Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial

Abstract

BackgroundIncreasing the biological effective dose (BED) of radiotherapy for non-small cell lung cancer (NSCLC) can increase local control rates and improve overall survival. Compared with conventional fractionated radiotherapy, accelerated hypofractionated radiotherapy can yield higher BED, shorten the total treatment time, and theoretically obtain better efficacy. However, currently, there is no optimal hypofractionated radiotherapy regimen. Based on phase I trial results, we performed this phase II trial to further evaluate the safety and preliminary efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy(3-DCRT) combined with concurrent chemotherapy for patients with unresectable stage III NSCLC.MethodsPatients with previously untreated unresectable stage III NSCLC received 3-DCRT with a total dose of 69 Gy, delivered at 3 Gy per fraction, once daily, five fractions per week, completed within 4.6 weeks. At the same time, platinum doublet chemotherapy was applied.ResultsAfter 12 patients were enrolled in the group, the trial was terminated early. There were five cases of grade III radiation esophagitis, of which four cases completed the radiation doses of 51 Gy, 51 Gy, 54 Gy, and 66 Gy, and one case had 16 days of radiation interruption. The incidence of grade III acute esophagitis in patients receiving an irradiation dose per fraction ≥2.7 Gy on the esophagus was 83.3 % (5/6). The incidence of symptomatic grade III radiation pneumonitis among the seven patients who completed 69 Gy according to the plan was 28.6 % (2/7). The median local control (LC) and overall survival (OS) were not achieved; the 1-year LC rate was 59.3 %, and the 1-year OS rate was 78.6 %.ConclusionFor unresectable stage III NSCLC, the accelerated hypofractionated radiotherapy with a total dose of 69 Gy (3 Gy/f) combined with concurrent chemotherapy might result in severe radiation esophagitis and pneumonitis to severely affect the completion of the radiotherapy. Therefore, we considered that this regimen was infeasible. During the hypofractionated radiotherapy with concurrent chemotherapy, the irradiation dose per fraction to esophagus should be lower than 2.7 Gy. Further studies should be performed using esophageal tolerance as a metric in dose escalation protocols.Trial registrationNCT02720614, the date of registration: March 23, 2016.

Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline

“…The second important issue related to the EBRT fraction size is its anticipated relationship with acute esophagitis. Studies investigating hypofractionated thoracic EBRT with CC in the curative setting have demonstrated an association between grade 3 radiation esophagitis and the radiation dose per fraction delivered to the esophagus 17 ; however, these studies typically use much higher cumulative doses of radiation than would be typical in the palliative setting and, therefore, it is unclear how relevant these findings are to the current question. There is no clear trend between grade 3 esophagitis and EBRT fraction size or cumulative delivered EBRT doses in the 3 trials reviewed here.…”

Prediction of Radiation Esophagitis in Non–Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels

“…Clinical factors associated with RE include concurrent chemotherapy, gender, age, body mass index, pretreatment dysphagia, and nodal stage [8] , [9] , [10] . Dose-escalated, twice-daily, and hyopfractionated radiotherapy courses increase risk [2] , [9] , [11] , [12] , [13] . Improved esophageal sparing with intensity-modulated radiotherapy (IMRT) has shown promise for reducing rates of grade 3+ RE compared to 3D-conformal (3DCRT), although this has not been consistent in all studies [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] .…”

Study protocol: a multicentre, prospective, phase II trial of isotoxic hypofractionated concurrent chemoradiotherapy for non-small cell lung cancer

“…22 Radiation oncologists will then review the delineation, ensuring that no layer of oesophagus is included in the PTV. 11 …”

“…One of the important reasons was the severe, intolerable radiation-induced oesophagitis. 11 After summarising and comparing the enrolled patients and the radiotherapy dose parameters in the phase I and phase II trials, we believe that administration of a uniform radiotherapy dose to all patients may give rise to the following two consequences due to tumour size differences and adjacent organs: First, for large tumours and/or tumours adjacent to important tissues, severe radiotherapy damage may occur, which is likely to prevent patients from completing the radiotherapy regimen. Second, for small tumours that are not adjacent to important organs, the radiotherapy dose may be insufficient, which causes a decrease in local control, and thus affects efficacy.…”