br higher ADC values in GTVADC than
higher ADC values in GTVADC than the rest of the patients (see Fig. A.2). In the ADC plot of all separate 46 Pronase E node GTVNx volumes no si-
milar ‘outliers’ could be identified with overall higher ADC values (see Fig. A.3).
In this study we evaluated ΔADC in primary tumour and pathologic lymph nodes during radiotherapy treatment and found consistent in-creases at both sites. Furthermore ADC measurements can be acquired using T2-based delineations, as long as there is no shift between T2 and ADC mapping. This study has not conclusively identified an appropriate cut-off point for the ΔADC in GTVADC for identifying patients that would have an increased risk for recurrence, due to the low number of events in the study.
To our knowledge, this is the first study that investigates changes in whole pathologic lymph node ADC values during treatment. In
Patients with recurrence (overall) after median follow-up of 15 months (range 7–22 months). Note that not all nodal recurrences could be found in retrospect on initial MRI before treatment. However, four of the 46 lymph nodes that were initially treated with a boost up to 55–60 Gy recurred. All regional recurrences included in-field nodal recurrences. In patient four, none of the lymph nodes that recurred were present at time of diagnose, therefore no ADC value could be derived during treatment.
Patient # with recurrence 1 2 3 4
FIGO stage IIB IIIB IB2 IIA Number of positive lymph nodes before treatment 10 4 2 Histopathologic subtype SCC SCC AC SCC Time of recurrence after treatment (months) 6 9 12 12 Type of relapse (local/regional/distant) regional/distant regional/distant local regional In field lymph nodes (yes/no) yes yes n/a yes Number lymph nodes within/near high dose boost volume at time of recurrence 6 1 n/a ΔADC in GTVADC or GTVNx between baseline and at 4 weeks during treatment (mm2/s) 0.08; 0.57; 0.42 0.75 0.03 n/a*
Fig. 5. Primary tumour volume (GTVADC) decrease in relation to ADC increase. There was no significant correlation found between the two parameters. Recurrences are visualised in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Our study is limited by the relatively low number of patients and identified individual affected lymph nodes and the low number of events after treatment. Secondly, the follow-up period of 15 months is relatively short since 80% of the recurrences occur within up to 3 years after treatment [6,11,29]. However, this study corresponds well with former results in the literature; the primary tumour volume is reduced on average by 51% (literature 50%), and the lymph node tumour vo-lume by 40% (literature 38%) [3,30,31]. Furthermore both ΔADC va-lues of GTV and pathologic lymph nodes rise during treatment within the expected range. Another limitation was the small size of the lymph nodes making measurements of volume and ADC susceptible to greater uncertainty (see Fig. A.3). Furthermore, all 46 lymph nodes were ana-lysed as being independently. However, within the same patient, tu-mour biology of within separate lymph nodes may be similar. During median follow-up of 15 months, lymph node relapse rate was 15% (literature 11–13%), and overall failure was 20% (literature 20%) [5,32–34].
Higher GTV ADC values were seen in four patients (Fig. A.3). Two of these cases show tumours that infiltrate around multiple benign cysts which have a high ADC value. Three of the four patients had adeno-carcinomas and two of the four patients show regional recurrences. In future studies, ADC values in adenocarcinomas would be interesting to investigate, especially because of the well-known worse outcome of this histopathological type . Additionally, it might be interesting to add a dynamic contrast enhanced (DCE) sequence to tumour assessment as some have found non-enhancement a potentially useful predictor for
tumour recurrence .
Although there was no significant relation between ΔADC of tumour or lymph nodes and relapse, all four patients that relapsed (one local and three regional) showed little tumour reduction (median 19%, range 3–30%) in comparison with the group of non-relapsed patients (median 57%, range 21–100%) (Fig. 4). From past literature we have learned that initial tumour size (along with other clinical factors like FIGO stage and histopathologic subtype) and tumour response during EBRT are important prognostic factors for overall survival and LC [11,37]. Fur-thermore, available data indicate that FIGO > stage IB2 and (para-aortic) lymph node involvement before treatment is associated with higher chance of lymph node and distant relapse [5,13]. Recent lit-erature from Schernberg et al., demonstrates significantly higher pro-gression free survival and distant relapse free survival in patients that showed a GTV reduction > 90% during EBRT in a cohort of 255 pa-tients treated with CRT and IGABT . They also found significantly worse local, regional and distant outcomes when GTV and CTVHR were > 7.5 cm3 and > 25 cm3 respectively at the time of bra-chytherapy. Therefore, the question is; could poor local response pre-dict poor regional response to the same treatment that might ask for intensifying treatment? Schernberg et al. showed a relation between tumour reduction during EBRT and required dose to the D90% of the CTVHR for LC, however, they emphasised that more research is needed to identify those patients that would need dose escalation or dose de-escalation . As IGABT has improved 5 year LC to > 90% for most patients , the EMBRACE II study  focuses on identifying risk factors for lymph node recurrences.