Thirty inoperable patients with recurrent H&N cancer, treated with IMPT for the second course, were selected for retrospective analysis. For this study group we evaluated treatment efficacy and related toxicity using IMPT for re-irradiation.
Locoregional recurrence after H&N therapy continues to be the most frequent pattern of failure, especially in locally advanced tumors, so it causes death in most of the cases. The highest period at risk is the first two years after the treatment, with more than 2/3 of incidences [15]. Almost 15% of H&N patients are at risk of developing secondary primary cancer, with an increasing incidence rate within long-term survival [7].
Maximal surgical resection remains to be the treatment of choice, with 5-years OS reached 40% reported [5,16]. Janot et al. showed in GORETEC phase III trial adjuvant chemoradiation improved both locoregional control (p<0.0001) and disease-free survival (p=0.01), without significant influence on overall survival (p=0.50). However, significantly higher toxicity rates were observed (grade 3 in 28% cases, and 39% with late grade 4 complications) [17]. Nevertheless, salvage surgery can only be provided for around 30% of all such patients. However, the success of the operation always linked with tumor location (better outcomes for laryngeal cancer and neck nodes) and extension, alongside with co-morbidity [18]. For those patients, who are not operable, chemotherapy alone has only a median survival of 7.4 months, with quite low impact of cetuximab addition (to 10.1 months) [19]. It is obvious that in the final results of most studies, dedicated to the H&N re-irradiation, surgery plays a remarkable role. Meanwhile, poor outcomes of our cohort at the second year corresponds to the lack of up-front surgery, as all of our patients were inoperable.
Two randomized trials, RTOG 9610 [10] and RTOG 9911 [20] had positive outcomes, combining RT and chemotherapy. These studies showed that 1/3 of patients were locoregionally controlled, with 10 to 30% 2-year OS rate, and yet with severe toxicities grade 3-4 observed in around 40% of re-irradiated patients. At the same time, 10% of patients suffered from toxicity-related death.
The most complicated points of re-irradiation are persistence radioresistant tumor cells (even after high-dose RT) and reduced tissue tolerance [14,21,22]. So, the main challenges in re-irradiation are determination of actual tumor extent, delivering high doses (>60 Gy), and sparing normal tissue. In the last decade, an increasing use of IMRT-technique shows promising outcomes, with 32% 5-years OS, but with a severe toxicity risk of up to 48% [23]. However, even with IMRT, the high doses cannot be delivered, being met with OAR constraints from the previous course of radiotherapy. Proton therapy advantages (i.e., precise dose distribution, rapid dose fall, biological and immune features) may potentially benefit H&N patients with recurrence [24].
In 2016, Phan et al. published the retrospective data about proton re-irradiation, with 60 patients included, demonstrating 1-year OS 83.8% and 16.7% of grade 3 late toxicity [11]. After completing PT 58% of the patients received upfront surgery, and 73% received concurrent and adjuvant systemic therapy, though without significant consequences for the outcomes. The multi-institutional study by McDonald et al. included 61 patients, re-treated with PT for H&N recurrence or second primary tumor. Authors reported 2-year estimated OS 32.7%, with remarkable impact of surgery on outcomes: median OS with salvage surgery was 25.1 months vs 10.3 months without operation, p=0.008. Acute grade ≥3 toxicities were seen in 14.7%, and 24.6% in the late setting, including 3 related deaths [25]. A multi-institutional report, published in 2016 by Romesser et al., with 91 patients involved, described 25.1% risk of failure in 12 months, and a favorable toxicity profile.
In our study group, we observed 73.4% of 1-year OS, while all of our patients were not able to undergo surgery, so the initial prognosis was quite poor. The patterns of relapse are in agreement with other studies: with mostly in-field or marginal recurrences and relative low risk of distant progression [26]. Bulky tumors (prevailed in our cohort) or CTV>50 cm3 are shown to be associated with higher toxicity and poor outcomes [11, 23]. Though, the lower toxicity rate of protons is usually being accounted for in its dose distribution, recent experimental studies reported lower expression of factors involved in lymph- and angiogenesis, inflammation, and immune tolerance [27].
Adverse events from re-radiation play a significant role in decreasing the QoL in H&N patients. Besides, conventional radiotherapy is associated with severe complications. Even with novel photon RT approaches, second irradiation still causes a significantly higher toxicity rate. The low toxicity outcomes observed in proton studies are promising, although longer follow-up of long-term survivors is necessary, to estimate tissue damage risks related to re-irradiation. Balance between RT-treatment intensification and adverse events is quite challenging in H&N re-irradiation. Recommended re-RT dose for tumor growth control might be ≥ 60-66 Gy, whereas the most of critical OARs located at H&N area, are already exceed their limits after prior radiotherapy. Furthermore, there is still no consensus about dose constraints for re-irradiation. Chan et al. published data about re-irradiation of recurrent T3/T4 nasopharyngeal cancer, dividing OAR’s limits into absolute (i.e., spinal cord D1cc<65 Gy or brain stem D1%<78 Gy) and desirable doses (e.g., optic nerve 78 Gy, temporal lobe D1cc<84.5 Gy) [28]. In contrast, some authors maintain more conservative doses (e.g., myelon BED < 100-120 Gy) [9].
Generally, however, because of poor survival chances with recurrent H&N cancer, many patients may not survive long enough to meet potential adverse effects. We observed 1 death related to carotid bleeding, which is one of the most morbid toxicities associated with re-irradiation in the head and neck area [29]. Nevertheless, dose constraints for the carotid artery are used mostly for SBRT (with value from 32.5 to 34.0 Gy for hypofractionation) [30].
As re-treatment of H&N cancers is extremely controversial and complicated, defining significant prognostic factors to divide patients into several groups, which could guide for therapy choice, is important. Thus, Mattew C. et al., based on the results of IMRT of 412 patients, identified 3 groups of patients: 1) >2 years from RT and resected tumor (2-year OS, 61.9%); 2) >2 years from RT and unresected tumor, in a good performance status (2-year OS, 40.0%) and 3) the rest of patients, who do not meet these criteria, with a poor prognosis (2-year, 16,8%) [31]. This classification can potentially help for a better understanding of patient selection for re-RT and adjuvant treatment, following given indicators.