Most of the therapeutic failures of head and neck cancers are represented by locoregional recurrences, which are the main cause of death of these patients. Usually, relapses occur in previously high-dose irradiated areas, most of them occurring within the first two years after treatment completion. One of the problems of long-term survivors is the high risk of developing a second neoplasm, this risk being estimated at around 30% at 10 years.
The optimal treatment in cases of locoregional relapses is represented by salvage surgery, which in some cases is impossible due to the patient’s medical condition or the neoplastic localization. It is considered that only 20% of patients will benefit from salvage surgery and most cases will be operated with positive margins(1,2). Historically, most cases were addressed to palliative chemotherapy, with response rates <50% and a benefit of 1-5 months regarding the overall survival (OS) compared to best supportive care. The overall survival advantage of adding a monoclonal antibody (cetuximab) to the chemotherapy of locally advanced or metastatic squamous cell carcinoma of the head and neck (HNSCC) was proven by the results from the EXTREME randomized controlled trial, comparing cetuximab plus chemotherapy with chemotherapy as the unique treatment method. Compared to chemotherapy alone, the combined treatment has brought a benefit to the OS (10.1 months versus 7.4 months) and an advantage regarding the progression-free survival (PFS) of 5.6 months versus 3.3 months. Recently, the phase II GORTEC study used the taxane-platinum-cetuximab combination (TPEx) in the first-line treatment of recurrent or metastatic head and neck cancers, this combination showing promising results, and further studies will establish the superiority of the TPEx regimen against the EXTREME regimen(3-5).
In cases where it is possible, salvage surgery is the first therapeutic option, but the rate of severe complications exceeds 25% and the perioperative mortality is about 5%. Considering the high rate of therapeutic failures, in this situation it was proposed the postoperative re-irradiation associated or not with chemotherapy.
Patients outcome and toxicities
Iseli et al. performed a study including 87 re-irradiated nasopharyngeal squamous cell carcinoma patients in order to compare toxic effects and functional outcomes in two different scenarios (when re-irradiation was associated with salvage surgery or when it was used as the only method). Because the study extended over several years, the combination of platinum-based concomitant chemotherapy and intensity-modulated radiotherapy (IMRT) technique was used only in part of the patients. The acute and late toxic effects of radiotherapy treatment (definitive tracheostomy, gastrostomy tube dependence), as well as survival were analyzed. The results revealed a higher rate of grade II toxicity >50% at relapse after salvage surgery, but also with an improvement in survival (median OS 17.3 months), with a two-year OS of approximately 25% and an 8% OS rate at 5 years. The authors concluded that re-irradiation represents the only chance of healing in patients with unresectable disease and the increased toxicity rate of patients treated after the year 2000 can be explained by the more frequent combination of concomitant chemotherapy. Flap reconstruction is considered a factor that reduces the toxicity rate(6).
Re-irradiation, using the intensity-modulated radiation therapy technique, is considered feasible, with a severe toxicity rate of approximately 20% – one case with grade 5 toxicity in the 78 patients study cohort, reported by Sulman and collaborators. The mean re-irradiation dose was 60 Gy and the mean dose received during the patient’s life-time was 116.1 Gy. With a 58% survival rate and a locoregional control rate of 64% at two years, the authors concluded that, although the rate of severe toxicities remains high, the results are favorable in terms of severe toxicity compared to studies from the literature that used conventional radiotherapy(7).
With the development of the concept of multimodal treatment, the rate of locoregional relapses for oral cavity cancers and squamous oropharyngeal cell carcinoma has decreased significantly, with a tendency to increase the rate of distant metastases. For laryngeal cancers, this trend was not noticeable, the ratio of locoregional recurrences/distant metastases remaining approximately constant (2:1) over time(8).
The inclusion criteria, according to the small number of existing studies, must balance the risk-benefit ratio very well. The main exclusion criteria would be: severe toxicities at the first radiotherapy sequence, less than 6 months after the initial treatment, spinal cord dose <50 Gy at the initial treatment, a minimum Eastern Cooperative Oncology Group (ECOG) performance status, volume of recurrence <50 cm2 evaluated in imaging. Also, some authors identify the biological equivalent dose (BED) >72 Gy for relapse, Karnofsky performance status and age (with a cutoff value of 70 years), as factors advocating for favorable outcomes in terms of survival of re-irradiated patients.
Regarding elective lymph node irradiation, most authors do not recommend it. Doses between 50 and 66 Gy are considered necessary to control the residual postoperative gross tumor. The possibility of re-irradiation with doses higher than 66 Gy is associated with local control improvement(9,10).
Dose assessment at which carotid blowout can occur is a benefit to the scientific community, as dosimetric guidelines may be proposed, the few studies considering the cumulative dose of 120 Gy associated with this potentially fatal toxicity risk. Considering that in the evolution of the disease fatal carotid hemorrhage is the main cause of death, in situations where the risk-benefit ratio is favorable for the re-irradiation with doses with curative potential (>60 Gy) by IMRT/VMAT techniques or stereotactic, radiosurgery is a viable option.
McDonald et al. reported 41 carotid hemorrhages out of 1554 patients (2.6%) who received re-irradiation for relapsed cancers of head and neck, of which 76% were fatal. The rate of carotid blowout was lower in patients who received conventional re-irradiation or accelerated hyperfractionation with 1.2 Gy two times daily (1.3%) compared with the one reported among patients receiving 1.5 Gy two times daily as a regime of accelerated hyperfractionation. The authors did not notice any statistically significant difference in the rate of events between the groups of patients who received or did not receive concomitant chemotherapy or whether or not they had undergone salvage surgery before re-irradiation. For patients treated with stereotactic body radiosurgery (SBRT) in an average dose of 44 Gy in five fractions, concurrent with cetuximab in 86% of 184 patients, the authors reported a low rate of carotid hemorrhage and did not identify correlations between carotid blowout risk and volume dose parameters for carotid artrery contoured as an organ at risc (OAR)(9,11,12).
Immunotherapy and re-irradiation
Immunotherapy has recently been shown to be effective in metastatic head and neck cancer treatment. The current research directions are oriented toward the integration of immunotherapy in the treatment of locoregional recurrences, but also in the neoadjuvant or adjuvant and salvage treatment. Several phase I trials associate the immunotherapy with durvalumab, nivolumab or pembrolizumab with concurrent or sequential radiation therapy. A randomized phase II/III study (NCT03258554) will evaluate the combination of cetuximab and radiation therapy with durvalumab plus radiation therapy for patients non-eligible for cisplatin-based chemotherapy treatment. The multi-institutional re-irradiation study (NCT03521570) with concurrent immunotherapy (nivolumab) aims to evaluate the feasibility of salvage re-irradiation in combination with immunotherapy as a therapeutic option for locoregional recurrences of head and neck cancers. The basic concept of the synergy radiotherapy-immunotherapy was demonstrated in the KEYNOTE-001 and PACIFIC studies, on patients treated for non-small cell lung carcinoma (NSCLC). In the PACIFIC trial, it was highlighted the increase of the effect of chemotherapy and radiotherapy in combination with immunotherapy. Lymphopenia is considered a possible negative prognostic factor, but radiochemotherapy treatment is often incriminated in the case of hematological toxicity. Considering that radiation therapy is also a treatment with immunogenic potential and balancing both the results of preclinical studies regarding the abscopal effect and the increased effect of using hypofractionation, the use of high dose per fractions of re-irradiation to maximize the imunogenic effect and minimize the effect lymphopenia is a strategy of interest in the therapeutic approach(13,14,15,16).
Re-irradiation acquires new perspectives by introducing the IMRT techniques and the image-guided radiotherapy (IGRT) by the superior protection of the radiosensitive organs, especially the carotid, with the increase of the ballistic precision of the irradiation. The use of immunotherapy in recurrent head and neck cancers in combination with hypofractionated or SBRT regimens increases the immunogenic potential of radiation therapy, with possible therapeutic benefits.
Conflicts of interests: The authors declare no conflict of interests.