Risk stratification of pulmonary toxicities in the combination of whole lung irradiation and high-dose chemotherapy for Ewing sarcoma patients with lung metastases: a review

Abstract

Background Whole lung irradiation (WLI) represents an important part of multimodal therapy in Ewing sarcoma (EwS) patients diagnosed with pulmonary metastases. This review discusses pulmonary toxicity in EwS patients with pulmonary metastases treated with WLI, who received different modes of high-dose chemotheray (HD-Cth). Methods Literature was compiled using the Cochrane Library, PubMed database, and the National Institute of Health (NIH) clinical trials register. Relevant patient information, including nature of HD-Cth, acute and late lung toxicities, and pulmonary function disorders, was selected from the above databases. Results Nine reports with a total of 227 patients, including 57 patients from a single randomized trial were included in this review. No acute or chronic symptomatic pulmonary toxicities were observed in patients that received WLI after HD busulfan-melphalan (HD-Bu/Mel), but 8% of these patients were diagnosed with asymptomatic restrictive lung disease. Grade 1 or 2 acute or chronic lung adverse effects were observed in up to 30% of patients that received WLI after HD treosulfan/Mel (HD-Treo/Mel) or HD etoposide (E)/Mel. Interstitial pneumonitis was present in 9% of patients treated concurrently with E/Mel and total body irradiation (TBI) with 8 Gy. Radiation doses as well as time between HD-Cth and WLI were both identified as significant risk factors for pulmonary function disorders. Conclusion The risk of adverse lung effects after WLI depends on several factors, including cumulative radiation dose and dose per fraction, HD-Cth regimen, and time interval between HD-Cth and WLI. A cumulative radiation dose of up to 15 Gy and a time interval of at least 60 days can potentially lead to a reduced risk of pulmonary toxicities. No evident adverse lung effects were registered in patients that received simultaneous therapy with HD-Cth and TBI. However, pulmonary function testing and lung toxicity reports were lacking for most of these patients.

Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

“…Only a minority of patients showed significant pulmonary function abnormality after WLI [ 189 ]. The risk of adverse lung effects after WLI depends on several factors, including cumulative radiation dose and dose per fraction, high-dose chemotherapeutic regimen, and time interval between high-dose treatment and WLI [ 193 ]. The radiosensitization effect and toxicity of busulfan-containing chemotherapy before RT for EwS has been repeatedly described [ 192 , 194 ].…”

“…The radiosensitization effect and toxicity of busulfan-containing chemotherapy before RT for EwS has been repeatedly described [ 192 , 194 ]. Severe toxicities leading to death have been observed in single patients who received high-dose large-volume RT following busulfan-containing high-dose treatment [ 193 , 194 , 195 ]. In patients with an indication for RT, the patient will not be offered busulfan-containing high-dose treatment if there are critical organs such as gut or lung in the fields, unless the technique can be provided which limits the dose to critical organs.…”

“…If RT is mandatory, the time interval between stem cell reinfusion following high-dose chemotherapy and the start of RT should be at least 8–10 weeks (stable engraftment provided) to avoid rebound toxicity. Interestingly, no acute or chronic symptomatic pulmonary toxicities were observed in patients that received WLI after high-dose busulfan-melphalan, while grade 1 or 2 acute or chronic lung adverse effects were observed in up to 30% of patients that received WLI after high-dose treosulfan/melphalan or high-dose etoposide/melphalan regimens [ 193 ]. The safety of treosulfan in patients receiving radiation to the spinal cord or brain has not been established yet.…”

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study

“…Few published data to evaluate the feasibility of WLI combined with high-dose chemotherapy are available, due to the relatively limited number of cohorts and the lack of treatment homogeneity across the studies [ 34 ]. This study is the largest report on toxicity and outcome following BU-MEL and WLI in lung metastatic ES.…”

“…The minimum time interval of eight weeks between BU-MEL and WLI may have contributed to limit the incidence and the grade of the observed toxicities. In a recent review, a time interval of 30–60 days between HDCT and WLI showed a significant impact on pulmonary function disorders [ 34 ].…”