Phase I study of radiotherapy dose escalation on the 18F-FDG-PET avid region of the primary tumor in locally advanced oropharynx and oral cavity tumors eligible for concurrent chemoradiation.

Local relapse remains an important problem in advanced head and neck tumors
(1,2), most recurrences occur in the primary tumor/high dose area (3). Several
studies have suggested that dose escalation can improve local control (4,5) and
consequently overall survival (1,6). IMRT with Simultaneous integrated boost
(SIB) makes dose escalation possible while keeping the dose to the organs at
risk acceptable (7). Fluoro-2-deoxy-D-glucose positron emission tomography
(18F-FDG-PET) is of interest for delineating radioresistant subvolumes (8).
Volume change during radiation therapy can be tracked with implanted gold
markers (9). A replanning after 3 weeks of radiotherapy will be performed. In
the second plan, it is only allowed to adjust the GTV-PET based on the
deformation of implanted gold markers.

References:
1. Posner MR, Herschock DM, Blajman CR, et al. Cisplatinum and Fluorouracil
alone or with Docetaxel in head and neck cancer. New Eng J Med 2007,
357;17:1705-1715.
2. Knegjens JL, Pameijer FA, Balm AJ, et al. Tumor Volume as Outcome Predictor
in Chemoradiation for Advanced Head and Neck Cancer. Int J Radiat Oncol Biol
Phys 2007, 69;S410-S411
3. Dawson LA, Anzai Y, Marsh L, et al. Patterns of local-regional recurrence
following parotid-sparing conformal head and neck cancer. Int J Radiat Oncol
Biol Phys 2000, 46;1117-1126
4. Eisbruch A, Dawson LA, Kim HM, et al. Conformal and intensity modulated
irradiation of head and neck cancer: the potential for improved target
irradiation, salivary gland function, and quality of life. Acta
Otorhinolaryngol Belg 1999, 53;3:271-5.
5. Levendag PC, Nowak PJCM, van der Sangen MJC, et al. Local tumor control in
radiation therapy of cancers in the head and neck. Am J Clin Oncol 1996,
19;5:469-477.
6. Wadsley JC and Bentzen SM. Investigation of relationship between change in
locoregional control and change in overall survival in randomized controlled
trials of modified radiotherapy in head and neck cancer. Int J Radiat Oncol
Biol Phys 2004, 60;5:1405-1409.
7. Madani I, Duthoy W, Derie C, et al. Positron emission tomography-guided,
focal dose escalation using intensity-modulated radiotherapy for head and neck
cancer. Int J Radiat Oncol Biol Phys 2007, 68;1:126-135.
8. Ragendran JG, Mankoff DA, O`Sullivan F, et al. Hypoxia and glucose
metabolism in malignant tumors: evaluation by [18F]Fluoromisonidazole and
[18F]Fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res
2004, 10;2245-2252.
9. Hamming-Vrieze O, Kranen SR, van Beek S et al. Evaluation of tumor
variability in head-and-neck cancer patients over the course of radiotherapy
with implanted gold markers. Poster 241, ESTRO 27, Goteburg 2008.

Primary objective:
• To determine the maximum tolerated dose of radiation to the FDG-PET avid
subvolume within the GTV of the primary tumor.
Secondary objectives:
• To determine the incidence and severity of acute and late toxicity of dose
escalation according to the CTCAE toxicity scales v3.0
• To document tumor response (loco-regional control, overall and cause specific
survival and cause of death).
• To analyse pattern of failures
• To determine the effect of replanning of the PTV-PET after 3 weeks of
radiotherapy

A single centre, phase I, radiation dose escalation trial using time-to-event
continual reassessment strategy

Schedule of events:

Prepartations: Week 1: Week 2: Week 3: Week 4: Week 5:
Week 6: Week 7: 4 months: Recurrence:
MRI diagnostic 5x RT 5x RT 5x
RT 5x RT 5x RT 5x RT 5x RT
MRI MRI mask
OON + markers CDDP CT masker
CDDP
CDDP CT mask
CT mask
PET-CT mask
(OON: Investigation under anesthesia, RT = radiotherapy, CDDP = Cisplatinum 100
mg/m² i.v., MRI/CT mask: scan with radiotherapy mask).

All patients receive a radiochemotherapy treatment with dose escalation in the
PET positive region of the primary tumor according to these dose levels:
Dose level 0
Dose level I Dose level II Dose level III Dose level IV
PTV-PET primary tumor 35x2.0 (70.0) 35x2.1 (73.5) 35x2.2 (77)
35x2.3 (80.5) 35x2.4 (84)

A replanning after 3 weeks of radiotherapy will be performed. In the second
plan, it is only allowed to adjust the GTV-PET based on the deformation of
implanted gold markers.

No additional pretreatment investigations have to be done since patients with
large inoperable oropharynx or oral cavity tumors scheduled for
radio-chemotherapy, already undergo a PET scan and investigation under
anesthesia with implantation of gold markers, to aid tumor delineation. During
treatment, patients participating in this study, have to undergo an extra
planning CT scan after three weeks of radiation therapy. Furthermore, if
residual disease or a local recurrence is suspected, an additional MRI and CT
in old treatment mask should be done to visualize the recurrence in reference
to the markers. Otherwise, no extra investigations or visits are necessary.
In conclusion, one additional CT scan is negligible relative to the treatment
with external radiation therapy. Only patients with a local recurrence undergo
a second additional CT scan and a MRI in treatment mask.