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Effect of neoadjuvant chemoradiation on preoperative pulmonary physiology, postoperative respiratory complications and quality of life in patients with oesophageal cancer

It remains controversial whether neoadjuvant chemoradiation (nCRT) for oesophageal cancer influences operative morbidity, in particular pulmonary, and quality of life. This study combined clinical outcome data with systematic evaluation of pulmonary physiology to determine the impact of nCRT on pulmonary physiology and clinical outcomes in locally advanced oesophageal cancer.


Introduction
Although recent trends indicate reduced postoperative mortality after oesophagectomy, major morbidity, in particular pulmonary, remains high, with considerable health and economic costs 1 . In a recent modern international collaborative series 1 of 2704 patients from high-volume centres, with an approximately equal mix of open and minimally invasive approaches, major respiratory complications were evident in 28 per cent of patients, pneumonia in 15 per cent and respiratory failure in 7 per cent. In other series 1,2 , respiratory failure was reported in up to 15 per cent of patients, and was the most common cause of death. The prediction of risk and prevention of respiratory morbidity are therefore of considerable importance, and in this context baseline determination of lung physiology complements clinical assessment. Neoadjuvant therapy is increasingly the standard of care for locally advanced oesophageal cancer, with the combination of chemotherapy and radiation therapy underpinned in the modern era by the CROSS trial (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study) 3 , which combined 41⋅4 Gy, carboplatin and paclitaxel. The impact of radiation on lung physiology and its relevance to postoperative complications and survivorship are rarely studied. Modern radiation therapy is underpinned by three-dimensional (3D) conformal methods or intensity-modulated approaches, and dose-volume histograms (DVHs) are set to limit radiation delivery to non-target tissues such as lung; however, approximately 25 per cent of total lung tissue is irradiated up to 20 Gy in standard protocols. It remains unclear whether this has any clinical impact, in particular in relation to postoperative pulmonary complications. On the one hand, in the CROSS trial 3 , where 46 per cent of patients experienced pulmonary complications in the multimodal cohort, there was no difference compared with surgery alone, with a 4 per cent operative mortality rate in both cohorts. Moreover, a meta-analysis 4 of RCTs including 431 patients showed no added risk of respiratory complications or operative mortality with a variety of multimodal protocols. Conversely, several studies have suggested caution in this interpretation, as chemoradiation was associated with a significant fourfold increased operative mortality rate in the FFCD (Fédération Francophone de Cancérologie Digestive) 9901 RCT 5 , a threefold but non-significant increase in mortality compared with chemotherapy in the POET (PreOperative therapy in Esophagogastric adenocarcinoma) trial 6 , and a non-significant doubling of mortality in the NeoRes (Neoadjuvant Chemotherapy Versus Radiochemotherapy for Cancer of the Esophagus or Cardia) trial 7 , with a significant increase in major pulmonary complications. It is also inarguable that, until recently, the definition, prospective documentation and reporting of operative morbidity, including pneumonia and pulmonary complications, in published RCTs were relatively weak and inconsistent 8 . Accordingly, the question of whether neoadjuvant chemoradiation (nCRT) has a clinical or a more nuanced impact on pulmonary function remains of great relevance, and demands rigorous assessment. In this study, lung function was measured systematically before and after nCRT, and the incidence of clinically evident radiation-induced lung injury, subclinical changes in physiology that may be linked to postoperative complications, and quality of life in survivorship were evaluated.

Methods
The Oesophageal and Gastric Centre at St James's Hospital, Dublin, is a high-volume national centre, and a detailed clinicopathological database is maintained prospectively for all patients with oesophageal cancer. Records for consecutive patients with locally advanced oesophageal cancer treated with nCRT with curative intent over 7 years between 2010 and 2016 were assessed retrospectively for inclusion. Patients undergoing emergency or palliative surgery, or salvage oesophagectomy, were excluded. Pulmonary function testing was undertaken routinely for all patients being considered for surgery. All eligible patients for whom pulmonary function data were available at a minimum of one preoperative time point were included in the analysis of operative and/or oncological outcomes. Health-related quality of life (HR-QoL) among disease-free patients was assessed using validated questionnaires (European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OG25 and QLQ-OES18) 9,10 . The study was approved by the institutional review board and registered at ClinicalTrials.gov (NCT03462524).

Neoadjuvant therapy and surgery
During the trial, patients with locally advanced oesophageal cancer received nCRT, either cisplatin and 5-fluorouracil (5-FU) with 40 Gy in 15 fractions or carboplatin and paclitaxel with 41⋅4 Gy in 23 fractions) 3,11 , or perioperative chemotherapy (etoposide, cisplatin, fluorouracil or capecitabine) 12 . A lung DVH of V20 (total lung volume receiving less than 20 Gy of radiation) below 25 per cent was set, with total radiation between 40 and 41⋅4 Gy, and delivery by 3D conformal methods. Patients underwent resection approximately 6 weeks after completion of nCRT. The operative approach entailed open oesophagectomy with a gastric conduit and thoracic or cervical anastomosis, or extended total gastrectomy with mediastinal Roux-en-Y reconstruction 13,14 ; transhiatal resection was used selectively in higher-risk patients 13 .
Single-lung ventilation was achieved using a double-lumen endotracheal tube. A multidisciplinary enhanced recovery protocol was used, with intraoperative fluid restricted to 500 ml/h, thoracic epidural, immediate extubation and mobilization on day 1 as standard in this interval, with all patients post oesophagectomy monitored in a critical care setting for at least the first 48 h after surgery. All patients were seen by respiratory physiotherapists on the day after operation and underwent personalized intensive respiratory physiotherapy until discharge. A 10-Fr needle catheter jejunostomy was routinely placed at surgery, and feeding commenced on the first postoperative day 15 . All patients underwent nutritional and physiotherapy assessment at a multidisciplinary clinic at diagnosis, before surgery and at serial postoperative time points, as described previously 16,17 . Postoperative complications were coded using the Clavien-Dindo classification 18 and comprehensive complications index (CCI) 19 . Postoperative pulmonary complications were defined according to the criteria of the Esophageal Complications Consensus Group 20 , and pneumonia was diagnosed clinically in accordance with guidelines of the Centers for Disease Control and Prevention 21 . Prolonged intubation was defined as respiratory failure of any aetiology requiring reintubation or mechanical ventilation more than 24 h after operation.

Pulmonary function testing
Pulmonary physiology, including diffusion capacity for carbon monoxide (DLCO), forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), was assessed in the pulmonary laboratory at baseline and 1 month after completion of neoadjuvant therapy using the Vmax ® Encore PFT system (Vyaire Medical, Mettawa, Illinois, USA), in accordance with European Respiratory Society (ERS) and American Thoracic Society technical standards 22 23,24 . Radiation-induced lung injury was defined according to EORTC common toxicity criteria, and the incidence of lung injury of grade 2 or above was monitored.

Statistical analysis
Continuous data are reported as mean(s.d.) unless specified otherwise. Univariable comparisons were performed using linear regression, Student's t test or the Mann-Whitney U test for continuous variables, and the χ 2 or Fisher's exact test for categorical variables. For multivariable analyses, clinically relevant variables were included in linear, logistic or Cox proportional hazards regression models using a forward stepwise selection procedure. The predictive accuracy of baseline pulmonary function with respect to subsequent radiation-induced lung injury was assessed using receiver operating characteristic (ROC) curve analysis. P < 0⋅050 was considered statistically significant. Data were analysed using GraphPad Prism ® version 6.0 for Windows ® (GraphPad Software, San Diego, California, USA) and SPSS ® version 23.0 (IBM, Armonk, New York, USA).

Results
A total of 228 patients received nCRT and these represent the study cohort (Fig. 1). One hundred and thirty-three patients (58⋅3 per cent) received carboplatin and paclitaxel with 41⋅4 Gy, whereas 93 (40⋅8 per cent) received cisplatin and 5-FU with 40 Gy; the regimen was not available for two patients who had nCRT at another hospital. Some 181 patients underwent resection with curative
Reduced post-treatment DLCO was independently associated with smoking (P = 0⋅005) and increased age (P < 0⋅001), whereas smoking was independently associated with a greater absolute and relative decline in DLCO (Table S1,  On ROC analysis, baseline DLCO demonstrated 85 (s.e. 4) per cent accuracy (P = 0⋅017) for the prediction of subsequent lung injury precluding surgery (Fig. 3). A threshold baseline DLCO of less than 81⋅5 per cent predicted radiation-induced lung injury with 100 per cent sensitivity and 79 per cent specificity.

Pulmonary function and health-related quality of life
Among those who were disease-free 1 year or more after surgery (104 patients, with HR-QoL data available for 40), reduced post-nCRT DLCO was associated with poorer physical function (P = 0⋅047) and subjective trouble taking a long outdoor walk (P = 0⋅011). The neoadjuvant regimen did not influence physical function or HR-QoL in survivorship. Similarly, no baseline or post-treatment pulmonary function parameter had a significant impact on overall HR-QoL. On multivariable analysis, background respiratory co-morbidity (P = 0⋅011) and lower post-treatment DLCO (P = 0⋅038) independently predicted poorer physical function scores.

Discussion
This study has highlighted the fact that pulmonary physiology is altered negatively by modern nCRT protocols, and the impact, although nuanced and subclinical, can have a direct influence on risks of postoperative pulmonary complications and recovery of quality of life. Although FEV1 and FVC were significantly reduced by nCRT, the loss of diffusion capacity, measured by DLCO, was most pronounced and associated with clinical outcomes. The overall mean decrease in DLCO was 14⋅8 per cent compared with less than 4 per cent each for FEV1 and FVC, the latter functional lung volume data being consistent with those of the NeoRes trial 25 . In NeoRes, however, DLCO was not measured and, despite detailed cardiopulmonary evaluation, the increased burden of major pulmonary morbidity among patients treated with nCRT remained unexplained.
On the other hand, in a study of 20 patients receiving 50⋅4 Gy, oxaliplatin and 5-FU, Gergel and colleagues 26 reported a 16⋅9 per cent reduction in DLCO, with a decrease of 2⋅5 per cent in total lung capacity. Similarly, in a study from the Cleveland Clinic 27 , including 155 patients treated with a combination regimen including cisplatin and 5-FU, 108 of whom received 45 Gy and 47 received 30 Gy, decreases in DLCO of 21⋅7 and 8⋅6 per cent respectively were observed 27 . This dose-response effect is consistent with the results of Riedel et al. 28 , who reported no significant change in pulmonary function in 77 patients with locally advanced oesophageal cancer, with grade 1 radiation-induced lung injury in just one patient (1 per cent) after treatment with 5-FU and 30 Gy.
In the present study, although radiation doses were similar and the chemotherapy regimens varied, a greater decline in DLCO was observed following administration of the CROSS regimen (carboplatin, paclitaxel and 41⋅4 Gy) compared with cisplatin, 5-FU and 40 Gy. Although baseline differences in pulmonary function, and the non-contemporaneous nature of the cohorts, preclude definitive conclusions being drawn from these data, administration of carboplatin and paclitaxel with neoadjuvant radiation has been reported to increase synergistically the risk of radiation-induced lung injury, with a 3⋅3-fold increased risk of at least grade 2 lung injury among patients with non-small cell lung carcinoma, and increased pneumonitis in those with oesophageal cancer 29,30 . Furthermore, in a contemporaneous cohort of 156 patients undergoing neoadjuvant chemotherapy at the authors' centre, although reductions in DLCO were observed (P < 0⋅001), the relative reduction in DLCO was significantly greater after chemoradiation (-14⋅8(14⋅0) per cent for nCRT in the present cohort versus -7⋅3(14⋅9) per cent for neoadjuvant chemotherapy in the contemporaneous cohort; P = 0⋅003), and on multivariable analysis chemoradiation independently predicted the absolute (P = 0⋅017) and relative (P = 0⋅018) decline in DLCO during neoadjuvant treatment (data not shown). Importantly, in the present study, reduced baseline DLCO was associated with an increased risk of lung injury precluding surgery, with a threshold of less than 81⋅5 per cent exhibiting 79 per cent specificity for prediction of such injury.
Although clinically evident lung injury is rare, observed in just five patients here (2⋅2 per cent), this study has identified important associations between reduced diffusion capacity and clinical consequences, in particular respiratory failure, prolonged intubation, increased CCI and major pulmonary morbidity. Specifically, a post-treatment DLCO of less than 65⋅0 per cent predicted postoperative respiratory failure and prolonged intubation with 90 per cent specificity. The mechanisms linking changes in pulmonary physiology to postoperative complications require further investigation. Whether radiation-induced lung injury occurs as a consequence of direct radiation injury, perhaps in synergy with taxaneinduced pneumonitis, or a 'first hit' sensitization or priming of alveolar and immune cells to an exaggerated immune and inflammatory response to a 'second hit' such as single-lung ventilation, bacteraemia or pneumonia, is uncertain 31 . Fibrosis is thought to occur owing to activation of latent transforming growth factor (TGF) β, which increases the generation of reactive oxygen species via reduced nicotinamide adenine dinucleotide phosphate oxidases and resulting activation of SMAD, stimulating myofibroblast proliferation via epithelial-to-mesenchymal transition, and promoting extracellular matrix deposition 31 . These changes perpetuate tissue hypoxia and manifest as impaired diffusion, with overt fibrosis and hypoxemia its most severe clinical expression. Experimentally, increased circulating levels of TGF-β1, as well as interleukin (IL) 1α, IL-6 and monocyte chemoattractant protein 1, have been demonstrated during the development of radiation-induced lung injury, suggesting the possibility of biomarker development to facilitate treatment modification when features of lung injury are detected 32 .
In the present cohort, no difference in postoperative pulmonary morbidity was observed among patients undergoing transhiatal compared with transthoracic resection, which is probably a reflection of selective use of this operative strategy for high-risk patients; the baseline pulmonary co-morbidity rate was 45⋅0 per cent for patients having a transhiatal procedure compared with 15⋅5 per cent for those undergoing a transthoracic procedure (P = 0⋅004). A transhiatal approach has been suggested for patients with significant pulmonary co-morbidity, owing to a reduced incidence of postoperative pulmonary complications and because the need for single-lung ventilation in obviated 33 , and the present data may inform such discussions. However, minimally invasive approaches may produce similar benefits for patients with significant baseline pulmonary co-morbidity 34 , while producing favourable oncological outcomes even compared with open transthoracic resection 35,36 .
Longer-term implications of reduced DLCO after nCRT were also observed, including reduced physical function scores and increased difficulty in taking a long outdoor walk among disease-free patients on HR-QoL analysis, consistent with long-term outcomes in the NeoRes trial 25 . Given the short-and long-term implications of reduced diffusion capacity, there is great impetus to develop an understanding of the factors, both patientand treatment-related, influencing individual risk. Clearly dose is important, with increased risk at greater total radiation doses, and increased irradiated lung volumes on DVH analysis 26,37,38 . Although a DVH of V20 below 25 per cent was set in the present study, as in the CROSS protocol, clinical tumour stage tended to predict reduced percentage DLCO after treatment on multivariable analysis, probably reflecting planned clinical target volumes with greater lung exposure. Smoking also independently increased DLCO loss, an effect also reported in lung cancer, further emphasizing the need for smoking cessation in patients commencing multimodal protocols 39 .
The strength of the study is the detailed profiling of a large number of patients initially deemed fit for major surgery based on clinical assessment, with standard operative approaches underpinned by quality assurance measures. However, some limitations are acknowledged. First, although a DVH of V20 below 25 per cent was set for all patients, individual DVH re-analysis was beyond the scope of this study. Second, even though multivariable analysis was undertaken to minimize confounding between groups, the treatment allocation was not randomized, and so differences between the two chemoradiation protocols may be subject to uncontrolled bias. In addition, these data represent a single-centre experience; further multicentre collaborative efforts may lend external validity to the present data. Attrition during neoadjuvant therapy was significant compared with that in clinical trials 3,40 , but similar to that of previous consecutive cohort data 41,42 . Although three RCTs 35,43 -45 have reported reduced pulmonary morbidity with minimally invasive approaches, all patients in the present study underwent open surgery, so the implications for minimally invasive oesophagectomy are unclear. However, the present data provide a useful framework for further research in this context. This study has demonstrated that nCRT, although rarely causing clinically evident radiation fibrosis, is associated with a significant decline in pulmonary diffusion capacity overall. Reduced pulmonary diffusion was associated with an increased risk of major postoperative complications and impaired long-term quality of life. Prospective detailed recording of operative morbidity and quality of life is embedded in ongoing RCTs including ESOPEC and NeoAEGIS (NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study), which are comparing best current chemotherapy with the CROSS regimen, and these secondary endpoints will be of major interest, particularly if there is oncological equivalence 46,47 . At this time, notwithstanding advances in minimally invasive approaches, pulmonary complications remain the most common cause of postoperative major morbidity and mortality in oesophageal cancer surgery, and these data provide a rationale towards personalized treatment where pulmonary physiology, in particular diffusion capacity, a potentially targetable parameter, must be considered.