroup analysis was then performed to assess differences in terms of clinical stage (T1 vs. T2) between the two groups, but no difference in OS neither in LC was found. Importantly, Inoue et al. found a statically significant difference (P<0.0005) in terms of OS in patients with a tumor size (diameter) of 5–20 mm (n=58) vs. 21–45 mm (n=57) (13). Some hypothesis could be made to understand the lack of difference in OS related to dimension, as reported in Verstegen et al. and Inoue et al. (10,13). In the Japanese cohort, the median follow-up was quite short (14 months), also including 11 patients with a follow up shorter than 4 months. For these reasons, definitive conclusions about OS are difficult, not being possible to completely exclude the option that benign lesions were treated in the group with a median smaller nodule dimension. Similar results were also reported in Sakanaka et al. (14), where patients with clinical T1a stage had a significantly higher OS and PFS than those presenting clinical T1b/T2a tumors. On the other hand, no differences in terms of LC were found. The same authors also reported a crude rate of relapse equal to 41%, occurring 36 months after treatment. It should be noted that the vast majority of the studies included in our review reported a median FUP inferior than 24 months, thus probably underestimating the overall incidence of relapse and cancer related death.
Clinical differences are very clear in the inclusion criteria used in the different studies. Hasan et al. (12) included patients mostly aged >70 with a smoking history characterized by >50 pack-year, oxygen therapy dependent and with a median predicted forced expiratory volume equal to 42%. This cohort of patients was not suitable for surgery and usually diagnosed by regular CT scan during the management of chronic obstructive pulmonary disease. Conversely, in the series of Verstegen et al. (10) patients were mostly defined as operable and diagnosed by the national screening program. These characteristics necessarily reflected the different results in terms of OS and may explain the low rate of OS in the paper published by Hasan et al. (12).
In elderly patients, SBRT was evaluated by Wang et al. (16). In a small series of 25 patients with more than 75 years and usually not suitable for to surgery (76%) due to comorbidities, 1-, 3- and 5-year local control and cancer specific survival were 100%, 78.8%, 65.7% and 100%, 81.3%, and 67.0%, respectively. Acute and late toxicity was very low. Similar results were reported in most of the studies analyzed (see Table 1) where 3-year local control and OS varied between 80–94%, and 54–90%, respectively.
Elderly patients with multiple comorbidities, such as poor pulmonary function, could be at high risk of complications when treated by ablative SBRT, causing an increased and not justified mortality. However, poor pulmonary functions seemed not to be associated to increased mortality or toxicity in patients treated with SBRT for early stage NSCLC (40). Verstegen et al. and Takeda et al. then confirmed these findings (10,19). As reported in Shaik et al. (41), the different results in terms of efficacy could be potentially affected by the presence of benign lesions in the cohorts of patients analyzed, particularly when nodules’ diameter was smaller than 2 cm. At univariate analysis, cancer specific survival and OS were better in patients without histological confirmation as reported in the SEER database series. Regarding these findings, Verstegen et al. (10) reported a 3-year local control superior than 90% with local failures observed in only 10 and 18 patients with a pathological or clinical diagnosis, respectively. In the meanwhile, taking into account that benign granulomas were considered unlikely to shrink after SABR, the proportion of patients with stable disease after SBRT in the not pathologically confirmed cohort were 3.5% and 3.7% at 6 and 12 months, very similar to those with pathological confirmation.
Also the presence of previous cancer diagnosis may help in decision-making, but sometimes it could led to confounding results: in Verstegen et al., 34% of total patients presented a previous history of cancer and approximately 50% of them had previously been treated for lung cancer (10).
Other confounding factors could be the presence of lesions other than NSCLC: indeed it is estimated that 4–12% of patients with solid solitary pulmonary nodule may have a SCLC diagnosis (42), so that it could be questionable if a “radical” treatment with SBRT should be used.
When choosing the optimal radiation treatment, the absence of pathological confirmation plays an important role: in Woody et al. (24), despite the selection bias, an increased rate of local failure was reported in patients with squamous cell carcinoma treated with SBRT. So, the authors advocate different schedules depending on different histology.
Finally, one of the main limits of all the studies selected was the long time of accrual that may have a crucial impact on the different radiation therapy schedules. Recently, several authors (40,43) supported the important role of biologically equal dose (BED)10 >100 Gray (Gy) to improve OS and local control in NSCLC treated with SBRT. However, in the studies analyzed (when reported) median BED10 was usually superior to 100 Gy, but many patients received inferior doses. In the cohort of Zehentmayr et al. (26) the minimum BED10 used was 15% lower, while only 15% of patients had a BED10 <100 Gy in Inoue et al. (13).
Our review is characterized by several limitations. First, the vast majority of international literature was characterized by a significantly different selection criteria and treatments delivered, probably due to the long period of accrual and the retrospective nature of each study. Second, clinical outcome reported were very different, due to several reasons such as the different populations analyzed in terms of comorbidities and performance status or the different tumor features. Similar limitations were encountered in the comparative studies (Table 1), even if the cohorts were apparently more homogenous. Notably, results in terms of efficacy and clinical outcomes were similar between comparative and not-comparative studies, while toxicities were usually very low.
In conclusion, the introduction of validated probability test together with the wider diffusion of metabolic imaging such as 18 FDG PET CT scan may facilitate the clinical diagnosis of cancer in patients with solid solitary pulmonary nodules. Furthermore, clinical outcomes following SBRT seem to be similar in patients either with or without a pathology-proven diagnosis of early stage lung cancer. Prospective well-designed clinical trials are needed in this subset of patients so that stronger recommendations may be proposed in patients with not proven solid solitary pulmonary nodule.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Duilio Divisi and Roberto Crisci) for the series “Solitary Pulmonary Nodule” published in AME Surgical Journal. The article has undergone external peer review.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-21-39/rc
Peer Review File: Available at https://asj.amegroups.com/article/view/10.21037/asj-21-39/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-21-39/coif). The series “Solitary Pulmonary Nodule” was commissioned by the editorial office without any funding or sponsorship. EDA reports personal payments for lectures from Nestle’, MSD, Astra Zeneca, and support for attendance meeting. AB reports payment for advisory board, manuscript writing, educational events, and conference presentations from ATREA ZENECA, payment for conference presentations from MSD and ASTELLAS, support for attending meetings and/or travel from ASTRA ZENECA, MSD, ASTELLAS, IBSEN and TAKEDA. LR reports honoraria for presentations from ASTRA ZENECA and MSD. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Cite this article as: D’Angelo E, Lauro C, Rubino L, Bruni A. Non-invasive approach to treat primary solid solitary pulmonary nodule: a narrative review by the radiation oncologist perspective. AME Surg J 2022;2:26.