Abstract
Background/Aim: In some patients with lung cancer scheduled for thoracic radiotherapy (RT), treatment is discontinued before reaching the planned dose. For optimal treatment personalization, a tool estimating whether a patient can complete radiotherapy would be helpful. Patients and Methods: Eleven pre-RT characteristics were analyzed in 170 patients receiving local RT for lung cancer. Characteristics included age, sex, tumor site, histology, tumor and nodal stage, distant metastasis, surgery, systemic treatment, pulmonary function, and smoking history. Results: Age >75 years (p=0.038), distant metastasis (p=0.009), and forced expiratory volume in 1 second <1.2 l (p=0.038) were significantly associated with discontinuation of RT. A prognostic instrument was developed in 126 patients with complete data regarding these characteristics. It included three groups (0, 1, and 2-3 points) with non-completion rates of 33.3%, 55.0% and 75.0% (p=0.004). Conclusion: This new instrument can help estimating the probability that lung cancer patients assigned to local RT cannot complete the planned course of RT.
Lung cancer represents the second most common type of cancer (new cases per year) and is associated with the highest number of cancer-related deaths worldwide (1). Locally advanced tumors are often treated with radiotherapy (RT) alone or RT combined with systemic treatment (2, 3). The increasing use of modern RT techniques such as volumetric modulated arc therapy (VMAT) or, in case of early-stage tumors, stereotactic body radiation therapy (SBRT) or even ultra-precise techniques such as scanning carbon-ion and proton beam therapy, has improved outcomes in terms of toxicity and local control (4–9). However, despite these advances in technology, lung cancer patients often cannot complete the intended course of RT, since many of them present with loco-regionally advanced tumors, a poor performance status and significant comorbidity.
In addition to the different techniques, a variety of dose-fractionation regimens are available for RT of lung cancer including conventionally fractionated (daily doses per fraction of 1.8-2.0), hypo-fractionated (less fractions with doses per fraction of >2 Gy) and hyper-fractionated (lower doses per fraction given twice or three times per day) programs (10, 11). To select the optimal radiation technique and dose-fractionation treatment for an individual patient, it would be helpful if one could estimate the probability that the patient will or will not be able to complete the intended course of RT. Patients, in whom discontinuation of their radiation treatment appears likely, should be offered intensive supportive care as soon as possible to help them to receive as much as possible of their planned treatment with acceptable toxicity.
Major goals of this study included identification of risk factors for discontinuation of RT in lung cancer patients and development of a prognostic instrument to support physicians who wish to estimate a patient’s inability to complete the intended total radiation course.
Patients and Methods
Data of 170 patients treated with local or loco-regional RT for lung cancer between 2016 and 2019 were retrospectively analyzed with respect to discontinuation of the radiation treatment before achieving the full planned dose. Minimum intended total doses were 56 Gy for small-cell lung cancer (SCLC) and 60 Gy for non-small cell lung cancer (NSCLC), respectively. The study received approval from the local ethics committee at the University of Lübeck (reference 22-049). In all patients, RT was performed as VMAT with 2 Gy fractions planned to be administered on five consecutive days per week. Eleven pre-RT characteristics (Table I) were evaluated for associations with discontinuation of treatment including age at RT (≤75 vs. >75 years), sex (female vs. male), main tumor site (upper lobe vs. lower/middle lobe vs. central/main bronchus), histology (NSCLC vs. SCLC), stage of primary tumor (T1-2 vs. T3-4), nodal stage (N0-1 vs. N2-3), distant metastasis (no vs. yes), upfront surgery (no vs. yes), pre-RT systemic treatment (no vs. yes), forced expiratory volume in 1 second (FEV1 <1.2 vs. ≥1.2 l), and history of smoking (no vs. yes). For statistical analyses regarding associations between these characteristics and discontinuation of radiotherapy, the Chi-square test was used. Significant characteristics were included in the prognostic instrument aiming to estimate the probability of not receiving the complete radiotherapy dose as planned.
Distribution of characteristics analyzed with respect to non-completion of radiotherapy.
Results
In the entire cohort, 88 patients did not receive the minimum intended doses as described above. Five patients died during their course of radiotherapy. Discontinuation of radiotherapy was significantly associated with age >75 years (p=0.038), distant metastasis (p=0.009), and FEV1 <1.2 l (p=0.038). In addition, a trend was found for nodal stage N2-3 (p=0.053). These results and the findings related to the other investigated characteristics are shown in Table II. The three significant characteristics were used for creating the prognostic instrument. The data regarding these characteristics were complete and, therefore, usable for the instrument in 126 patients. Scoring points for each characteristic were “0” (lower risk of discontinuation) or “1” (higher risk of discontinuation) (Table III). The scoring points of the three characteristics were summed for each patient to obtain the patient scores. Thus, the patient scores were 0, 1, 2 or 3 points. The corresponding probabilities of not reaching the intended radiotherapy dose were 33.3% (14 of 42 patients), 55.0% (33 of 60 patients), 76.5% (13 of 17 patients) and 71.4% (5 of 7 patients), respectively (p=0.011). When combining 2 and 3 points to one group, the probabilities were 33.3%, 55.0% and 75.0%, respectively (p=0.004).
Associations between investigated characteristics and discontinuation of radiotherapy. p-Values were generated using the Chi-square test.
Characteristics significantly associated with discontinuation of radiotherapy and corresponding scoring points.
Discussion
A considerable number of patients with lung cancer patients assigned to local or loco-regional radiotherapy cannot receive the planned total dose. In order to select the optimal dose-fractionation regimen for an individual patient, it would be helpful if treating physicians could estimate the probability that this patient might not be able to receive the complete intended radiation treatment. This knowledge would contribute to the avoidance of over- or under-treatment. Therefore, the present study was conducted to identify prognostic factors and develop a prognostic instrument to support treating physicians with this matter. To achieve these goals, 11 pre-RT characteristics were analyzed with respect to the rates of discontinuation of radiotherapy prior to achieving the minimum intended dose, namely 56 Gy for SCLC and 60 Gy for NSCLC. These characteristics included age at RT, sex, main tumor site, histology, primary tumor stage, nodal stage, distant metastasis, upfront surgery, pre-RT systemic treatment, FEV1, and smoking history. Of these characteristics, age >75 years, presence of distant metastasis and FEV1 <1.2 l were significantly associated with discontinuation of radiotherapy, and a trend was found for nodal stage N2-3. A negative impact of impaired pulmonary function on tolerance of treatment was previously described for lung cancer patients treated with concurrent radio-chemotherapy (12–16). In the study of Videtic et al., a diffusion capacity for carbon monoxide (DLCO) of <60% was significantly associated with the incidence of toxicity-related interruptions of radiochemotherapy in patients with limited-stage SCLC (p=0.043), and a trend was observed for a FEV1 of <2 l (p=0.1) (12). In another previous study, a lower FEV1 was associated with the occurrence of severe acute radiation pneumonitis in patients receiving intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy for locally advanced NSCLC (p<0.05) (13). In a more recent study, lung function was represented by the carbon monoxide diffusing capacity (DLCO), which was significantly associated with acute severe radiation pneumonitis (14). Moreover, an impaired lung function was reported to be also negatively associated with the survival of lung cancer patients. In the retrospective study of Kim et al. that included 115 patients with NSCLC receiving post-operative irradiation, a FEV1 of <1.68 l (vs. ≥1.68 l) at the start of radiotherapy was independently associated with worse survival (15). Another retrospective study investigated 313 patients with metastatic NSCLC and 136 patients with extended-disease SCLC receiving palliative systemic treatment (16). In the subgroup of patients with NSCLC and chronic obstructive lung disease who were treated with chemotherapeutic agents, a FEV1 <80% of the predicted value was significantly associated with worse survival.
Regarding the impact of age on the rate of discontinuation of treatment, it is well known that (very) elderly patients with lung cancer often have limited physical reserve, which decreases the probability of receiving the whole treatment as planned (17–20). Moreover, in our previous study, 33.3% of the patients who developed symptomatic radiation pneumonitis were 74 years or older (21). The presence of distant metastases often has a negative impact on the patient’s performance status, which likely decreases the ability to tolerate intensive anticancer treatment (22, 23). Higher nodal stage also represents a more advanced disease and usually requires a larger treatment volume of radiotherapy, which is generally associated with a higher risk of acute toxicity including esophagitis and dysphagia leading to premature discontinuation of the radiation treatment (24–26).
The three significant characteristics, age >75 years, presence of distant metastasis and FEV1 <1.2 l, were used for the prognostic instrument. Three prognostic groups were designed, i.e. 0, 1 and 2-3 points. In these groups, 33.3%, 55.0% and 75.0% of the patients, respectively, did not receive the intended total radiation dose. Considering the comparably high rates of discontinuation of radiotherapy in patients with 1 or 2-3, it becomes obvious that these patients require intensive supportive care as early as possible, ideally prior to the start of radiotherapy.
When considering these findings, the limitations of this study should be kept in mind. The number of patients who did not receive the complete planned radiation dose was comparably high, which reflects the situation that our department likely treats more patients with unfavorable characteristics including high age, high comorbidity index, poor pulmonary function, and poor performance score when compared to other institutions. This aspect may reduce the generalizability of our results. Moreover, the retrospective nature of this study including the risk of hidden selection biases should considered. However, it may be difficult to use the rates of discontinuation of radiotherapy from prospective trials, since patients included in such trials generally represent a selected patient cohort of patients who have good performance scores. Moreover, pulmonary function results specified in the eligibility criteria of the trials are not representative of many patients developing lung cancer.
In summary, a new prognostic instrument was developed that can help estimating the probability of discontinuation of thoracic RT for lung cancer prior to completion of the intended total radiation dose. Patients with more than 0 points require intensive supportive care as soon as possible with the hope of allowing them to receive the planned treatment course.
Acknowledgements
As part of the project NorDigHealth, this study was funded by the European Regional Development Fund through the Interreg Deutschland-Danmark program.
Footnotes
Authors’ Contributions
D.R., E.G., S.B. and E.M.W. designed this study. E.G. provided the data that were analyzed by D.R. Interpretation of the data was performed by all Authors. D.R. and S.E.S. drafted the manuscript, which was reviewed and finally approved by all Authors.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there are no conflicts of interest related to this study.
- Received February 14, 2022.
- Revision received February 25, 2022.
- Accepted February 28, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
