Pneumonitis After Radiotherapy of Breast or Lung Cancer

Background Breast cancer and lung cancer belong to the most common types of solid cancer in Europe and Northern America. The majority of breast cancer patients receive adjuvant radiotherapy, either following breast-conserving surgery or mastectomy. And most patients with small-cell lung cancer (SCLC) receive radiotherapy in combination with chemotherapy as definitive treatment. Also, a considerable number of patients with advanced non-small-cell lung cancer (NSCLC) are treated with radiotherapy with or without concurrent chemotherapy, particularly if they are not candidates for surgery.

Major goals of radiotherapy include local disease control and improvement of the patients' prognoses. One possible side effect of radiotherapy of breast or lung cancer is radiation pneumonitis. Severe (grade ≥3) radiation pneumonitis can even be fatal in approximately 2% of the patients. Therefore, it would be very important to identify and treat pneumonitis at an earlier stage (grade 2).

According to a systematic review, the prevalence of symptomatic (grade ≥2) pneumonitis after radiotherapy of breast cancer ranges between 0.8% and 2.9%. In our own center, the prevalence of grade ≥2 pneumonitis in patients receiving radiotherapy for breast cancer between 2016 and 2019 was 1.8%, i.e. in this range. Moreover, the prevalence of symptomatic (grade ≥2) pneumonitis in patients irradiated for lung cancer in our center between 2016 and 2019 was 7.6%.

Pneumonitis can occur up to 23 weeks following radiotherapy. Therefore, patients and their general practitioners may not associate symptoms of pneumonitis such as cough, shortness of breath and fever with the radiation treatment that took place several weeks ago. Thus, radiation pneumonitis can be missed at an early stage, and the patients are often treated with antibiotics for bronchitis or pneumonia. Treatment with antibiotics alone is not effective for radiation pneumonitis, which often becomes more severe before eventually diagnosed.

In the present study, the patients are asked to complete a questionnaire (paper version) once a week during the period of radiotherapy and up to 24 weeks following radiotherapy. In this questionnaire, the patients are asked to state and rate their symptoms potentially associated with pneumonitis. Scoring points are assigned to the severity of the symptoms (symptom scores), and the resulting sum score (patient score) will be used for identification of radiation pneumonitis.

Primary endpoint To assess the performance characteristics of the symptom-based scoring system for detection of radiation pneumonitis the receiver operating characteristic (ROC) curve is used to show the connection between sensitivity and specificity for every possible cut-off for the scoring system and to select the optimal scoring point for detection of radiation pneumonitis- The area under the ROC curve (AUC) is calculated to prove the diagnostic ability of the scoring system.

General trial design and duration This is a single-center prospective study, which aims to assess the performance of a new symptom-based score and to identify its optimal scoring point with respect to the detection of patients developing pneumonitis following radiotherapy of breast cancer or lung cancer. The recruitment of all 78 patients (74 patients plus drop-outs) should be completed within 24 months. The treatment period will be 6-7 weeks, and the follow up period 24 weeks. This equals a total running time for the trial of approximately 31 months.

Symptom-Based Scoring System (Paper Version) The patients are asked to complete a paper-based questionnaire (symptom-based scoring system, paper version) once a week during the period of radiotherapy and up to 24 weeks following radiotherapy. The patients are asked to state and score their symptoms that are potentially associated with pneumonitis, namely cough, shortness of breath and fever. Scoring points are assigned to the severity of the symptoms (= symptom scores), and the resulting sum score (patient score) will be used to identify radiation pneumonitis.

During the time of radiotherapy, the patients will complete the paper-based questionnaire directly prior to their appointment with a physician who will perform a physical examination once a week. Following radiotherapy, the patients will be contacted by phone once a week and asked to answer the questions of the questionnaire. In case of a score of 0-1 points, no further action is required. In case of a score of ≥2 points, patients will either receive a follow-up telephone call (visit) after 3 days, will be asked to come to the hospital as an outpatient within 24 hours or will be admitted to hospital on the same day. In case of suspected pneumonitis, the patient will undergo a lung function test and measurement of the transfer factor of the lung for carbon monoxide (TLCO). If the suspicions of pneumonitis are substantiated, the patient receives a chest x-ray in accordance with the current standard procedures at the University Medical Center Schleswig-Holstein in Lübeck.

If the diagnosis of pneumonitis is confirmed, the patients receive standard treatment with prednisolone until the symptoms disappear or show considerable improvement, generally over a period of 12 weeks. The symptom-based sum score will be correlated to the diagnosis of pneumonitis (yes vs. no).

Subgroup Analysis: Symptom-Based Scoring System (Mobile Application) In 10 patients (5 breast cancer and 5 lung cancer patients), the paper version of the symptom-based scoring system (questionnaire) will be supplemented by a mobile application (app) asking the same questions regarding cough, shortness of breath and fever. The symptoms collected by the app will not be evaluated or analyzed. With regard to the app, only its functionality will be tested in this study. The patients will be asked to complete the questionnaire of the app directly after completing the questionnaire of the paper version.

Statistics / Sample size calculation The main goal of this trial is to evaluate the usefulness of a new symptom-based scoring system with respect to the identification of patients developing pneumonitis after radiotherapy of breast or lung cancer. The discriminative power of the symptom-based scoring system will be assessed by calculating the area under the ROC curve (AUC). Assuming a ratio between patients without and with radiation pneumonitis of 2.33, a sample size of 74 patients is required in the full analysis set to yield statistical significance at the significance level of 5% with a power of 90% if the AUC under the alternative hypothesis is in fact at least 0.9. Taking into account that 5% of patients will not qualify for Full Analysis Set, a total of 78 patients should be recruited.

If statistical significance of the AUC is reached, the most-informative (optimal) scoring point to identify radiation pneumonitis will be derived. Sensitivity analyses will be conducted to further investigate the performance of the symptom-based scoring system.