Abstract
Background/Aim: Recent studies suggested that target volume size impacts survival in patients with non-small cell lung cancer (NSCLC) receiving radical radiotherapy. Little is known about the impact of target volume size in palliative radiotherapy or chemoradiotherapy. Therefore, we analyzed the overall survival stratified for clinical and planning target volume (CTV and PTV) size. Patients and Methods: A retrospective study of 77 patients who received palliative (chemo)radiotherapy (at least 30 Gy) for non-metastatic NSCLC, largely stage III was performed. Typical radiation doses were 10-13 fractions of 3 Gy and 15 fractions of 2.8 Gy. Results: Median survival was 12 months (2-year rate 18%). Three prognostic factors emerged in the multivariate analysis. Hospitalization in the last 4 weeks before radiotherapy increased the hazard of death by a factor of 2.8 (p=0.002). Presence of a T1 or 2 tumor decreased the hazard of death by a factor of 0.5 (p=0.03). Concomitant chemoradiotherapy decreased the hazard of death by a factor of 0.4 (p=0.003). Conclusion: Target volume size was not significantly associated with survival, suggesting that large size should not preclude palliative (chemo)radiotherapy as long as normal tissue dose constraints can be met.
Patients with inoperable, locally advanced non-small cell lung cancer (NSCLC) are often treated with combined platinum-based chemotherapy and radiotherapy (radical RCT) (1-5). Due to ineligibility resulting from advanced age, comorbidity or reduced performance status, other options may become the preferred approach, e.g. radical radiotherapy alone, palliative radiotherapy alone or palliative RCT (6-8). Decision-making is tailored to individual patients’ ability to tolerate treatment, as well as motivation and goal of treatment. Different survival prediction tools have been developed, which may stratify patients into distinct prognostic groups (9-11). Such information can be used to support pretreatment assessment. However, prognostic scores are commonly derived from a limited number of baseline variables. Newly emerging prognostic factors should be studied to improve already existing tools. In the context of radical RCT, several studies have suggested that gross tumor volume (GTV) or planning target volume (PTV) predicts overall survival (12-15). These metrics of tumor burden have rarely been studied in the setting of contemporary palliative radiotherapy or RCT. Therefore, we performed a retrospective study addressing the prognostic impact of target volume size in patients who started palliative radiotherapy or RCT at our Institution.
Patients and Methods
A retrospective review of 77 consecutive patients treated with palliative 3-dimensional conformal radiotherapy or RCT between 2009 and 2019 was performed. Inclusion was limited to patients with a prescribed total dose of 30-54 Gy and those without distant metastases (stage II or III). Four patients (5%) failed to complete radiotherapy. An additional exploratory analysis of 57 patients with stage IV NSCLC who received identical treatment was also performed. Patients treated with low-dose radiotherapy, primarily 2 fractions of 8.5 Gy, were excluded from both analyses. All 77 study patients had Eastern Cooperative Oncology Group (ECOG) performance status 0-2. In case of RCT, most patients received the Norwegian CONRAD regime (15 fractions of 2.8 Gy, Carboplatin/Vinorelbine before and during radiotherapy) (16, 17). Treatment plans were calculated with Varian Eclipse TPS® and no intensity-modulated or arc-based techniques were employed. Contouring of the GTV was not mandatory. However, the clinical target volume (CTV) and PTV was contoured in all patients. Therefore, analysis was limited to CTV and PTV. Elective lymph node stations were not included in the CTV. The CTV margin expansion varied, depending on availability of 4-D treatment planning scans allowing for an internal target volume (ITV) concept. In case of ITV contouring, 5 mm were added to create the PTV. Otherwise, the CTV was expanded by 8-10 mm to create the PTV. Positron emission tomography (PET) was available in a minority of patients. The typical approach was computed tomography (CT)-based contouring without 4-D registration of respiratory motion. IBM SPSS v.25 was employed for statistical analyses. The latter included chi-square test and univariate Cox regression for associations between overall survival from the start of radiotherapy and clinical and dosimetric variables. Significant variables, i.e. p≤0.05 in two-sided tests, were then included in multivariate forward conditional Cox regression analysis. Actuarial overall survival was calculated according to the Kaplan-Meier method and the log-rank test was employed for comparison of survival curves. At the time of the analysis, 22 patients were alive (censored observations after a median follow-up of 12.6 months). Date of death was known for all remaining patients.
Results
The baseline characteristics of the study population are shown in Table I. The median age was 72 years, range=47-89 years. The median CTV size was 135 ml, range=10-860 ml (25th percentile 60.5 ml, 50th percentile 135 ml, 75th percentile 261.5 ml). The median PTV size was 402 ml, range=45-1272 ml. Table II shows the results of the survival analyses. Three prognostic factors emerged in the multivariate regression analysis. Having been hospitalized in the last 4 weeks before radiotherapy increased the hazard of death by a factor of 2.8 (p=0.002). Having a T1 or 2 tumor decreased the hazard of death by a factor of 0.5 (p=0.03). Receiving concomitant RCT decreased the hazard of death by a factor of 0.4 (p=0.003). Median survival in this study was 12 months (all 77 patients; 2-year rate 18%). Among four patients who failed to complete radiotherapy, three had been hospitalized in the last 4 weeks before start. In the additional exploratory analysis, target volume size did not predict overall survival in patients with stage IV disease, identical to the result of the main study.
Baseline characteristics before palliative radiotherapy in 77 patients.
Prognostic factors for overall survival in 77 patients.
Discussion
Patients with NSCLC not amenable to radical treatment commonly receive palliative thoracic radiotherapy (6, 7, 18, 19). Heterogeneity between studies has been observed regarding prognostic factors for survival (9, 20). A relevant impact of GTV or PTV size has emerged from the literature on radical radiotherapy (12-15) and therefore, we performed this retrospective study in patients treated palliatively. Typical patients were in their 70s, had stage III disease and received 13 fractions of 3 Gy without chemotherapy or 15 fractions of 2.8 Gy with up to 4 cycles of Carboplatin/Vinorelbine. The concomitant RCT regime emerged as a major factor associated with improved survival. The same was true for the presence of T1-2 disease, but not N stage, CTV and PTV. Finally, a history of previous hospitalization (4 weeks before radiotherapy, any cause) impacted survival. The hospitalization variable might be related to other potential predictors of survival, which were not available in our database, e.g., weight loss, comorbidity and frailty. This would also explain why three of four patients who failed to complete radiotherapy had a history of previous hospitalization. Concomitant RCT for patients without contraindications is also endorsed in a recent American guideline (7).
The main limitations of our study are its retrospective design, group size (or statistical power), lack of GTV data, and heterogeneity regarding PET utilization. PET-assisted treatment planning might have resulted in different CTV contouring and should be considered mandatory in the radical treatment setting (21, 22). However, in elderly patients with comorbidity and limited treatment options, routine PET staging is economically difficult to justify, especially if transportation to an outside PET center is needed like in our healthcare region (23). Given that early palliative interventions may influence the outcomes of care for patients with NSCLC (24), it would be interesting to study this paradigm in a patient population like ours, and not just in patients who receive primary systemic therapy. Fortunately, the radiation treatment strategies continue to evolve and it will be interesting to see whether immune checkpoint inhibitors show added benefit in the palliative, non-metastatic setting (25). Overall, our study suggests that large CTVs should not preclude palliative RCT (or monotherapy) as long as normal tissue dose constraints can be met. Recently, recommendations for esophageal dose were published (17), but the risk of pneumonitis must also be considered.
Footnotes
Authors’ Contributions
CN participated in the design of the study and performed the statistical analysis. KSI collected patient data. CN, KSI, BM and RY conceived the study and drafted the article. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare that they have no conflicts of interest regarding this study.
- Received November 20, 2020.
- Revision received December 7, 2020.
- Accepted December 8, 2020.
- Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
