Margriet Kwint

Chapter 8 150 Several trials investigated dose escalation using such isotoxic planning strategy without extending the overall treatment time (15-19). An overview is given in Table 1. The reported acute and late toxicity rates of these trials are classified ‘acceptable’. Altogether, these studies indicate that dose escalation with reduced overall treatment time by increasing the dose per fraction or twice daily irradiation, is a promising method. Several (randomized) trials are ongoing in which isotoxic hypofractionated dose escalation with the use of an FDG-PET scan are investigated (16, 20-24). The results regarding treatment outcomesarepending. Thephase II PETboost trial (NCT01024829) (21) toxicity outcomes were recently reported (22). In this international trial, LA-NSCLC patients were randomized between dose escalation to the entire primary tumor (arm A) or to the high FDG-uptake region inside the primary tumor (>50% SUVmax, arm B), whilst giving 66 Gy in 24 fractions to the involved lymph nodes. Grade≥3 toxicity were reported in 41% (acute) and 25% (late) of the patients. In 9 patients (8%) fatal pulmonary hemorrhages and esophageal fistulas were observed (22). This is a higher incidence compared to our cohort results (acute & late toxicity combined grade≥3 was 29% and 10% for the reference- and reduction cohort respectively). In the PET boost trial, the same dose as our reference cohort (24x2.75 Gy) was given to the involved lymph nodes, however in patients selected with large primary tumors (> 4 cm). Combining these findings we can conclude that a differentiated dose prescription to the involved lymph nodes combined with dose escalation to the primary tumor with restricted overall treatment time, is a promising option for further testing. To summarize, many recent studies revealed that the paradigm ‘the higher the dose, the better the outcome’ is not always true. Caution is required in dose escalation trials especially when dose-escalation is combined with a prolonged overall treatment time. Currently, new strategies for dose escalation are investigated, such as personalized isotoxic planning. These promising strategies will hopefully lead to further improved local control without compromising the dose to organs at risk.