Advanced RT technique and planning systems (IMRT, VMAT, etc.), provide significantly better results in terms of target coverage and dose constraints. In our study, the cases were treated with 2DRT before the year 2004, and 3DCRT or VMAT technique after the year 2005. The clinical T2 / T3 disease was found to be 28.9% in Group 2 and 3.6% in Group 1. The distribution of patients in terms of T4 disease was high in Group 1 (Table 1). Node negative disease was mostly in Group 2, whereas the distributions of N2/N3 cases were similar. Furthermore, early-stage (stage 3) disease was detected at a higher rate in Group 2 and almost all cases in Group 1 were stage 4 disease (Table 1). A statistically significant difference was found between the two groups in terms of stage (p = 0.013). The reason for this difference can be explained by the fact that RT applications for organ preservation before 2004 were rare and surgery was preferred in the early stages of hypopharyngeal carcinoma. However, in the current treatment modality, surgery has been replaced by RT or CRT in early-stage disease [12, 13, 14].
Many studies have emphasized the prognostic significance of clinical T and N stages in patients with hypopharyngeal cancer [14, 15, 16]. In our study, T and N stages were found to be prognostic factors affecting both OS (p = 0.001, p = 0.035) and LRRFS (p = 0.02, p = 0.026) in multivariate analysis. Excluding stage 3 patients, and analyzing only stage 4A and 4B patients on both arms revealed a similar result in terms of T and N stages (p = 0.034, p = 0.044 and p = 0.05, p = 0.045). Advanced age was found to be a prognostic factor affecting OS, but we detected that elderly patients with long-term follow-up patients died due to comorbid disease (p = 0.027). Besides, we believe that elderly patients with comorbid diseases may experience higher rates of toxicity.
Concurrent chemotherapy application was also significantly higher in Group 2 for the same reason (p < 0.01). In the literature, an increase in concurrent chemotherapy applications has been reported after the year 2000 [17, 18, 19, 20]. In a meta-analysis of 93 randomized trials, the efficacy of concomitant chemoradiotherapy in locally advanced heads and necks cancers has been demonstrated . The use of concurrent chemoradiation is supported by extrapolation from larynx cancer and subgroup analysis of head and neck cancer trials [3, 4]. There is however still some level of equipoise in the optimal management of locally advanced hypopharynx cancer and the assumed equivalence of organ preserving and surgery is contested in T4 disease . In our study, 45 (54.2%) patients underwent concurrent chemotherapy. Local-regional control and disease-specific survival was better in patients who underwent concurrent chemotherapy (p = 0.024, p = 0.010).
In terms of radiotherapy technique, one of the largest series of studies in the literature, Gupta et al. evaluated 501 hypopharyngeal cancer patients treated with conventional methods . At a median follow-up of 12 months, the 3-year local-regional control rate was 50% for T1-2 tumors and 43.1% for T3-4 tumors. In addition, Blanchard et al. reported 5-year local and regional control rates as 68% and 69% respectively in 249 piriform sinus cases who underwent radical radiotherapy . Huang et al. evaluated 33 patients with hypopharyngeal cancer and reported a 3-year locoregional control rate 68.2% at a median follow-up of 18.8 months treated definitively with Intensity Modulated Arc Therapy (IMRT) technique . In a study conducted by Reis et al. the 2 and 5-year overall survival (OS) and disease-free survival rates (DFS) in 25 hypopharyngeal cancer patients treated with 3DCRT, (IMRT) or VMAT technique were reported as 47.5%, 29.2% and 39.1%, 24.1% respectively . In our study, the 2 and 5-year OS and loco-regional control rates were 27.4%, 20.6% and 34.7%, 29.8% in Group 1 and 58.3%, 42.1% and 79.5%, 72.9% in Group 2 respectively (p = 0.035, p < 0.001). Results were found to be statistically significant in favor of Group 2 and were consistent with similar studies in the literature.
In a study published in 2015 by Mok et al., IMRT and 3DCRT techniques were compared in the treatment of patients with hypopharyngeal cancer and a higher local control rate was detected in patients treated with IMRT than in 3DCRT (75% vs 58%; p: 0.003). There was no difference in terms of OS and DFS . In a similar single-center study conducted by Katsoulakis et al. in 2015, comparing 3DCRT and IMRT techniques in hypopharyngeal cancer patients, no difference was found between the two groups in terms of local control and OS . Bertelsen et al. showed that doses of organs at risk can be reduced if patients with hypopharyngeal carcinoma treated with VMAT compared to IMRT technique . Suat et al. evaluated the data of 3928 hypopharyngeal cancer patients in 2018 and in terms of RT technique overall survival advantage was found in IMRT Group (p = 0.013) . In addition, few studies have shown that treatment with image-guided radiotherapy (IGRT) which is a new technology increases the local-regional control rate in patients with head and neck cancer [30, 31]. In our clinic since 2014 patients with hypopharyngeal cancer are treated with VMAT technique with daily image guidance. This new technology treatment modality has led to both a reduction in side effects and an increase in local control rates. Additionally, multivariate analysis revealed a better LRRFS rate in patients in Group 2 receiving RT with new technology (p = 0.025). The increase in local-regional control improved both OS and DSS. This difference was appreciated not only to be caused by modern methods of treatment, but also by the difference in stage and number of patients between the groups. However, in multivariate analyses, the fact that RT technique was found to be a significant factor can be interpreted as the positive effect of modern technology in this patient group. This group of patients after the effective results of radiotherapy in function preservation shows justification for the use of radiotherapy to improve survival and quality of life with modern techniques.
In a study published by Fu-Min Fang et al in 2006, patients treated with conventional and 3DCRT were evaluated for side effects and quality of life scores were found statistically significant in favor of patients treated with 3DCRT (p = 0.02) . Two separate prospective studies have reported that long-term side effects are less frequent in patients who are treated with modern RT systems compared to conventional methods since the pharyngeal constrictor muscles involved in swallowing function receive fewer doses [33, 34]. Lee et al. reported that patients with hypopharyngeal cancer may require a feeding tube because of stricture after CRT . Mok et al. in a study comparing IMRT and 3DCRT treatment techniques, there was no difference between the two groups in terms of feeding tube . Al-Mamgani et al. detected less permanent dependence on PEG in patients planned with IMRT than the conventional method . In our study, 16 patients underwent PEG during treatment and 3 of these had persistent PEG due to limitation of oral intake and pharyngeal stricture after treatment and this difference was statistically significant between two groups against Group 1 (p = 0.035). Grade 3–4 early side effects were significantly more frequent in Group I patients than in Group II patients (p = 0.04). The reason for the higher incidence of side effects in Group I patients can be interpreted as the fact that the dose distribution outside the planning target volume could not be kept at an intended level in patients planned by a conventional method. Besides, in Group 2, the dose could be applied to the target volume with a more homogeneous dose distribution and close safety margins while preserving the healthy tissues with the 3DCRT / VMAT technique. With the advantage of the new technology, the late side effect was more often in Group I (p = 0.038).
The limitations of our study were the different patient number and stage distribution between the groups, non-randomized study and the numbers of patients receiving chemotherapy were high in Group 2. The use of PET-CT in staging method is an important evolution which can certainly confound the findings of this study and the result of better staging could influence the difference in cancer control outcomes. However, it is important to achieve similar results obtained in prospective studies with selected patient groups in routine practice.
In conclusion, with the use of chemoradiotherapy and new technology RT methods proposed in the literature higher local-regional control rates could be obtained with lower side effects. It is seen that longer life expectancy with better organ function can be achieved with new treatment methods. The development and widespread use of new technological treatments with prospective protocols is recommended.