Hypofractionated Accelerated Radiotherapy With Concomitant Full Dose Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: Phase I/II Study

1. Background Lung cancer is the most common malignancy in Poland. In 2013, the annual lung cancer incidence in Poland was 175/100 000 in men and 95/100 000 in women, substantially higher than the EU value. Poland and UK are the first countries in Europe, where the mortality from lung cancer has overtaken the mortality from breast cancer and became the first cause of mortality from cancer in women. Thus besides the problem of prevention, the efficient and rational from economical point of view treatment of lung cancer is one of the crucial problems in Polish healthcare system. Prolongation of overall treatment time is deleterious for patients with locally advanced (LA) - non-small cell lung cancer (NSCLC) even if radio-chemotherapy (RT-CHT) is used. Current standard of treatment for LA-NSCLC is concurrent radio-chemotherapy (RT-CHT), because survival benefit with the increase of esophageal toxicity was demonstrated in a meta-analysis. Acceleration of radiotherapy (RT) via hyperfractionation results in survival benefit as it was shown also in a meta-analysis but at the expense of higher esophageal toxicity Hyperfractionated RT schedules were used with low-doses of CHT, because of the fear of accumulation of acute toxicity Hyperfractionation represents an additional burden for equipment, staff and health care system and cannot be routinely realized, especially in limited .resources setting. For patient, it is also associated with higher treatment cost, i.e. by payment of cost of transport twice a day.

Alternative for acceleration of RT time is the use of hypofractionated RT schedule. Such a radiation schedule is in the routine use in some countries. However, hypofractionation has been often considered as palliative approach and even in limited resources countries is still rarely proposed for curatively treated patients. In only three out of 36 (8%) analysed Eastern and Central European centres that responded in the IAEA pattern of care survey, the hypofractionation was used for curative treatment of LA-NSCLC. We have also very few data from prospective studies that report on the concomitant hypofractionated RTwith full dose CHT. The RTOG 0117 study arm that used slightly hypofractionated RT schedule with dose escalation (75.25 Gy with 2.15 Gy fractional dose) and concomitant full-dose CHT was interrupted because of the excessive toxicity. However, the total dose escalation used in this study might be a reason for a failure of such an approach. Recently, the concept of dose escalation with concomitant CHT has been compromised for LA-NSCLC. When using hypofractionation, the total radiation dose should probably be adapted to correspond to biological doses of around 66 Gy, because we have reports that confrm safety of such a schedule. In opposite to that the dose escalation using hypofractionation for central tumors led to the excessive long-term toxicity due to the bronchial tree stenosis and perforations. In a few centers in Poland, the hypofractionated RT with total dose of 58.8 Gy in 21 fractions (in 4 weeks; in the third week 6 fractions are given) following two cycles of CHT or as RT alone is routinely used. Safety and efficacy of this approach was established in a phase II prospective trial. A question arises if such a RT schedule may be used concurrently with CHT. Given the proven benefit of concurrent RT-(full dose)CHT in stage III NSCLC, data on the value of overall treatment time and in order to spare RT resources we have decided to conduct a phase I/II trial on concomitant RT-(full dose)CHT using accelerated hypofractionation schedule as currently being in routine use in Poland for sequential combination or RT alone. Confirmation that toxicity and outcome in terms of local control and overall survival are similar to those observed in contemporary series of conventionally fractionated RT-CHT will lead to the incorporation of this schedule into routine practice in Poland. Such a schedule with shortened overall treatment time via hypofractionation will contribute to essential sparing of RT resources, still insufficient in Poland. Positive outcome of this study may be also a basis for future conduction of phase III study that compares conventionally fractionated RT-CHT with accelearated hypofractionated RT-CHT for stage III NSCLC. 2. Objectives of the study:

To estimate toxicity and efficacy of accelerated hypofractionated RT combined with concurrent full-dose CHT for locally advanced NSCLC.

STUDY HYPOTHESIS:

RTOG/EORTC grade III and higher esophageal or pulmonary acute toxicity will not be higher than in conventionally fractionated concurrent RT-CHT i.e. 25%.