Long term results of postoperative Intensity-Modulated Radiation Therapy (IMRT) in the treatment of Squamous Cell Carcinoma (SCC) located in the oropharynx or oral cavity

Despite the relatively small sample size, we used univariate and multivariate analyses to investigate possible prognostic factors specifically for oral cavity and oropharyngeal cancer cases. Regarding locoregional control, we found that presence of ECE and number of positive nodes (n > 2) were associated with worse outcome in univariate analysis, but only the number of positive nodes remained significant according to multivariate Cox regression. Regarding FFTF and OS, worse outcome was associated with N2 stage, clinical stage 4 disease, number of positives nodes, presence of ECE and perineural invasion in univariate analysis, but again only the number of positive nodes remained significant according to multivariate analysis at least for FFTF. These findings were surprising at least to some extent as microscopic incomplete resection and presence of ECE have been reported as strongest factors influencing locoregional control and overall survival according to major prospective trials [3, 4, 6], while the number of positive nodes is a less established factor. For example, the combined analysis of EORTC 22931 and RTOG 9501 (which stratified patients according to slighty different risk factors) observed a significant benefit for adding chemotherapy to postoperative radiation only for the common factors (positive margin and ECE), while the presence of risk factors which have been used for risk assessment only in one of the trials (number of positive nodes ≥2, level 4/5 involvement, vascular embolisms, perineural disease, stage III/IV) had a weaker or no prognostic value at all [6]. However, our patients received chemotherapy based on the presence of the established risk factors close/positive margins or ECE, thus it cannot be ruled out that the addition of chemotherapy improved the results in those patients to a level comparable to patients at lower risk receiving postoperative RT alone and therefore mimicked their prognostic relevance with regard to the entire cohort. In contrast, the number of positive nodes did not trigger the use of additional chemotherapy, possibly maintaining its influence as highlighted by several reports supporting the significance of the number of positive nodes or the lymph node ratio as prognostic factors in head and neck cancer [21, 22]. For example Hua et al. [21] described a highly significant association between number of positive nodes (threshold ≤ 3 vs > 3) and lymph node ratio with the median overall survival in 81 patients suffering from hypopharyngeal cancer treated by surgery only. Wan et al. [22] evaluated 1510 patients with head and neck cancer treated by surgery alone, adjuvant radiation or adjuvant chemoradiation and found a strong and significant association between the number of positive nodes and locoregional control, disease specific survival and overall survival. In a subset analysis, they further described no significant difference in DSS or OS between patients with one or two positive nodes but significant worsening if three or more nodes were involved. Similarly, we found that the number of positive nodes was the only factor which significantly influenced all oncological endpoints in univariate analysis and the only factor which influenced LRC and FFTF in multivariate analysis. Interestingly the strongest discrimination in our cohort was found for the same threshold (≤2 vs > 2) as in the study by Wan et al. [22]. We performed a separate analysis using the threshold introduced by Cooper et al. (<2 vs ≥ 2) [3], which provided similar results in univariate and multivariate analysis with regard to significance but with weaker discrimination (data not shown). Given the different thresholds reported in the mentioned studies with similar results, it seems at least reasonable to assume, that locoregional control and overall survival will worsen with an increasing number of positive nodes irrespective of arbitrarily set distinctions.

We observed maximum acute grade 3 toxicities in about two thirds of our patients, mainly hematological and mucositis/dysphagia. These findings are in line with the reports of other studies investigating postoperative radio (chemo) therapy in head and neck cancer. For example Cooper et al. [3] found maximum acute grade 3/4 toxicities in 34 % of the patients treated by postoperative radiation alone and 77 % if chemoradiation was used. Geretschläger et al. [23] described 66 % acute grade 3 side effects in their cohort of patients with oral cavity cancer treated by postoperative IMRT. Regarding only hematological side effects, 30 % grade 3 and 8 % grade 4 hematological toxicities were found in the chemoradiation arm of RTOG 9501 [3] and 16 % severe leucopenia was reported in the chemoradiation arm of the EORTC 22931 study [4], indicating that those toxicities are mainly driven by the (similar) chemotherapy component and not influenced by radiation technique or disease site relevantly.

The combined rate of severe acute mucositis/dysphagia was also similar with roughly 60 % in our study compared to 66 % in the chemoradiation arm of RTOG 9501 [3] and 51 % in the EORTC 22931 study [4], however we found a different distribution. While in those trials more patients had severe mucositis than dysphagia, we observed an opposite ratio. This might be due to the fact that our analysis was limited to oral cavity and oropharyngeal cancer resulting in the inclusion of swallowing structures into the high dose boost areas in most patients, however it seems also linked to the definition and grading of dysphagia. In our analysis, all patients who had a feeding tube at any time during radiotherapy were scored at least as grade 3 dysphagia, although many of them received their PEGs already due to postoperative complications or prophylactically prior to RT. If only those patients were considered without PEGs at the beginning of RT, the severe dysphagia rate would have dropped to 28 %, similarly to the 25 % in the chemoradiation arm of RTOG 9501 [3]. Interestingly, we found a clearly increased risk of long-term PEG dependency in patients who had PEG placement due to postoperative complications compared to placement for other reasons or not at all. The use of feeding tubes for nutritional support is a common but heavily discussed issue in head and neck radiation therapy. It has been estimated that 50-70 % of patients require a feeding tube during definitive chemoradiation, 15-40 % with definitive RT and 20-40 % with surgery followed by adjuvant RT [24]. Many investigators favor the prophylactic use of feeding tubes because of numerous reports describing less weight loss, improved 6-month quality of life, less morbidity and fewer hospitalizations including one randomized trial supporting this approach [25‐27]. However, an increasing number of reports described high percentages of unnecessary (unused) prophylactic feeding tube placements of up to 50 % [28], a higher likelihood of prolonged or permanent dependency [29] and an increased rate of esophageal strictures [30], thus favoring a more reactive approach. Unfortunately most reports focused on patients with definitive radio (chemo) therapy resulting in very limited data for patients treated with postoperative radiation [31]. Collan et al. [5] described 5 % patients with long term PEG dependency but did not report details about reasons for placement. Bastos de Souza et al. [9] found 8 % long term dependency in a cohort of 256 patients treated by surgery alone or surgery plus radiotherapy. We did not observe a major difference in prolonged PEG dependency between patients with prophylactic (17 %), symptomatic (0 %) or no placement (9 %) during radiotherapy and therefore are not able to add evidence to this issue, however we found that patients with postoperative swallowing complications requiring tube feeding are at increased risk (39 %) for prolonged PEG-dependency after postoperative radio (chemo) therapy and should be counseled accordingly.

Consistent with prior results published by our group [14, 32, 33] and several other studies [12, 13] who found decreased rates of severe xerostomia with IMRT in head and neck cancer in general or in distinct subgroups, we observed a low rate (3 %) of severe xerostomia with postoperative IMRT also in the treatment of oral cavity and oropharyngeal cancers. For example Collan et al. [5], who focused similarly on the postoperative treatment of oral cavity and oropharyngeal cancers even observed no grade 3 xerostomia with IMRT at all. Wang et al. [11] compared IMRT with conventional RT in a similar subgroup and described a significant reduction of severe xerostomia in favour of IMRT (0 vs 35 %). Two randomized prospective trials have recently highlighted the value of IMRT [12, 13] by showing a significant reduction of late xerostomia compared to conventional or 3D-conformal RT in head and neck cancer in general, confirming a plethora of clinical and dosimetric studies with similar findings.

In contrast to other reports focusing on postoperative IMRT in oropharyngeal/oral cavity cancer most of our patients were treated with a simultaneously integrated boost (SIB) concept using slightly increased single doses (up to 2.2 Gy) in the boost area. SIB techniques allow a slightly reduced overall treatment time and result in increased dose conformity regarding the boost area but have been associated with concerns regarding additional toxicity. Although inter-study comparisons are generally difficult and possibly flawed with several biases including patient selection or the use of different scoring systems, we did not observe markedly increased rates of acute or late toxicities compared to reports on sequential IMRT boost techniques [5, 23]. This is especially true for damage to mucosal or swallowing structures, which are regarded as possibly associated with increased single doses. However, our acute grade 3 toxicity rates of 11 % for mucositis and 28 % for dysphagia (in patients without prophylactic PEG placement) were at least comparable to Collan et al. (mucositis grade 3: 25 %) [5] and Geretschläger et al. (mucositis grade 3: 36 %, dysphagia grade 3: 34 %) [23] using strictly sequential boosts. Regarding late dysphagia, our rate of 15 % was slightly increased compared to 5-9 % in the mentioned reports [5, 23], however Collan et al. [5] treated their patients with a considerably lower median total dose compared to our study and Geretschläger et al. [23] included only patients with oral cavity tumors probably resulting in lower doses to the swallowing structures. Gupta et al. [12] recently used an integrated boost concept very similar to ours in a prospective phase randomized trial and reported very low rates of grade 3 mucositis (6 %) and dysphagia (10 %). Finally, Spiotto et al. compared IMRT using sequential and integrated boost concepts in advanced head and neck cancers and reported significantly reduced acute grade 3 mucositis for the integrated boost group [34]. In summary, the use of an integrated boost technique with slightly increased single doses does not seem to result in markedly increased toxicities compared to sequential boosting techniques.