Cancers | Free Full-Text | Differences between Survival Rates and Patterns of Failure of Patients with Lung Adenocarcinoma and Squamous Cell Carcinoma Who Received Single-Fraction Stereotactic Body Radiotherapy

Lung cancer is the leading cause of cancer-related mortality nationwide [1]. Approximately 230,000 individuals in the United States are diagnosed annually with lung cancer, resulting in nearly 135,000 deaths annually [2]. Lung cancer classifications are derived from the World Health Organization, and approximately 85% of all lung cancers are non-small cell lung cancer (NSCLCs). Adenocarcinoma histology accounts for approximately 50% of NSCLC diagnoses, followed by squamous cell carcinoma at 30% [1].

For medically operable patients with early stage lung cancer, surgical intervention is the preferred treatment modality. For patients who are medically inoperable or decline surgery, stereotactic body radiation therapy (SBRT) provides a highly conformal, tumoricidal radiation dose to thoracic tumors [3]. SBRT can be applied in one to five treatments, as well as hypofractionated regimens, for patients with early stage node-negative NSCLC who are not candidates for surgical intervention [4]. Prospective SBRT trials in medically inoperable and select operable patients with early stage NSCLC demonstrate a 3-year overall survival ranging from 43% to 95% with loco-regional control of up to 98% at 3 years [5].

The expediency of single-fraction SBRT was particularly highlighted during the coronavirus disease 2019 (COVID-19) outbreak, during which single-fraction SBRT was utilized to a higher degree to treat NSCLC patients [6,7,8]. The fewer treatment fractions correspond to an approximately 40% lower cost associated with single-fraction SBRT compared to the more traditional NSCLC fractionation of three fractions [6]. The adoption of single-fraction SBRT for NSCLC has still been relatively limited due to a multitude of factors, including a lack of understanding about its toxicity and efficacy, as well as a paucity of research pertaining to SBRT outcomes based upon the histological subtypes of NSCLC [9].

The potential impact of histological subtypes of NSCLC, either adenocarcinoma (ADC) or squamous cell carcinoma (SCC), on SBRT outcomes remains unclear. Kita et al. reported that the risk of LR after SBRT was higher for SCC than for ADC after applying a four-fraction regimen [10]. Additionally, Woody et al. found that SCC patients were significantly more likely to experience LR after employing five-fraction SBRT [11]. We aimed to investigate the utility of a single-fraction SBRT regimen for NSCLC in order to further our understanding of how to optimize SBRT treatments on the basis of a patient’s histology.

This absence of the impact of histology on LF with SF-SBRT contrasts with prior studies that have shown that LF was significantly higher in SCC versus ADC treated with five-fraction SBRT. Woody et al. reported that the 3-year cumulative incidence of local failure for SCC was significantly higher, 18.9% versus 8.7% (p = 0.008), than for ADC following 50 Gray (Gy) SBRT in five fractions [11]. Similarly, Kita et al. found that SCC histology had a hazard ratio of 2.41 (p = 0.012) for local failure [10]. Kita et al. also reported a multivariate subgroup analysis based on tumor sizes ≤2.5 cm and >2.5 cm; the authors reported that in the >2.5 cm group, SCC was an independent factor for local failure (HR 2.61, p = 0.036) [10]. Our analysis demonstrated a median SCC tumor size of 1.9 cm with no significant change in local failure with increasing size, which is concordant with the findings of Kita et al. [10]. In addition, Baine et al. also found SCC to be a risk factor for local failure after SBRT for early stage NSCLC [20].

A number of prior studies have demonstrated that SCC is more radiosensitive than other histologies [21,22,23,24]. Our study suggests relatively a similar radiosensitivity between SCC and ADC in the lung, reflected in the similar local failure rates in our patient population. More importantly, our results suggest that a therapeutic strategy for distal control is more important for cancer control in the ADC group than in the SCC group.

Therapeutic strategies designed to control distant metastases post SBRT, outlined by the ESTRO/ACORP guidelines for the treatment of NSCLC with SBRT, do not take the neoplastic histology into account [25]. In order to control the higher rates of DF in ADC that our study identified; we postulate that future studies will investigate the role of systemic therapeutics alongside SF-SBRT. Potential therapy regimens include utilizing SBRT with neoadjuvant immunotherapy [26,27,28]. Immunotherapy and SBRT have been shown to exhibit a synergistic affect when used together in the treatment of NSCLC [29,30]. Additionally, the NEOSTAR clinical trial found that monoclonal antibodies, when paired with chemotherapy, induce greater pathologic response rates when compared with chemotherapy alone in the treatment of NSCLC [31]. Future clinical trials could aim to evaluate the impact of such systemic regimens with SF-SBRT.

The radiobiological mechanisms contributing to differential distal failure in ADC due to SF-SBRT is unclear. Park et al. stated that single-fraction doses of higher than 10 Gy cause severe vascular damage to the tumor, which makes the tumor environment hypoxic, acidic, and deprived of nutrients when compared to a traditionally fractionated treatment regimen [32,33]. Future studies elucidating the differences in tumor biology based on histology could lead us to better understand these patient outcomes.

Data from multiple trials and analyses show no difference in NSCLC outcomes in terms of SF- versus fractionated-SBRT [9,16,29,34]. In addition, based on 2009 Medicare reimbursements, SF-SBRT for NSCLC was approximately 40% less expensive compared to three-fraction SBRT [6]. If confirmed in other analyses, this excellent local control of SCC by SF-SBRT, which is not maintained with multi-fraction regimens, may be added to the reduced cost and increased patient convenience as a reason to choose single-fraction SBRT. There are also data suggesting that SF-SBRT may have different patterns of failure than multi-fraction regimens [16,17]. Siva et al. reported that single-fraction SABR patients with primary renal cell carcinoma appear to be less likely to progress distantly or die of cancer compared to multi-fraction SABR [29].

Our study is limited by its retrospective nature and as it is a single-institution study. In addition, while this study incorporates NSCLC histology, it does not consider the pathological subtypes of adenocarcinoma. One subtype, lepidic pattern adenocarcinoma, has been noted to be indolent and less likely to metastasize when compared with other subtypes [35,36]. Furthermore, toxicity was not contemporaneously captured in our database and, therefore, is not quantitated. However, qualitatively, the toxicity of single-fraction SBRT (including in the chest wall) is quite low in our experience. This is consistent with prospective data [9,37].