IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients

Background Preliminary very encouraging clinical results of intensity modulated radiation therapy (IMRT) in Head Neck Cancer (HNC) are available from several large centers. Tumor control rates seem to be kept at least at the level of conventional three-dimensional radiation therapy; the benefit of normal tissue preservation with IMRT is proven for salivary function. There is still only limited experience with IMRT using simultaneously integrated boost (SIB-IMRT) in the head and neck region in terms of normal tissue response. The aim of this work was (1) to establish tumor response in HNC patients treated with SIB-IMRT, and (2) to assess tissue tolerance following different SIB-IMRT schedules. Results Between 1/2002 and 12/2004, 115 HNC patients have been curatively treated with IMRT. 70% received definitive IMRT (dIMRT), 30% were postoperatively irradiated. In 78% concomitant chemotherapy was given. SIB radiation schedules with 5–6 × 2 Gy/week to 60–70 Gy, 5 × 2.2 Gy/week to 66–68.2 Gy (according to the RTOG protocol H-0022), or 5 × 2.11 Gy/week to 69.6 Gy were used. After mean 18 months (10–44), 77% of patients were alive with no disease. Actuarial 2-year local, nodal, and distant disease free survival was 77%, 87%, and 78%, respectively. 10% were alive with disease, 10% died of disease. 20/21 locoregional failures occurred inside the high dose area. Mean tumor volume was significantly larger in locally failed (63 cc) vs controlled tumors (32 cc, p <0.01), and in definitive (43 cc) vs postoperative IMRT (25 cc, p <0.05); the locoregional failure rate was twofold higher in definitively irradiated patients. Acute reactions were mild to moderate and limited to the boost area, the persisting grade 3/4 late toxicity rate was low with 6%. The two grade 4 reactions (dysphagia, laryngeal fibrosis) were observed following the SIB schedule with 2.2 Gy per session. Conclusion SIB-IMRT in HNC using 2.0, 2.11 or 2.2 Gy per session is highly effective and safe with respect to tumor response and tolerance. SIB with 2.2 Gy is not recommended for large tumors involving laryngeal structures.


Background
Preliminary very encouraging clinical results of IMRT in HNC are available from several large centers [1][2][3][4][5][6]. Tumor control rates seem to be kept at least at the level of conventional three-dimensional radiation therapy (3DCRT); the benefit of normal tissue preservation with IMRT is proven for salivary function; reduced dose exposure of the mandibular bone is described (manuscript submitted).
There is still only limited experience with simultaneously integrated boost (SIB) application in the head and neck region in terms of normal tissue response. As known from 3DCRT, dose, fractionation and treated volumes are the tumor control and normal tissue tolerance defining parameters. Dosimetric and volumetric relationships need to be newly defined for SIB, as the radiobiological response of intermediate dose volumes encompassing relatively small high-dose areas with increased doses per fraction seems to substantially differ from the situation in conventional techniques.
The intention of this prospective study was to present 3year experiences in SIB-IMRT of HNC patients, focused on tumor response and tissue tolerance following different SIB schedules.

Results
115 of 310 head and neck carcinoma (HNC) patients referred to our radiation oncology institution were treated curatively with IMRT (nasopharyngeal tumors excluded from analysis). The analysed patients were irradiated between January 2002 and December 2004; the mean follow up time was 18 months (10 -44).
The specific aims for performing IMRT were parotid gland sparing (n ~100), and/or mandible bone sparing (n = 76) and/or anterior visual pathway and/or brain sparing (n = 10). 34 patients (30 %, 30 following an R1 resection) were treated in a postoperative setting, 80 patients (70 %) underwent a primarily definitive radiation, re-irradiation after high dose 3DCRT was performed in one patient. One patient received preoperative irradiation.

Subacute and late toxicity (> 90 days from treatment completion)
19 (18 %) grade 3/4 subacute or late effects (included 2 cases with a grade 3 xerostomia) in 18 out of 109 individuals treated with SIB-IMRT, were observed so far (Table 4); all lesions were localized in the high dose SIB area (PTV1, mean 176 cc, range 78 -299), and developed 2 -12 months after SIB-IMRT completion. This includes a dysphagia grade 4, a laryngeal fibrosis grade 4 requiring a permanent tracheostoma, an osteo-radionecrosis grade 3 of the mandible, which was resolved by lingual bone decortication, grade 3 dysphagia in 2 cases, grade 3 xerostomia 1 year after IMRT in 2 (in one of them no parotid gland sparing was performed), and mucosal ulcers in 12 cases.
The most frequent grade 3/4 late term effect was mucosal ulceration in the area of the SIB. This was characterized by its appearance mean 4 months (2 -6) after IMRT completion, by its persistence for mean 3 months (1 -7), and spontaneous healing in all locally controlled cases. All ulcers occurred in oro-hypopharyngeal and oral cavity tumor patients, no ulcer was observed in paranasal sinus or nasopharyngeal cancer patients. In 3 patients who suffered from persisting ulceration for a period longer than 7 months, underlying tumor persistence was histologically confirmed 8, 10 and 11 months after completion of treatment. One of these three patients experienced substantial ulcer bleeding from the large tumor ulceration which was already present before IMRT start.
The patient with grade 4 laryngeal fibrosis became symptomatic after a latency of 12 months following treatment with SIB 2.2 to 66 Gy for a large T4 hypopharyngeal cancer that involved the oropharynx, hypopharynx and larynx.
No hot spot was delivered to the area of the actinic lesion. 3.5 years post treatment, this patient is free of disease.
The 3 patients with grade 3/4 dysphagia were treated for extended T3 primaries of the hypopharynx (2) and oropharynx (1); all three affected patients are women. After follow up periods of 9 and 14 months, no improvement was observed in two; a third patient was lost of follow up 9 months after treatment completion.
SIB-IMRT resulted in a 1-year swallowing / salivary function of grade 0 -1 dysphagia / xerostomia in 95 / 80 % (n = 77). In only 2 patients, less than 30 % of the total parotid gland volume (both parotid glands = 100 % volume) could be kept below mean doses of 26 Gy; in 74 % of the patients the spared glandular total volume ranged between 60 % and 100 %, in ~25 % of the patients, the protected glandular volume ranged between 30 and 60 % ( Figure 7 and Figure 8 illustrate an example of spared total parotid gland volume of 62 %).
When late reactions are analysed according to the different SIB schedules, the following distribution was found: 7 events developed in the 33 SIB 2.2 cases (21 %), 10 events in the 47 SIB 2.11 (21 %), and 2 in the 22 of 29 SIB 2.0 patients (9 %) with doses > 65 Gy.
At one year post treatment, mean weight loss was 4 % (range minus 24 % to plus 13 % of pre-treatment value); 7/77 patients with 1 year follow up still had ≥ 10 % less weight than before treatment, 18 patients reached their initial weight or more (n = 10).

Disease control
The high 2-year locoregional disease free survival as well as the locoregional failuare pattern in our patients is comparable to the excellent results reported in the literature on IMRT of head and neck tumors ( Table 5). Most of these results are superior to historic results following 3DCRT series with disease free survival rates ranging between about 40 and 88 % [4,7].
Actuarial 2 year local disease free survival according to the T-stages Figure 3 Actuarial 2 year local disease free survival according to the T-stages.  Operated patients in our cohort showed half as large tumors and half the local recurrence rate as primarily irradiated patients. The significant correlation between tumor size and tumor control is shown by several investigators [8,9].
Considering own and published results on locoregional failure analyses [1,5,10,11], one can conclude that the volumetric concept used so far in HNC IMRT is appropriate, and the loco-regional control can hardly be improved by volumetric optimisation.

SIB-IMRT
The advantage of SIB-IMRT consists in a better target conformity [20][21][22][23][24], less dose to critical structures, moderate treatment acceleration with reduced total treatment time, and the option of dose escalation in the gross tumor volume.
There is limited experience in normal tissue tolerance following SIB-IMRT in HNC.
We found SIB 2.11 and SIB 2.2 equally well tolerated and safe with respect to acute and late normal tissue tolerance compared to 3DCRT, except of the described grade 4 reactions when 2.2 Gy per session delivered to larger laryngeal areas. The weakness of this comparison lies in its retrospective approach.
The unexpected observation of very few (~15 %) cases with grade 3 acute mucositis despite full SIB dose delivered to the mucosa, and observed better tissue healing, are interesting and clinically relevant findings that may indicate a higher tolerance, when surrounding tissue volumes are exposed to lower doses. This phenomenon has been described decades ago, based on the clinical observation of the so called 'grid therapy' [30][31][32][33][34], a technique used to deliver high single fraction doses of radiation by converting a large treatment field into many smaller fields. The use of this technique goes back to the beginning of the last century when orthovoltage radiation was mainly used for external beam radiation therapy. Small areas of skin within an irradiated field, shielded from direct radiation, are reported to serve as centers for re-growth of normal skin tissue, and allowed up to six times the conventional open doses without an increase in skin reactions or complications to underlying structures.
Moreover, grade 3/4 late effects could not be related to hot spots in the majority of our cases, indicating additional factors determining normal tissue tolerance in IMRT.
With respect to future proceeding, mild dose escalation limited to the GTV in patients with intermediate tumor LRF loco-regional failure; DF distant failure; LC local recurrence; LRR loco-regional recurrence; NR nodal recurrence; TTF time to failure; GTVPT primary gross tumor volume, GTV LN lymph node gross tumor volume; PTV1 planning target volume 1 (boost).

Conclusion
IMRT in HNC, using the planning target volume and dose concept as described, is a highly effective technique with respect to tumor response and tolerance. SIB-IMRT is safe and similarly well tolerated using either 2.11 or 2.2 Gy per fraction to total doses of 66-70 Gy, although is not recommended for large tumors involving laryngeal structures.
There is clinical evidence for increased normal tissue tolerance following IMRT.

SIB schedules
SIB was performed in 109/115 patients; in the remaining six cases a single dose-volume was painted.

Biomathematical consideration
In order to employ a slightly accelerated SIB schedule, 30 × 2. During the first 20 months, SIB-IMRT was performed with SIB 2.2 according to the RTOG study protocol H-0022.
Intermediate doses were individually defined to regions considered at high risk for microscopic disease (PTV3, doses ranging from 56 -60 Gy).
In 7 / 33 patients subacute mucosal ulcers were observed. As a consequence the decision was made to change the In all patients with tumor extension close to, or invading the central nervous system (CNS), and in most patients treated in a postoperative setting (n = 22/34), SIB 2.0 was prescribed. Doses to CNS structures never exceeded 2.0 Gy per fraction and 70 Gy total dose, respectively.

Planning Computerized Tomography (Planning CT)
Planning CT (Somatom Plus 4, Siemens) was acquired with 2 -3 mm slice thickness and no interslice gap throughout the whole sequentially acquired region of interest. Patients were immobilized in a commercially available thermoplastic mask with fixed head and shoulder. An integrated individually customized bite block.
In patients with postoperative irradiation gross tumor volumes were drawn slice by slice in the planning CT, based on diagnostic preoperative MRIs and PET-CTs, which were available for all patients. In the majority of the definitively An example of an IMRT isodose plan using simultaneously integrated boost Figure 6 An example of an IMRT isodose plan using simultaneously integrated boost. Depicted is an axial slice, 64 mm above the isocenter of the plan. Contoured are PTV1 (69.6 Gy), PTV2 (60 Gy) and PTV3 (54 Gy), gross tumor volumes of the primary and macroscopic nodal disease, and normal structures (spinal cord, brain, parotid glands, anterior soft tissues, dorsal soft tissues). Note the well-spared spinal cord and parotid glands despite of bilateral nodal disease covered with high doses (nodal and primary gross tumor volumes included into the PTV1).

Delineation of planning target volumes (PTVs) Definitions
Gross Tumor Volume (GTV) with a margin of 10-15 mm was included in the SIB volume (PTV1, 60 -73 Gy) Elective lymph node regions (PTV2, doses between 48 -56 Gy): In hypopharyngeal, central oropharyngeal and lateral oropharyngeal tumors extending to midline structures, An example of an IMRT isodose plan using simultaneously integrated boost Figure 7 An example of an IMRT isodose plan using simultaneously integrated boost. A more distal axial slice 12mm above the isocenter bilateral lymph node regions level 2 -5 and retropharyngeal nodes were included.
In lateral oropharynx tumors with bilateral nodal disease, bilateral nodes level 2 -5 were irradiated. In cases with minimal contralateral nodal disease, level 2 -5 excluding the uppermost part of contralateral level 2 was included.
In nodally negative lateral T1-2 oropharynx tumors without infiltration of the tongue and without palatinal infiltration crossing the midline, the elective node irradiation was limited to the ipsilateral side. In T3/4 N0 or ispilateral N1/2 situations, ipsilateral level 2 -5 and contralateral level 2 -4 without the uppermost part were included, respectively.
Submandibular nodes have been electively included only in oral cavity tumors, or in tumors extending to the oral cavity.
Dose constraints for normal tissues / organs at risk (OARs) outside PTVs (see also Figures 6,7,8,9) Dose planning aimed at target doses of 60 -70 Gy. Normal tissue doses were defined as follows: Spinal cord/brain stem: maximum dose (Dmax) < 45 Gy, mean dose (Dmean) < 35 Gy (spinal cord was contoured with an at least 5 -10 mm margin, > 10 mm at the ventral aspect) An example of an IMRT isodose plan using simultaneously integrated boost Figure 8 An example of an IMRT isodose plan using simultaneously integrated boost. A sagital view of a T2N2c staged hypopharyngeal cancer patient.
Parotid (entire or partial) gland volume, spared to the degree possible without compromising target coverage: Dmean < 26 Gy (outlined was the partial volume provided to be spared, no overlapping with PTVs; contouring of the entire glands for analytic purposes) Optic nerve outside PTV: Dmax < 50 Gy (optic nerve, retina and chiasm were contoured with a safety margin of 2 -4 mm) An example of an IMRT isodose plan using simultaneously integrated boost Figure 9 An example of an IMRT isodose plan using simultaneously integrated boost. A coronar view of a T2N2c staged hypopharyngeal cancer patient.

Radiation
Irradiation was delivered by 6 MV photon beams on a Varian linear accelerator with sliding window technique. The technical solution of choice was a 5 field arrangements ('class solution') for most patients (n = 100); 6 fields were applied in 7, 7 fields in 8 patients.
Patient alignment was checked before radiation by portal imaging. Deviations of > 2 mm in nasopharyngeal cancers and paranasal sinus tumors, of > 3 mm in all other tumors, respectively, were corrected before treatment. Three-dimensional position deviations from the digitally reconstructed radiographs (DRRs) were compared and calculated automatically (lateral and axial deviation, rotation).
In the first 30 patients treated with IMRT at our institution, the accepted deviation was only 2 mm, independent of the diagnosis. The position in all patients used to be checked on a daily base for the entire treatment time and was prospectively analysed.
Deviations of >2 mm occurred in 108 out of 241 evaluated treatment sessions in patients (1:2.2 incorrect-to-correct position-ratio); 2/3 of all deviations that required a pre-treatment correction were observed in patients with large fields (when lymphatic pathways included in the treatment volume).
Based on those data we went over to a) an accepted 3 mm deviation for all patients except of those with sinonasal and nasopharyngeal tumors, and b) to the following portal vision check rhythm: daily checks only in the first three treatment days, followed by a once to twice a week portal vision check in all patients in whom positioning is initially found in the tolerated range. Every correction was followed by another daily check period of three days.
The dose homogeneity within the PTV was aimed to be in close accordance with the RTOG guidelines: The dose was normalized to the mean dose in PTV1 which corresponds, in the majority of cases, approximately to the 95 % dose level in that volume.
-The prescription dose is the isodose which encompasses at least 95 % of the PTV -no more than 20 % of any PTV will receive >110 % of it's prescribed dose -no more than 1 % of PTV1 will receive < 93 % of its prescribed dose -no more than 1 % or 1 cc of the tissue outside the PTV will receive > 110 % of the dose prescribed to the primary PTV

Clinical quality assurance (QA) -Follow up
During the course of irradiation, all patients were clinically assessed at regular weekly intervals, and 2 weeks and 2 months after completion of treatment.
Approximately 6 weeks after completion, all patients were also seen regularly in our joint clinics at the Department of Head and Neck Surgery or Maxillofacial Surgery. Further follow up visits were scheduled every 2 -3 months in the first 2 years, 3 -4 monthly in the third year. When clinical and/or endoscopic examination showed no evidence of disease no radiological investigations were performed; suspect findings were specified with CT-PET, suspect lymph nodes by needle aspiration and/or biopsy, respectively.
-QA with respect to posttreatment events Isodose plans of all patients who experienced locoregional failure or grade 3/4 late term effects were reviewed at the radiation planning work station, in order to check local dose distributions at the regions of interest.
-QA with respect to quality of life (QoL) Toxicity was assessed based on SOMA LENT and RTOG/ EORTC Radiation Morbidity Score. Both classifications have been considered; for simplification, grade 3 or 4 late reactions were termed 'grade 3/4' reactions.
StatView ® program Version 4.5 was used for calculation of Kaplan Meier actuarial survival curves. Mann-Whitney-U test was used for comparison of volumes. P values < 0.05 were considered statistically significant.

Declaration of competing interests
The author(s) declare that they have no competing interests.