Abstract
Background/Aim: Many patients with non-small cell lung cancer (NSCLC) receive palliative radiotherapy (RT). Several factors were analyzed to aid in prescribing an optimal treatment for these patients. Patients and Methods: This prospective observational multicenter study investigated several potential factors for associations with overall survival (OS) in 61 patients with NSCLC receiving palliative RT with or without chemotherapy (CT). Investigated factors included age, sex, performance status, history of smoking or alcohol, hemoglobin, co-morbidities, different clinical symptoms, and quality-of-life aspects. Results: Median OS was 10.8 months, and OS rates at 6, 12, and 24 months were 58.5%, 42.5%, and 28.4%, respectively. On multivariate analysis, RT alone (without CT), RT doses ≤30 Gy, advanced tumor stage (stage IV), and poor emotional functioning at diagnosis were associated with significantly worse OS. Conclusion: Patients with NSCLC assigned to palliative RT may benefit from RT doses >30 Gy and additional CT. Sequential CT appears preferable, since concurrent CT increases esophageal toxicity.
- Non-small cell lung cancer
- palliative radiotherapy
- overall survival
- prognostic factors
- prospective study
Non-small cell lung cancer (NSCLC) accounts for approximately 90% of all lung cancer diagnoses (1). 40% of patients present symptoms originating in the chest, such as dyspnea, cough, pain, or hemoptysis. At diagnosis, more than 50% of patients have distant metastases (2). The prognosis of patients with NSCLC not amenable to curative treatment is poor. The median overall survival (OS) times without treatment or with platinum-based chemotherapy (CT) are seven and 8-10 months, respectively (3). In these patients, palliation of symptoms is essential to maintain an acceptable quality-of-life (QoL). Palliative thoracic radiotherapy (RT) is a therapeutic option for control of symptoms and tumor-derived complications that impair quality of life (QoL). The treatment scheme should be adapted as far as possible to the individual characteristics of the patients, but an optimal total dose and fractionation regimen has not yet been established.
A recent systematic review did not find consistent results showing that long-course radiation regimes schemes provided better or longer lasting palliation when compared to short-course regimens (4). Furthermore, there were modest improvements in survival associated with RT regimens using higher biological doses. This fact is important, considering that the prescription of high doses can increase toxicity, especially in the case of the frail or elderly, or in patients with comorbidities. Therefore, there is currently no evidence for the best regimen that provides longer-lasting symptomatic relief or improves survival. The objective of our study was to describe new factors that may aid in the prescription of an optimal palliative RT regimen in patients with NSCLC not amenable to curative treatment. To this end, we carried out an analysis of clinical factors derived from the patient, as well as factors derived from radiotherapy treatment, which influence the OS of patients with NSCLC treated with palliative intent.
Patients and Methods
This prospective observational multicenter study consecutively included all patients diagnosed with NSCLC, treated with RT with palliative intent between January 2013 and October 2018. Written informed consent was obtained from each patient. This study was approved by the Institutional Ethics Committees (study code EPA2015028) and was carried out in accordance with the principles of the Declaration of Helsinki. Inclusion criteria were as follows: Patients >18 years, diagnosed with NSCLC in locally advanced or metastatic stages, who presented symptoms derived from local (pulmonary) progression evaluated by a multidisciplinary committee, with indication for palliative RT with or without CT (sequential or concomitant). Total radiation doses given as equivalent doses in 2 Gy fractions (EQD2) were ≤50 Gy. The exclusion criteria included pregnancy, previous treatment with thoracic RT, pulmonary recurrence, or history of another malignancy.
Patient evaluation and treatment. Therapeutic decisions were made by a multidisciplinary tumor board at the corresponding participating centre. Prior to the start of RT, a clinical record was completed, including clinical and treatment-related variables, categorized as follows: Age (<65 vs. 65-75 vs. >75 years), Karnofsky performance score (KPS <70 vs. ≥70), pretreatment weight loss (yes vs. no), diabetes mellitus (yes vs. no), chronic obstructive pulmonary disease (COPD) (yes vs. no), presence of heart disease (yes vs. no), tumor stage (IV vs. II-III), alcohol consumption (yes vs. no), smoking habit (smoker vs. ex-smoker; intensity of smoking habit: ≤30 vs. 31-75 vs. >75 pack years), pre-treatment hemoglobin level (<12 vs. ≥12 g/dl), existence of pre-treatment thromboembolic events (yes vs. no), type of treatment (RT + concomitant CT vs. RT + sequential CT vs. RT alone), RT dose (EQD2 ≤30 vs. >30 Gy), CT (yes vs. no) (5-8).
Additionally, as a possible relationship between pre-treatment QoL and prognosis has been documented in the literature, patients were asked to complete (at baseline evaluation) the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire QLQ-C30 and the QLQ-LC13 lung cancer-specific module (9). Functional scales and symptom scores were categorized according to the score obtained pre-treatment (0-100) in the following categories ≤33.3 vs. 33.3-66.6 vs. >66.6 points (10).
Treatment. Treatment planning was performed in the supine position, and a vacuum sealed cradle was used to immobilize the patient when it was considered necessary. A contrast-enhanced computed tomography scan (with a slice thickness of 0.5 cm) was performed, covering the neck and both lungs from the atlas (C1) to the second lumbar level (L2).
Radiotherapy treatment planning was carried out using a 3-dimensional (3D) conformal radiotherapy, volumetric modulated arc therapy (VMAT), or intensity modulated radiation therapy (IMRT), after defining the treatment volumes. In summary, the primary tumor (GTV_P) and/or the macroscopically involved lymphadenopathy (GTV_N) were outlined by radiological imaging, including suspicious tumor lesions seen by endoscopy. The GTV (primary and lymphadenopathy) was expanded by 6-8 mm to obtain the clinical target volume (CTV), which in turn was expanded by 10 mm laterally and vertically to obtain the planning target volume (PTV). Palliative RT treatment could be given with sequential or concomitant CT at the discretion of the responsible Medical Oncology service. In the design of the radiotherapy treatment, an effort was made to apply the minimum possible dose to surrounding healthy tissues, following the international Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) recommendations (11).
Follow-up. Patients were followed up weekly during RT, and every three months after completion of RT. Acute toxicity (up to three months after RT) and late toxicity (occurring from the third month after completion of RT) were categorized according to the CTCAE, version 5.0 (12).
The influence on survival of the following variables was analyzed: Age, sex, tumor stage, KPS, toxic habits, comorbidities, hemoglobin levels, pre-treatment weight loss and pre-treatment QoL scores from the EORTC QLQ-C30 and QLQ-LC13 questionnaires (13). High scores on the global health and function status scales (both ranging between 0 and 100 points) indicated a better QoL, while on the symptoms scale this would indicate a decreased QoL. The impact of treatment-dependent factors, such as radiation dose and addition of chemotherapy on OS, was also analyzed.
Statistical analysis. The data were analyzed using the Statistical Package for the Social Sciences (SPSS, version 23.0; IBM Corp, Armonk, NY, USA). Continuous variables are expressed as median and range, while categorical variables are described as frequencies and percentages. The main outcome was the assessment of OS of the population. The analysis was performed by comparing Kaplan–Meier curves. The time interval considered for calculating OS was the time elapsed between the end of radiotherapy treatment until the date of death (from any cause), or date of last follow-up. Analyses were carried out regarding the impact of clinical and treatment-dependent variables on OS; continuous variables were categorized for evaluation. To establish the cut-off point for statistical analysis of the continuous variables, we based our study on the significant cut-off points for these variables previously described in the literature (7-10).
To identify which clinical or treatment-related factors are predictive of OS, univariate Cox logistic regression analysis was used. Variables with p-values <0.1 in the univariate analysis were additionally included in a multivariate analysis (stepwise non-automatic model) to evaluate whether they are independent variables. Cox regression analysis was performed to calculate the hazard ratio (HR) and the confidence interval (CI). Statistical significance was set at p<0.05.
Results
A total of 61 consecutive patients with NSCLC who received palliative RT with an EQD2 ≤50 Gy were enrolled. The median age was 75 years (range=42-88 years) with 85% of the cohort being ≥65 years old. Fifty-four patients (88.5%) were male, and 14 patients (23%) had a KPS <70%. A large number of our patients suffered from diseases that had an impact on their health status, including COPD in 30 patients (49.2%), diabetes mellitus in 24 patients (39.3%), and heart disease in 23 patients (37.7%). Squamous cell carcinoma was the most common histological subtype (60.7%). The patient characteristics are shown in Table I.
Patient characteristics.
The 3D RT technique was used in 54 patients (88.5%). The median RT dose (EQD2 of 42.5Gy for tumor cell killing) was 39 Gy (range=12-50 Gy), with a median number of 13 fractions (range=2-28 fractions). Twenty-seven patients (44.3%) received RT alone, whereas 34 patients (55.7%) received additional treatment with CT (33 patients) or surgery (one patient). CT was administered as a sequential treatment in 27 of the 33 patients. CT was platinum-based in 29 patients. In five patients, other agents were used including paclitaxel, pemetrexed, nivolumab, docetaxel, or gemcitabine.
Median follow-up in the entire cohort was 6 months (range=1-55 years) with a median OS of 10.8 months (95%CI=5.2-16.4 months). OS rates at 6, 12, and 24 months were 58.5%, 42.5%, and 28.4%, respectively (Figure 1). Several factors were significantly associated with OS on univariate analyses (Table II and Table III), namely tumor stage (p=0.009), RT dose (p=0.001), and addition of CT (p=0.001), as well as the QoL aspects, such as role functioning (p=0.035), emotional functioning (p=0.002), and physical function (p=0.001). According to the multivariate analysis (Table IV), patients who received RT without CT (Figure 2), received RT doses ≤30 Gy (Figure 3), or had a stage IV tumor, and patients with low emotional functioning at diagnosis had a higher risk of mortality. Thus, these factors were considered independent predictors of OS.
Kaplan–Meier curve of overall survival of the entire cohort.
Median overall survival (OS) related to clinical, tumor-related and treatment-related characteristics (univariate analyses).
Median overall survival (OS) related to quality-of-life aspects (univariate analyses).
Results of the multivariate analysis of overall survival.
Comparison of radiotherapy alone (Chemo: No) and radiotherapy supplemented by chemotherapy (Chemo: Yes) with respect to overall survival (Kaplan–Meier analysis).
Comparison of radiation doses ≤30 Gy vs. >30 Gy with respect to overall survival (Kaplan–Meier analysis).
Toxicity. The most frequent acute toxicity was esophagitis, which occurred in 24 of 60 evaluable patients (40.0%). Of this group, 21 patients (87.5%) had grade I-II esophagitis and three patients (12.5%) grade III-IV esophagitis. Subacute toxicity in terms of pneumonitis was observed in 23 of 60 patients (38.3%), of whom 14 patients had grade I-II (60.9%), and nine patients grade III-IV pneumonitis (39.1%) (Table V). Regarding late toxicity, eight of 57 patients (14.0%) had grade I or II pneumonitis, eight of 57 patients grade II or IV pneumonitis, and four of 61 patients (6.6%) grade I or II esophagitis.
Treatment-related acute and late toxicities.
A sub-analysis was performed to evaluate whether toxicity (esophagitis, pneumonitis, cardiac) was influenced by the RT dose (≤30 vs. >30 Gy), the use of concomitant CT (no vs. yes), or pre-treatment KPS (<70 vs. ≥70). Patients receiving >30 Gy had significantly more acute esophageal toxicity of any grade when compared to those patients who received ≤30 Gy (54.8% vs. 5.9%, p<0.001). In the 23 patients of the >30 Gy group who experienced esophageal toxicity, this was grade I in 17.4%, grade II in 69.9%, grade III in 8.7%, and grade IV in 4.3% of the patients, respectively. However, only one patient of the ≤30 Gy group developed esophageal toxicity that was grade II (p<0.001). There were no significant associations between RT dose and late toxicity in terms of esophageal toxicity, pneumonitis, or cardiac toxicity.
Five of the six patients (83.3%) who received concomitant CT experienced some degree of acute esophageal toxicity, while, of the 54 patients who did not receive concomitant CT, 19 patients (35.2%) had some degree of acute esophageal toxicity (p=0.033). Only one of five cases and two of 19 patients experienced grade III-IV acute esophageal toxicity (p=0.521). The use of concomitant CT had no impact on late esophageal toxicity or other types of acute or late toxicity.
Discussion
Many patients with stage IV NSCLC and/or locally advanced stages receive palliative RT for the relief of symptoms associated with the disease (4, 14, 15). In the literature there is great heterogeneity of the characteristics of the patients (the staging procedure, KPS, weight loss, age), as well as the treatments administered with RT (dose, schedule and its combination or not with CT using different drugs and timing). These factors likely have an impact on OS. The median OS in our study was 10.8 months (95%CI=5.2-16.4 months) with a 12-month survival of 42.5%. These results are in line with previously published data, namely median OS times ranging from 5.9 to 8.5 months and 1-year OS rates ranging from 20.0% to 40.0% (4).
The dose used in palliative RT ranges from hypo-fractionated schemes (14-17 Gy in 2 fractions) to high doses of 66 Gy (16). In our study, the dose ranged from 17 Gy in 2 fractions to 50 Gy in 25 fractions. Mostly hypo-fractionated schemes were used with doses ≥30 Gy (median EQD2 of 42.55 Gy for tumor cell killing). Patients who received doses >30 Gy had significantly better OS although this was at the expense of an increase in esophagitis. A review of at least 14 randomized studies with a total of 3576 patients concluded that patients who received regimens with doses of 30 Gy in ≥10 fractions had a modest improvement in survival (5% at 1 year and 3% at 2 years), especially in patients with good KPS. Fairchild et al. also reported better OS and lower symptomatic scores with higher dose regimens (30 Gy in 10 fractions) (17). A recent retrospective study including 664 patients with NSCLC also found that doses ≥30 Gy were associated with improved OS, regardless of KPS (18).
Systemic treatment is a standard of care in patients with metastatic or recurrent NSCLC. Several randomized studies have shown that compared with best supportive care alone, treatment with CT can increase survival and improve QoL by relieving symptoms (19). In our study, 33 patients (54.1%) received CT, which was a significant independent prognostic factor for improved OS. The CT was administered concomitantly in six of 33 patients. In this respect, three randomized studies were published in which the role of CT given concurrently with palliative RT was evaluated (20-22). According to Ball et al., the use of concomitant CT significantly improved response rates from 16% to 39% but had no significant impact on OS or QoL. According to Nawrocki et al., patients who received concomitant CT had a significant increase in median survival from nine to 12 months (21). And in the study by Strøm et al., concomitant CT improved median OS from 9.7 to 12.6 months but was associated with an increase in grade 3 esophagitis (30% vs. 1.5%) (22). However, during follow-up these patients showed better QoL scores (social functioning, and physical functioning scores) (22). It should be noted that these QoL improvements did not occur before three months after the end of treatment, and therefore, only patients with an expected survival of at least 3 months should receive concomitant CT associated with palliative RT. This is possibly more feasible in patients with stage III and not suitable for the majority of patients with stage IV disease. In our study, the use of concomitant CT was associated with a higher rate of esophagitis, similar to the previous studies (21, 22). It should be considered that short palliative regimens, such as 17 Gy in 2 fractions or 20 Gy in 4-5 fractions, have also shown symptomatic relief. Therefore, considering that increasing the dose of RT and/or the combination of CT can increase toxicity (especially esophageal), hypo-fractionated regimens with doses <30 Gy may be used, particularly in patients with a poor performance status.
In this study, pre-treatment QoL was evaluated to analyze the effect of patients’ subjective perception of pre-treatment well-being on OS (23). According to the univariate analysis, various parameters, such as role functioning, emotional functioning, and physical function, representing a better QoL, were significantly associated with improved OS. These results are similar to those obtained in other studies (9, 24). However, in the multivariate analysis of our study, only better emotional functioning persisted as a significant predictor of OS. This information could be used as additional guidance in decision-making alongside other prognostic factors. When using this information, the limitations of the present study need to be considered including its moderate sample size. However, it is a representative study of routine clinical practice with a palliative treatment decision adopted by a multidisciplinary tumor board and a prospective assessment of toxicity. To our knowledge, there are no validated criteria to identify patients (especially with stage III) that would benefit from radical treatment. The decision is often based on the patient’s poor general condition, significant weight loss, and large (bulky) tumor size with the impossibility of achieving dosimetric objectives, among others. These criteria have also been considered by other authors (25). It is important to highlight the impact of new high-tech solutions, such as IMRT or stereotactic body radiation therapy (SBRT), including image guided radiation therapy (IGRT), since most of the data published included patients treated with conventional 3D conformal RT.
Future prospective studies of palliative pulmonary RT should evaluate the technological aspects of the treatment. These studies should consider that the total dose may be important for the OS of these patients and that the technology may be a determining factor with respect to toxicity and RT doses that can be safely administered (26-28). Finally, over the last two decades, notable advances have occurred in the systemic treatment of NSCLC, such as immunotherapy, which have improved patient survival. This fact may further increase the role of palliative RT in patients with metastatic disease (29, 30). Symptomatic relief can in some cases help to improve the patient’s general condition, enabling the possibility of continuing new lines of systemic treatment not possible in case of a poor performance status.
Conclusion
Given the limitations of the present study, patients with NSCLC assigned to palliative RT may benefit from RT doses >30 Gy and additional CT. Since concurrent CT leads to increased esophageal toxicity, it should be considered for selected patients after careful balancing the advantages and disadvantages of this treatment. Additional prospective studies are required to identify patients with NSCLC who are candidates for palliative concurrent chemoradiation.
Footnotes
Authors’ Contributions
All Authors participated in the design of the study. The data were collected by AA, FS, DB, RO, FPA, ODH, and analyzed by AN, JLG, AGI, VC. DR and JC drafted the article, which was reviewed and approved by all Authors.
Conflicts of Interest
The Authors declare no conflicts of interest related to this study.
- Received October 14, 2024.
- Revision received October 21, 2024.
- Accepted October 22, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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