With the advent of IMRT in RT for HNSCC as a standard of care, diverse individual concepts have been implemented in different radiotherapy departments. Thereby, the application of a SIB and moderately hypofractionation are often applied to ensure individual dose painting and reduction of overall treatment time, which is crucial in RT for HNSCC [15].
To our knowledge, there is only little prospectively randomized evidence to evaluate the efficacy of IMRT in comparison to 3D-RT in RT of HNSCC. One study (PASPORT) randomized n = 94 patients between IMRT and 3D-RT (with parallel opposed lateral fields) [16]. This study was focused on avoiding xerostomia. At 12 and 24 months, xerostomia at least grade 2 was significantly less prevalent after IMRT. Other late toxicities and loco-regional-control, or overall survival did not differ between both groups. Comparable results were obtained in a small randomized trial (n = 60 patients) from India [17].
In nasopharyngeal cancer, this advanced technique has demonstrated a higher oncological efficacy in n = 616 patients compared to outdated 2D planning techniques: OS and progression-free survival were significantly improved. At the same time, high-grade chronic toxicity was reduced [18].
The recently published GORTEC 2004-01 randomized phase III trial showed again that the IMRT technique can even reach a dose escalation with markedly decreased late xerostomia, but without a significant improvement of local tumor control [31]. The authors used a slightly different irradiation concept with a sequential moderate hypofractionated boost to 75 Gy overall dose (25Gy/10F boost dose) in a total of 35 fractions. The frequency of grade ≥ 2 xerostomia was around 2/3 lower after 1 und 3 years in the IMRT group.
At last, Gupta et al. showed repeatedly in a prospective randomized trial with a very long follow-up and enough power and sample size that the moderate hypofractionation with 66 Gy in 30 fraction and IMRT technique leads to a meaningful reduction in severe xerostomia and fibrosis with comparable locoregional control and overall survivial in the 3D control group [32].
Other observational studies support the assessment of lower acute and chronic toxicity by IMRT in RT for HNSCC in comparison to 3D planning. In this context, Jirkovska et al. demonstrated that acute toxicity and xerostomia were significantly reduced in HNSCC treated by IMRT [19]. Modesto et al. showed similar data, especially for severe late toxicities like xerostomia, dysphagia, or feeding-tube dependency [20]. Our data confirm these findings showing lower toxicity in the IMRT-SIB group for dysphagia, dermatitis, xerostomia, fibrosis, and edema.
Other retrospective studies also showed an advantage for IMRT concerning prognosis in LRC [21] or even OS [22]. In contrast, in our patients LRC was equal between both groups. However, OS differed to the disadvantage of IMRT-SIB. This finding is most likely explained by more aggressive tumors in IMRT-SIB, as more patients had ECE and had to receive concomitant chemotherapy. Furthermore, despite the matched pair analysis, other biases due to the study's retrospective nature might play a role. However, such a finding is not totally in conflict with the literature. A recent meta-analysis on IMRT versus 3D-CRT in RT for HNSCC confirmed the superiority of IMRT in terms of toxicity (mainly xerostomia) but did not find improved oncological outcomes. The authors concluded that a positive impact of IMRT on tumor control and survival mains to be proven [8].
As concomitant chemotherapy in RT for locally advanced HNSCC is crucial for prognosis in the definitive and specific postoperative-adjuvant situations, RT approaches have to be designed so that the dose-fractionation concepts do not compromise the use of concurrent systemic therapy and vice versa. Therefore, we chose a chemotherapy protocol with weekly low dose cisplatin (40 mg/m² BSA up to at least cumulative ≥ 200 mg/² BSA, see above) as a continuous radiosensitizer and decided against a higher hypofractionated RT schedule > 2.2 Gy in the volume. Such a low dose weekly cisplatin application is an established regimen [23] besides likewise often used high dose application - for example 100 mg/m² BSA twice or thrice during radiotherapy [3]. A cumulative cisplatin dose of approximately 200 mg/m2 BSA, independent of the schedule, might be sufficient to yield a beneficial antitumor effect [24]. However, prospective studies in adequately sized phase III trials on this subject are still pending [25]. We saw good tolerance and feasibility of our approach with moderately hypofractionation without compromising one part of the combined treatment. Other studies actually show that higher hypofractionation (with single doses in SIB volumes up to 2.25 or 2.4 Gy) combined with chemotherapy seems to be possible [26, 27].
IMRT-SIB RT concepts will further be modified according to human papillomavirus (HPV) status in locally advanced HNSCC. On the one hand, HPV positive tumors have a better prognosis and are possible candidates for dose reduction, which is the subject of several ongoing clinical trials [28]. On the other hand, other studies examine the feasibility of dose-escalated hypofractionated chemoradiation in HPV-negative cancer [29]. Unfortunately, in our retrospective patient cohorts, HPV-status was not available for most of the tumors.
In summary, the presented moderately hypofractionated IMRT-SIB-concept showed to be feasible with an acceptable loco-regional-control and less toxicity compared to conventional 3D-CRT. IMRT is the standard of care in RT for locally advanced HNSCC. The optimal dose-/fractionation concept concerning moderate hypofractionation still has to be defined.