Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers – an observational clinical trial

Twenty six patients with HN tumors were treated between 2012 and 2014 and retrospectively evaluated in this study (patient characteristics are summarized in Table 1). All patients were treated with standard of care normo-fractionated (84.6%) or SIB-IMRT (15.4%) plans in a curative approach. After the consent of an interdisciplinary tumor-board, patients were treated with concurrent IMRT-chemotherapy or with IMRT alone. Cumulative doses ranged between 60 and 70.4 Gray (Gy) (median dose 65 Gy) at single doses ranging between 1.7 and 2.2 Gy for SIB concepts with otherwise normo-fractionated schemes (2 Gy up to 50 Gy, then 2 Gy to a cumulative dose to the boost volume of 70 Gy). Four patients (15.4%) received a simultaneously integrated boost (SIB) to the primary tumor and to metastatic lymph nodes. IMRT or dynamic arc treatment planning was performed using Eclipse planning software (Varian Medical Systems, Palo Alto, CA) by experienced medical physicists.

For every patient a planning CT scan after manufacturing an individual thermoplastic mask fixation system in 3 mm slices after application of contrast media was performed. Nearly all patients got an additional MRI scan before treatment planning. MRI and CT data sets were merged for better target delineation and in the postoperative situation to exclude early relapse behind transplants and retropharyngeal lymph node involvement. For definitive normo-fractionated RT the GTV of the primary tumor (GTV-PT) and involved lymph nodes (GTV-LN) was delineated. The boost volume was generated by adding a margin of 10 mm around the GTV-PT and individual fit on each slice for anatomical boundaries considering set-up error was applied. To the GTV-LN 5–7 mm were added as margin to define the CTV. An additional margin of 3 mm was added for set-up error.

In the definitive SIB-IMRT the contouring was performed as explained: for the SIB high dose volume (2.2 Gy up to 70.4 Gy) GTV-PT/LN plus 5 mm margin, SIB intermediate dose volume (2.0 Gy up to 64.0 Gy) GTV-PT/LN plus 10 mm margin. The PTV for elective nodal irradiation was performed in all cases after the recommendations by Gregoire et al. The elective to treat lymph node drainage was either treated up to a total dose of 50 Gy definitive as well as adjuvant (single dose 2 Gy) or in a definitive SIB concept to 54,4 Gy (single dose 1.7 Gy). The involved lymph nodes received 70 Gy.

In the adjuvant treatment situation the pre-operative GTV of primary tumor and involved lymph nodes were delineated after merging the pre-operative imaging to the planning CT, to define the pre-op GTV exactly information from pre-operative imaging, histology report and surgery report) were used. Two different adjuvant RT schemes were applied. Either normo-fractionation or a SIB-concept was used. The PTV for normo-fractionation was defined as described above. For the adjuvant SIB-concept for the SIB-volume (2.14 Gy up to 64.2 Gy) the pre-operative GTV-PT and GTV-LN got a margin of 10 mm. Flap transplants of the initial primary tumor region were included into the SIB-volume, it is described that the transplants tolerated RT well. The PTV definition was made in the same way as mentioned above. Conventional constraints to the OAR were applied (e.g. brainstem D_max 54Gy, Spinal cord D_max 45Gy). Additionally to the OAR, the AP, the dorsovagal complex (DVC) and the VS were contoured retrospectively using co-registered MRI imaging. The brainstem was divided into two halves (a cranial one (Box 1) and a caudal one (Box 2). No constraints were set on these additional structures, because they were not considered during treatment planning (Fig. 1).

Normo-fractionated radiation was performed with linear accelerators (Varian Medical Systems, Palo Alto, CA) using 6 MeV photons.

Concurrent chemotherapy (Cisplatin 20 mg/ m² body surface/day 1–5 and day 29–33, Cisplatin 40 mg/m² body surface/once weekly (up to six cycles) or (in one advanced case) Paclitaxel, 30 mg/m² body surface/twice weekly, 4 cycles in total) was administered on our ward if indicated (in definitive chemo-irradiation and in the postoperative adjuvant/additive setting because auf extracapsular spread or R1-situation). Standard supportive care in the cisplatin protocol is the use of dexamethasone 16 mg IV and Granisetron 1 mg also IV in 100 ml NaCl 0.9% applied over 15 min prior to cisplatin. On the following 2 days patients get Dexamethason 16 mg per os and Metoclopramide three times a day 10 mg per os. Despite the antiemetics Pantoprazole 40 mg is given per os on each day.

At different time points during treatment (at the beginning, in the middle and last week of treatment) patients were evaluated concerning nausea and vomiting toxicity according to the National Cancer Institute’s Common Toxicity Criteria (v4.0) as standard procedure on ward rounds [12]. Symptoms recorded were intensity and duration of nausea, frequency of vomiting and accompanying symptoms such as pallor, cold sweating, tachycardia, hyper-salivation, gagging and neurological abnormalities. We also recorded if antiemetic drugs were given.

Later we correlated D_mean and D_max radiation doses of previously defined organs and volumes (AP, DVC, VS, Box 1 and 2) to present toxicity scores. Herein we evaluated 98 individual time points during radiotherapy.

For categorical data absolute and/or relative frequencies are presented. Within and between subjects correlation coefficients were determined in order to assess associations between administered doses and toxicity scores [13, 14]. A receiver operating characteristics (ROC) analysis was conducted to evaluate associations between doses administered to different sites and presence of any toxicity (toxicity score > 0). Due to multiple observations per patient, the method for correlated data proposed by Obuchowski was conducted [15]. Areas under the receiver operating characteristics curve (AUC) and corresponding 95% confidence intervals are presented. For all statistical tests, a significance level of 5% was used.