RP is the most common complication in radiation therapy for lung cancer [5–7]. Compared to lobectomy, it could be more threatening for patient underwent pneumonectomy[14]. However, there are (to our knowledge) no published studies expressly investigating the correlation between clinical or dosimetric factors and RP in patients underwent pneumonectomy. It is clinically important to explore possible predictors to mitigate the RP incidence in this special population who had already been in high risks. Hence, we conducted a retrospective study and verified V5 and V20 as predictors for grade ≥ 2 RP. To our knowledge, this is the first study to explore the predictors of RP in patients who once received pneumonectomy.
The dosimetric limitations of radiotherapy for NSCLC patients underwent pneumonectomy mainly drew on the experience of adjuvant hemithoracic radiotherapy for patients with malignant pleural mesothelioma (MPM) following extrapleural pneumonectomy (EPP) for a long time. While considering the difference in radiation volumes between the two malignancies, the experience directly exported to NSCLC patients seemed not conformable[17]. Interestingly, the conclusions drawn from our study were consistent with published literatures on mesothelioma patients. In a cohort of 63 patients treated with IMRT after EPP at the MD Anderson Cancer Center, Rice et al. found that V20 was the sole significant factor related to pulmonary-related deaths (PRDs). Strikingly, the results showed that patient with V20 > 7% increased a 42-fold risk of PRDs and V5 was almost more than 80%[18]. Similarly, Bece et al. described 55 patients receiving hemithoracic radiotherapy, none of whom developed RP under restriction on lung V20 < 10% and V5 < 60%[19].In a review of the literature, Chi et al. reported that high incidence of severe RP was observed when V20 and V5 were higher than 7% and 60%, respectively[20]. Moreover, our findings were also correlated with several studies exploring the predictors of RP in NSCLC patients underwent surgery. For instance, in a cohort of 109 patients with NSCLC received postoperative radiotherapy (PORT), Xin Tang et al.[21]reported that ipsilateral lung V5 (ilV5 > 64.9%) was significantly associated with severe acute radiation pneumonitis (SARP, grade ≥ 3) incidence. In another retrospective report of 199 NSCLC patients treated with PORT, including 23 patients who underwent pneumonectomy, V20 > 20% was identified as one of cutoff levels for predicting grade ≥ 2 RP [22]. Analogously, Gong Y and co-workers[23] found that both ipsilateral lung V5(iV5 > 71.2%) and total lung V20(V20 > 21.4%) showed a strong statistically association with acute severe RP in lung cancer patients after surgery.
In general, our findings suggested that V5 and V20 could keep as predictors of RP for patients with NSCLC following pneumonectomy. However, the cutoff values of our study seemed lower than the above researches, and we reasoned this discrepancy on two aspects as follows. On one hand, we discreetly set lung V5 < 30% and V20 < 10% in more than 85% of radiotherapy treatment plans in consideration of the high mortality and morbidity rate of pneumonectomy. Such strict dose limits have rarely been seen in previous studies that almost excluded patients received pneumonectomy. On the other hand, prior reports mainly set grade ≥ 3 RP as the endpoint leading to a much stricter limitation. Additionally, compared to grade 2 RP, grade ≥ 3 RP with more severe clinical symptoms and poorer survival needed to be treated with steroids and oxygen. In a study of 99 patients, the grade 3 pneumonitis was in 8% patients, and all of them died within 8 months after treatment[24]. Ascribed to the smaller case number and lower incidence, we had difficulty obtaining effective thresholds of grade 3 RP from ROC curve, therefore only descriptive results were showed. We found no incidence of grade ≥ 3 RP was observed whenV5 < 30%, V20 < 13% and MLD < 751.2 cGy, respectively. A recent publication, under restrictions on contralateral lung V20 < 10% in 32 patients with stage pIII-N2 NSCLC after pneumonectomy, there were only 2 patients developed RP[25]. This result was verified by our study with a larger population, and restrictions of V5 and V20 should be more strictly defined especially for patients with post-pneumonectomy.
In our research, 25(33.8%) patients developed grade ≥ 2 RP and 5(6.8%) patients were grade 3 RP, consistent with previously reported RP rate ranged from 15–40% in grade 2 and 2–9% in grade 3 RP[7, 26]. It seems reasonable to postulate that receiving chemotherapy could increase the risk of RP[27]. While neither chemotherapy agent nor timing was significantly associated with grade ≥ 2 RP, only a trend for chemotherapy with docetaxel (P = 0.080) was observed in the current study. That may be confounded by other factors related to the decision of whether using chemotherapy. Additionally, the heterogeneity of chemotherapy regimens also influenced the effect of timing and interval between chemotherapy and radiotherapy with respect to RP. In the researches by Boonyawan et al. and Kim et al., the same results were shown that chemotherapy did not increase RP risk[22, 28]. Like chemotherapy, poor pulmonary function tests (especially FEV1% predicted, DLCO) have also been classically described to increase risk of RP[29]. Because patients who undergoing pneumonectomy were routinely received pulmonary function tests before, they rarely had another test after surgery. We can almost ensure there was no significant heterogeneity in the basic lung function of these patients, as they can endure pneumonectomy after being evaluated by professional surgeons. In fact, the evaluation of pulmonary function was seldom considered in other published data if patients underwent surgery[5, 19, 20, 22, 23]. In a study involved 260 patients from two centers, poor pulmonary function at baseline was found to have no correlation with the risk of pneumonitis[30].
Right pneumonectomy was known to be associated with a higher mortality and morbidity compared with left pneumonectomy[31, 32]. Furthermore, Martin and co-workers observed that risks of perioperative death and complications were significantly higher for right pneumonectomy after preoperative radiation in patients with NSCLC[33]. Our results showed that mean DVH thresholds of developing grade ≥ 2 RP in right pneumonectomy group were significantly lower than that in left ones, but no difference in incidence between the two groups was observed. Consistent with the series of studies, it suggested that patient underwent right pneumonectomy not only suffered a worse prognosis but also had a lower tolerance to radiation. Therefore, receiving radiotherapy following right pneumonectomy should be performed only in selected patients.
As the nomogram quantifies risk by illustrating and combing the relative importance of various factors, it has been widely used in clinical assessment[34]. Thus, we developed a nomogram predicting the incidence of grade ≥ 2 RP and performed ROC curve and calibration plot to validate its prediction efficiency. The results showed that combing the values of V5 and V20 in our nomogram could be used in practical work with less bias and better accuracy. While there may be other factors influencing the occurrence of RP, further research should be carried to improve the nomogram.
This study had several limitations. Firstly, it was limited by its retrospective nature, with inevitably uncontrolled and unobserved selection bias in patient enrollment. Secondly, there were only 5 patients with grade 3 RP due to the low incidence, leading to difficulties in making further analyses. Finally, as a single-center research, the number of cases in this study was relatively insufficient. However, to be precise, they were rare but precious. Even as one of the lung cancer centers with the largest surgery quantity in China, there were only a few dozen patients with this procedure each year, and less than 10% of them received radiotherapy afterward. Notwithstanding its limitation, this is the first study exploring the optimal predictors for RP in patient with NSCLC underwent pneumonectomy, making a certain contribution to reduce the risk of RP and improve patients’ quality of life and survival.