Survival and Quality of Life After Stereotactic or 3D-Conformal Radiotherapy for Inoperable Early-Stage Lung Cancer

doi:10.1016/j.ijrobp.2011.03.052

International Journal of Radiation OncologyBiologyPhysics

Volume 81, Issue 4, 15 November 2011, Pages e291-e297

https://doi.org/10.1016/j.ijrobp.2011.03.052 Get rights and content

Purpose

To investigate survival and local recurrence after stereotactic ablative radiotherapy (SABR) or three-dimensional conformal radiotherapy (3D-CRT) administered for early-stage primary lung cancer and to investigate longitudinal changes of health-related quality of life (HRQOL) parameters after either treatment.

Methods and Materials

Two prospective cohorts of inoperable patients with T1-2N0M0 primary lung tumors were analyzed. Patients received 70 Gy in 35 fractions with 3D-CRT or 60 Gy in three to eight fractions with SABR. Global quality of life (GQOL), physical functioning (PF), and patient-rated dyspnea were assessed using the respective dimensions of European Organization for Research and Treatment of Cancer Core Questionnaire-C30 and LC13. HRQOL was analyzed using multivariate linear mixed-effects modeling, survival and local control (LC) using the Kaplan-Meier method, Cox proportional hazards analysis, and Fine and Gray multivariate competing risk analysis as appropriate.

Results

Overall survival (OS) was better after SABR compared with 3D-CRT with a HR of 2.6 (95% confidence interval [CI]: 1.5–4.8; p < 0.01). 3D-CRT conferred a subhazard ratio for LC of 5.0 (95% CI: 1.7–14.7; p < 0.01) compared with SABR. GQOL and PF were stable after SABR (p = 0.21 and p = 0.62, respectively). Dyspnea increased after SABR by 3.2 out of 100 points (95% CI: 1.0–5.3; p < 0.01), which is clinically insignificant. At 1 year, PF decreased by an excess of 8.7 out of 100 points (95% CI: 2.8–14.7; p < 0.01) after 3D-CRT compared with SABR.

Conclusion

In this nonrandomized comparison of two prospective cohorts of medically inoperable patients with Stage I lung cancer, OS and LC were better after SABR. GQOL, PF, and patient-rated dyspnea were stable after SABR, whereas PF decreased after 3D-CRT approaching clinical significance already at 1 year.

Introduction

Stereotactic ablative radiotherapy (SABR) is emerging as a new standard for medically inoperable patients with early-stage non–small-cell lung cancer (NSCLC) without nodal disease, although its superiority has never been validated with reference to conventionally fractionated three-dimensional conformal radiotherapy (3D-CRT) in a randomized controlled trial 1, 2. High-precision four-dimensional computed tomography (4D-CT) tumor imaging and online position verification considerably reduce and individualize the treated volume while improving targeting precision of SABR compared with classical 3D-CT–based CRT (3). This enables considerable escalation of the fraction dose and reduction of the overall treatment time. As a consequence, excellent local control (LC) rates of more than 80–90% have been reported for SABR 1, 4. Although one Phase II (Radiation Therapy Oncology Group 0618), and two Phase III studies comparing SABR with surgery (NCT00687986; NCT00840749) have been recruiting operable patients with early stage NSCLC, outside of these studies mostly patients unfit for or refusing surgery are presently offered SABR. Recently, a nonrandomized retrospective comparison between SABR and wedge resection has been published showing better LC after SABR, whereas overall survival (OS) was higher after wedge resection (5). In general, patients selected for 3D-CRT, SABR, or limited resection have severely compromised pulmonary function, considerable comorbidity, reduced general condition, and are at advanced age. SABR has been developed in this frail patient population. Among the features rendering this treatment attractive is its patient convenience in terms of noninvasiveness, short treatment duration, and outpatient delivery even for patients with a considerably reduced performance score.

Only one small study that included 39 patients undergoing CyberKnife® treatment for NSCLC has been published reporting on patient-rated health-related quality of life (HRQOL) and pulmonary symptoms after SABR, suggesting stability of HRQOL after SABR (6). A recent analysis in patients undergoing surgery for early-stage NSCLC showed that surgery had substantial temporary impact on HRQOL and some patients experienced HRQOL impairment for a long period (7). An earlier prospective study in patients undergoing 3D-CRT for early-stage NSCLC showed a gradual increase of patient-rated pulmonary symptoms after treatment (8). That study used an identical follow-up regimen for HRQOL as applied at our department and was conducted by one of the coauthors of the present study (J.A.L.), rendering it an ideal cohort to be compared with SABR in the current study.

The objectives of this study were twofold: (1) to investigate posttreatment longitudinal changes of HRQOL among patients treated with SABR and (2) to compare SABR with 3D-CRT regarding OS, disease-specific survival (DSS), LC, and longitudinal changes of HRQOL after either treatment.

This study is the first to investigate posttreatment HRQOL in a large cohort of patients receiving SABR and to compare HRQOL, survival, and LC, after SABR or 3D-CRT administered for early-stage lung tumors.

Section snippets

Selection of the cohorts

Between November 2006 and November 2009, 202 consecutive medically inoperable patients with T1-2N0M0 primary lung tumors were treated with SABR and all were included in this analysis. Patients were discussed in a multidisciplinary team consisting of thoracic surgeons, pulmonologists, anesthesiologists, radiation oncologists, nuclear medicine specialists, radiologists, and pathologists. All patients had technically resectable lesions, but were judged inoperable by specialized thoracic surgeons

Results

The SABR and 3D-CRT cohorts were balanced with the exception of age and WHO performance status, which were both in favor of 3D-CRT (see Discussion) (Table 1). SABR patients underwent a diagnostic fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) scan, whereas between 1994 and 1996, ¹⁸F-FDG-PET was unavailable. More lesions were pathologically confirmed in the 3D-CRT group (74% in the 3D-CRT cohort vs. 29% in the SABR cohort; p < .01; see Discussion).

Median follow-up was 13 months.

Discussion

In the last decade, SABR has rapidly been accepted as preferred treatment with curative intent for medically inoperable patients with NSCLC, mainly based on considerably higher LC rates reported for SABR in contrast to previously published two-dimensional RT or 3D-CRT series 1, 4, 19, 20, 21, 22. Although solely based on nonrandomized historical comparisons, LC is felt to be better with SABR at an extent that a randomized trial, though epistemologically preferable, seems unrealistic. Thus,

Acknowledgments

The authors wish to thank M. de Boer, N. A. Bylholt, and A.M. Pot for data entry.

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Cited by (71)

Optimal Radiation Therapy Fractionation Regimens for Early-Stage Non-Small Cell Lung Cancer
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A series of radiobiological models were developed to study tumor control probability (TCP) for stereotactic body radiation therapy (SBRT) of early-stage non-small cell lung cancer (NSCLC) per the Hypofractionated Treatment Effects in the Clinic (HyTEC) working group. This study was conducted to further validate 3 representative models with the recent clinical TCP data ranging from conventional radiation therapy to SBRT of early-stage NSCLC and to determine systematic optimal fractionation regimens in 1 to 30 fractions for radiation therapy of early-stage NSCLC that were found to be model-independent.
Recent clinical 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data of 9808 patients from 56 published papers were collected for radiation therapy of 2 to 4 Gy per fraction and SBRT of early-stage NSCLC. This data set nearly triples the original HyTEC sample, which was used to further validate the HyTEC model parameters determined from a fit to the clinical TCP data.
TCP data from the expanded data set are well described by the HyTEC models with α/β ratios of about 20 Gy. TCP increases sharply with biologically effective dose and reaches an asymptotic maximal plateau, which allows us to determine optimal fractionation schemes for radiation therapy of early-stage NSCLC.
The HyTEC radiobiological models with α/β ratios of about 20 Gy determined from the fits to the clinical TCP data for SBRT of early-stage NSCLC describe the recent TCP data well for both radiation therapy of 2 to 4 Gy per fraction and SBRT dose and fractionation schemes of early-stage NSCLC. A steep dose response exists between TCP and biologically effective dose, and TCP reaches an asymptotic maximum. This feature results in model-independent optimal fractionation regimens determined whenever safe for SBRT and hypofractionated radiation therapy of early-stage NSCLC in 1 to 30 fractions to achieve asymptotic maximal tumor control, and T2 tumors require slightly higher optimal doses than T1 tumors. The proposed optimal fractionation schemes are consistent with clinical practice for SBRT of early-stage NSCLC.
SABR for Early Non-Small Cell Lung Cancer: Changes in Pulmonary Function, Dyspnea, and Quality of Life
2023, International Journal of Radiation Oncology Biology Physics
The aim of this study was to report pulmonary function tests (PFTs) and clinician-reported and patient-reported quality-of-life (QoL) outcomes on a cohort of patients with non-small cell lung cancer (NSCLC) treated with SABR.
A total of 119 patients with NSCLC were treated with SABR in the prospective cohort SSBROC study of patients with T1-T2N0M0 NSCLC. PFTs and QoL measures were obtained at baseline pretreatment and at 6-month intervals. Here we report on the 6- to 18-month time points. Analysis of covariance (ANCOVA) methods adjusting for baseline analyzed potential predictors on outcomes of PFTs and patient-reported dyspnea at 18 months.
The only statistically significant decline in PFTs was seen in forced expiratory volume in 1 second (FEV₁) at 18 months post-SABR, with a decline of −0.11 L (P = .0087; 95% CI, −0.18 to −0.02). Of potential predictors of decline, only a 1-unit increase in smoking pack-years resulted in a −0.12 change in diffusing capacity for carbon monoxide (P = .026; 95% CI, −0.02 to −0.23) and a 0.003 decrease in FEV₁ (P = .026; 95% CI, −0.006 to −0.0004). For patient-reported outcomes, statistically significant worsening in both the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (QLQ-C30 Version 3) and the lung module (QLQ-LC13) dyspnea scores occurred at the 18-month time point, but not earlier. No potential predictors of worsening dyspnea were statistically significant. There was no statistically significant decline in clinician-reported outcomes or global QoL scores.
We found a statistically significant decline in FEV₁ at 18 months posttreatment. Smoking pack-years was a predictor for decline in diffusing capacity for carbon monoxide and FEV₁ at 18 months. Worsening of patient-reported dyspnea scores was observed, consistent with the expected progression of lung comorbid disease.
Quality of Life After Stereotactic Body Radiation Therapy or Surgery for Early-Stage NSCLC: A Systematic Review
2022, JTO Clinical and Research Reports
Quality of life (QOL) is a key consideration for patients with early-stage NSCLC choosing between treatment options. Currently, it is not well established whether stereotactic body radiation therapy (SBRT) or surgery offers superior QOL in early-stage NSCLC. The objective of this systematic review is to summarize the prospective literature on QOL in patients with early-stage NSCLC after treatment with SBRT or surgery. A comprehensive literature review using PubMed and EMBASE was performed in April 2022. Prospective studies evaluating QOL data across multiple time points in patients with early-stage NSCLC after SBRT or surgery were included. A total of 25 studies involving 1597 SBRT patients and 1652 surgery patients met the inclusion criteria. Across most studies, QOL remained stable after treatment with SBRT. After surgery, QOL initially decreased; however, it often returned to baseline in the next 6 to 12 months. Utilization of video-assisted thoracoscopic surgery and sublobar resection reduced the magnitude of the initial decrease in QOL after surgery and led to faster recovery to baseline. Owing to the heterogeneity of patient populations between studies evaluating SBRT versus surgery, direct comparisons between the two treatments remain difficult to make. Clinicians should appropriately counsel patients with this information to help guide patient-centered discussions on choosing the optimal treatment modality.
Hypofractionated proton therapy for non-small cell lung cancer: Ready for prime time? A systematic review and meta-analysis
2022, Cancer Treatment Reviews
Hypofractionated proton beam radiotherapy (PBT) is gaining attention in early-stage non-small cell lung cancer (ES-NSCLC). However, there is a large unmet need to define indications, prescription doses and potential adverse events of protons in this clinical scenario. Hence, the present work aims to provide a critical literature revision, and to investigate associations between fractionation schedules/ biological effective doses (BEDs), oncological outcomes and toxicities.
This systematic review and meta-analysis complied with the PRISMA recommendations. Inclusion criteria were: 1) curative-intent hypofractionated PBT for ES-NSCLC (≥3 Gy(RBE)/fraction), 2) report of the clinical outcomes of interest, 3) availability of full-text written in English. The bibliographic search was performed on the NCBI Pubmed, Embase and Scopus in September 2021; no other limitations were applied. The BED was calculated for each included study (α/β = 10 Gy); the median BED for all studies was used as a threshold for stratifying selected evidence into “high” and “low”-dose subgroups. Heterogeneity was tested using chi-square statistics; inconsistency was measured with the I² index. Pooled estimate was obtained by fitting both the fixed-effect and the DerSimonian and Laird random-effect model.
Eight studies and 401 patients were available for the meta-analysis; median follow-up was 32.8 months. The median delivered BED was 105.6 Gy(RBE). A BED ≥ 105.6 Gy(RBE) consistently provided superior OS, CSS, DFS and LC rates (i.e.: 4-year OS: 0.56 [0.34–0.76] for BED < 105.6 Gy(RBE) and 0.78 [0.64–0.88] for BED ≥ 105.6 Gy(RBE)). The meta-analysis of proportions showed a comparable probability of developing acute grade ≥ 2 toxicity between the two groups, while the probability of any late grade ≥ 2 event was almost three-times greater for BED ≥ 105.6 Gy(RBE), with rib fractures being more common in the high dose group.
Hypofractionated PBT is a safe and effective treatment option for ES-NSCLC; the delivery of BED ≥ 105.6 Gy(RBE) with advanced techniques for uncertainty management has been associated with improved oncological outcomes across all considered time points.
Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study)
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Citation Excerpt :
Our results show no significant impact of radiotherapy on overall HRQoL and its domains over time for the entire population, except for cognitive functioning, which significantly deteriorates with time. Previous research in ES-NSCLC already showed that radiotherapy in general has no impact on HRQoL, apart from an improved emotional functioning in those receiving SBRT [24,47]. However, a more pronounced decline in physical functioning and increase in dyspnea was reported in patients receiving 3D-CRT compared to SBRT for ES-NSCLC, emphasizing the importance of advanced radiotherapy techniques in that study [47].
Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study.
HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages.
Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually.
While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals’ HRQoL, symptoms and toxicity in treatment decision-making.
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The optimal treatment of stage I non–small-cell lung carcinoma is subject to debate. The aim of this study was to compare overall survival and oncologic outcomes of lobar resection (LR), sublobar resection (SR), and stereotactic body radiotherapy (SBRT).
A systematic review and meta-analysis of oncologic outcomes of propensity matched comparative and noncomparative cohort studies was performed. Outcomes of interest were overall survival and disease-free survival. The inverse variance method and the random-effects method for meta-analysis were utilized to assess the pooled estimates.
A total of 100 studies with patients treated for clinical stage I non–small-cell lung carcinoma were included. Long-term overall and disease-free survival after LR was superior over SBRT in all comparisons, and for most comparisons, SR was superior to SBRT. Noncomparative studies showed superior long-term overall and disease-free survival for both LR and SR over SBRT. Although the papers were heterogeneous and of low quality, results remained essentially the same throughout a large number of stratifications and sensitivity analyses.
Results of this systematic review and meta-analysis showed that LR has superior outcomes compared to SBRT for cI non–small-cell lung carcinoma. New trials are underway evaluating long-term results of SBRT in potentially operable patients.

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: Conflict of interest: none.

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Clinical InvestigationSurvival and Quality of Life After Stereotactic or 3D-Conformal Radiotherapy for Inoperable Early-Stage Lung Cancer

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Selection of the cohorts

Results

Discussion

Acknowledgments

Cancer/Radiotherapie

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Chest

Eur J Cancer

Radioth Oncol

J Chronic Dis

Eur J Cancer

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Cancer Treatment Rev

Radiother Oncol

Clinical Investigation
Survival and Quality of Life After Stereotactic or 3D-Conformal Radiotherapy for Inoperable Early-Stage Lung Cancer