Background
Intensity modulated radiation (IMRT) techniques are expected to improve the therapeutic index for head neck cancer (HNC) by limiting the dose to critical organs and possibly increasing loco-regional tumor control. The benefit of normal tissue sparing achievable with IMRT with resulting lower rates of late term effects in HNC survivors is broadly recognized. Data on successful parotid gland sparing, reduction of radio-osteonecrosis (RON) and dysphagia are published [
1‐
7]. The probability of specific late effects depends on the exposed tissue and on the dose, and sometimes on the chemotherapy.
Aim of this prospectively assessed single center data analysis was to evaluate transient and persisting IMRT late term effects related to subgroups at risk. Hypothesis was if a 2-year follow up (FU) is sufficient to estimate the long term tolerance in HNC patients irradiated in the IMRT era.
Methods
Patients
Between 01/2002-8/2012, 1211 HNC patients were consecutively treated with IMRT (or volumetric modulated arc therapy, VMAT) at our department. 707/1211 patients (58%) met the inclusion criteria of a FU time >12 months and loco-regional disease control (LRC), Table
1. 45% presented with advanced disease (T3/4 and/or N2c/N3), 55% were referred for curative definitive IMRT (66 Gy-72 Gy, 30–35 daily fractions), 45% underwent postoperative radiation (60-66 Gy, 30–33 daily fractions). Systemic therapy was administered in 85%. Seven LRC patients were lost after 4.3-10.4 months of FU (median 5.5); 12/707 (2%) LRC patients were lost after 12.2-51.6 months (median 39).
Table 1
Demographic and tumor characteristic
N patients | 707 |
Gender (f: m) | 25%:75% |
Mean age (range) | 62 (39-91) years |
Mean/Median FU (range) | 41/35 (15-124) months |
Diagnosis
| |
Unknown | 19 (3%) |
Central oropharynx | 96 (14%) |
Lateral oropharynx | 149 (21%) |
Hypopharynx | 69 (10%) |
Oral cavity | 111 (16%) |
Nasopharynx | 51 (7%) |
Larynx | 90 (13%) |
Sinonasal | 40 (5%) |
Parotid gland | 36 (5%) |
Skin | 33 (5%) |
Nasal | 10 (1%) |
Others | 3 (3%) |
Treatment (dose)
| |
Primary IMRT (66-72 Gy, 2.0-2.2 Gy/f) | 55% (n=388) |
Postoperative IMRT (60-66 Gy, 2.0 Gy/f) | 45% (n=319) |
T
| |
1 | 17% |
2 | 34% |
3 | 20% |
4 | 26% |
Unknown | 3% |
N stage
| |
Recurrence | 2% |
NO | 32% |
N1-2b | 45% |
N2c | 17% |
N3 | 4% |
Total gross tumor volume (n=388)
| |
Mean (range) | 62 cc (1-217) |
1-15 cc | 115 |
16-70 cc | 202 |
71-130 cc | 63 |
>130 cc | 8 |
Conc. systemic therapy
| |
None | 15% |
Cisplatin only | 62% |
Cetuximab only | 16% |
Cisplatin switched to Cetuximab | 7% |
Induction chemotherapy
| 3% |
In 26 of the 504 excluded patients with locoregional disease (1211–707), G3/4 late effects were assessed (5%), however this information is of limited value as tumor-related symptoms are not always reliably to disdinguish from treatment-related effects, survival time in patients with disease is shorter, FU of patients undergoing palliative systemic therapy often no longer regularly performed by ENT and maxillofacial surgery joint clinics.
Although acute toxicity was not focus of this work, the following characteristics of the study population may be of some interest: early skin tolerance was obviously better than in the pre-IMRT era (no quantitative comparison data) and has been published elsewhere [
8]. The percentage of patients needing a PEG insertion to support or replace oral nutrition (46% in the study population) may serve as a surrogate for acceptable dysphagia and mucositis. In addition, no patient had to interrupt his radiation course due to early radiation related side effects.
Methods
Highly consistent treatment procedures were performed with respect to contouring processes, dose constraints, radiation schedules, use of systemic therapy. Contours and treatment plans were always evaluated by the same two staff radiation oncologists (CG/GS).
Implemented changes as evolved from medical and technical progress over the study time period of 10 years were the following: use of cetuximab in patients with contraindications for cisplatinum (since 04/2006); slight tumor-volume based dose prescription adaptations implemented in 2007 (100% dose coverage of primary GTV in cases with tumor volume >15 cc); clinical implementation of VMAT in 4/2010.
Late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) radiation morbidity scoring criteria [
2].
There are several systems aiming to grade RON. We used the system proposed by Glanzmann and Graetz [
9]:
1.
Exposed bone without signs of infection for at least 3 months
2.
Exposed bone with signs of infection or sequester, but not grades 3–5
3.
RON, treated with mandibular resection, with satisfactory result
4.
RON with persistent problems despite mandibular resection
The advantage of this classification vs. that of EORTC (LENT/SOMA) or NCI [
10] is its connection to therapeutic clinical consequences; nevertheless, grade 2 events mutually correspond in all of the above named classification systems. Most frequent therapy for G2 was limited surgery (partial decortication or debridement, removal of sequesters); these surgical procedures are not defined in our grading system, and were counted as 'G2-3’.
All but the above mentioned 19 lost patients are in regular FU; nearly all (99%) are followed at our HN or maxillofacial surgery joint center clinics at the hospital. Routine tests included, besides the history, physical examination and endoscopy of the pharyngeal–laryngeal region. If these tests showed no evidence of disease, usually no further tests were done but a computed tomography scan (CT) or positron emission tomography (PET)–CT or magnetic resonance imaging at 1 year post-treatment in the majority of patients.
No specific functional swallowing testing was performed to assess subtle (G1-2) dysphagia; reasons to do so were: no baseline examinations available; many patients would have shown mild pathological swallowing findings of no significant impact on the final post treatment function; as we focused on high grade late term effects (G3/4) relevant dysphagia with consecutive swallowing problems (aspiration, aspiration pneumonia, difficulty swallowing solid food, weight loss, need of PEG) is supposed to reliably get communicated by patients themselves and/or diagnosed in the regular FU program in our joint center clinics.
Similarly, no specific tests were performed to assess xerostomia G3/4 but patients’ spontaneous complaints and/or suggestive interview questions in regular FU visits including objective clinical assessment of severe oral mucosal dryness. When we implemented IMRT in the routine, swallowing dysfunction and xerostomia were graded in the first 100 IMRT patients using subjective patient-reported (EORTC head-and-neck 35-item swallowing and aspiration (QLQ-H&N35) quality-of-life (QOL) questionnaire) and objective observer-assessed instruments. As subjective estimations were well fitting with objective assessments in routinely clinical FU interviews [
4], we did not continue to use the EORTC subjective estimation questionnaires for assessing clinical FU.
With respect to Lhermittes’ sign, no systematic specific assessments have been performed, which may likely would have revealed more events; however as this symptome is known for transient and spontaneous entire healing without any therapy, this is not of clinical consequence.
No case of brachial plexus neuropathy (BPN) with clinically evident dysfunction (grade >2) was diagnosed in our cohort (patients with post-IMRT neck dissection excluded); mild neuropathy (G1/2) may be missed without specific neurological examination.
Radiation therapy
In >90% of the cohort the pre-treatment standard imaging modality was PET–CT (mostly with intravenous contrast agent), + tomography (CT or MRI). Planning CT images (2 mm slice thickness) were acquired from the vertex or top of the orbita to the carina with contrast agent infusion in all eligible patients.
Gross tumor volume (GTV) delineation of all patients was based on physical examination and endoscopy as well as on diagnostic preoperative MRI, CT and PET. Contours and treatment plans were always evaluated by the same two staff radiation oncologists (CG/GS), in most cases also by a third staff physician.
Technique: Treatment plans were calculated by the Varian Treatment Planning System (Eclipse® External Beam Planning System, Version 7.3.10 and PRO 8.9, AAA 8.9, Varian Medical Systems).
We used an extended-field SIB-IMRT technique, where the primary tumor is covered in one phase along with the regional lymph nodes by a 6MV dynamic MLC system (Varian Medical Systems, Palo Alto, CA) using a sliding window technique (or using VMAT, since 04/2010). Patients were immobilized from head to shoulders with commercially available thermoplastic masks in the supine position.
Target volumes were delineated as follows: GTV included the gross extent of the primary disease and involved lymph node metastases, taking clinical and radiological findings into account; planning target volume 1 (PTV1) was defined by adding a (5–) 10–20 mm margin to the GTV, dependent on the GTV proximity to critical structures (tight margins mainly if proximity of the GTV to the mandible bone, spinal cord or brachial plexus/CNS, generous margins towards tongue and pharyngeal wall, or in cases with difficult identification of the GTV, or if clinical findings not entirely represented in the available imaging); PTV2 covered areas considered at high risk for potential microscopic disease; PTV3 included the clinically negative cervical lymphatic pathways (elective PTV coverage).
SIB IMRT was performed using the following schedules:
-
SIB2.00: Daily dose 2.00 Gy (PTV1)/1.70 Gy (PTV2)/1.54 Gy (PTV3) to a total dose of 70.00 Gy (5 fractions/week).
-
SIB2.11: Daily dose 2.11 Gy (PTV1)/1.80 Gy (PTV2)/1.64 Gy (PTV3) to a total dose of 69.60 Gy (5 fractions/week).
-
SIB2.2: Daily dose 2.2 Gy (PTV1)/2.0 Gy (PTV2)/1.64 Gy (PTV3) to a total dose of 66.0 Gy (5 fractions/week).
The dose was normalized to the mean dose in PTV1. The prescribed dose encompassed at least 95% of the PTV. In cases with central nervous system involvement, Dmax accepted was 2.00 Gy, to a Dmax of 70.0 Gy total dose (PTV1 = GTV; no margin).
No more than 20% of any PTV received >110% of its prescribed dose, whilst no more than 1% of any PTV received <93% of the prescribed dose. Hundred% of the prescription dose included the primary GTV in patients with a primary tumor volume >15 cc (since ~ 2007).
Our interdisciplinary in-house guidelines recommend an elective neck dissection in patients with initial nodal metastasis >3 cm.
Chemotherapy
Cisplatin was given in weekly doses of 40 mg/m2 at 1 day a week. Since 04/2006, cetuximab was used in patients with contra-indications for concomitant standard cisplatin chemotherapy (400 mg/m2 loading dose, followed by 250 mg/m2 at 1 day a week).
Follow up
3–6 weeks after completion of IMRT, all patients were also regularly seen in our joint clinic at the Department of Head and Neck or Maxillofacial Surgery. Institutional standards for patient assessment included physical examination with additional flexible fiber-optic endoscopy approximately every 2 months in the first year of follow-up, every 3 months in the second to third year and every 6 months in the fourth to fifth year.
Statistics
Kaplan Meier survival curves were performed using the statistics program implemented in StatView® (Version 4.5). P values < 0.05 were considered statistically significant. Unpaired T test and Mann Whitney U test was used to calculate the influence of the tumor volume on late tolerance.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
GS drafted the article and created the underlying data base; GS, Cl, OR, YN, MB and CG performed the contouring and were in charge for the isodose plan reviewing, and treated the assessed patient cohort; CG and GS double-checked all contouring and isodose plans and are responsible for the IMRT-SIB radiation treatment schedules as defined/applied; BY assessed the dose distribution to the arm plexus region of the cohort; TR was involved in systemic therapy decisions for at risk patients and performed the chemotherapy in NPC patients; GH, MB, SS(4), RZ operated on these patients and performed the regular FU; SS(2) was in charge with dental long term rehabilitation of our patients. All authors read and approved the final manuscript.