Introduction

Squamous cell cancer of the head and neck (SCCHN) is the 6th most common malignancy and the 8th leading cause of cancer mortality worldwide [1]. While technological improvements in surgical and radiotherapy (RT) techniques have largely increased the therapeutic ratio of these therapeutic modalities [2], up to 50% of patients develop recurrent disease, with a predominance of locoregional failure [3]. In about 90% of cases, the recurrence occurs within the first three years after the end of the primary treatment. Additionally, long-term survivors with a smoking history have a higher risk of second primary tumors in the head and neck region, which can be as high as 20–25% in 10 years [4]. The treatment of recurrent/second primary (LRR)/SP SCCHN is challenging due to the overall dismal prognosis. Given the heterogeneity of R/M SCCHN, the main goal of any approach is balancing the chance of disease control and the burden of treatment-related toxicities on the patient’s quality of life. The treatment may encompass salvage surgery (usually requiring post-operative re-irradiation), curative re-irradiation (reRT), palliative-intent systemic therapies, and best supportive care [5,6,7,8]. Surgery is considered the treatment of choice [9]. However, several factors as disease extent or morbidity associated with such an approach, make the surgical option available only in about 20% of the cases. If surgery is nor indicated or feasible, the only potentially curative therapeutic alternative reRT alone or combined with systemic therapy. In addition, a significant proportion of patients treated with salvage surgery necessitate post-operative radiation treatment due to histological high-risk features [10]. Clinical stage as well as other radiological signs (e.g., extracapsular extension) indicate the need for postoperative reRT since the baseline assessment. Therefore, management of such complex cases should always be managed by a multidisciplinary team. Historically, reRT of recurrent and second primary SCCHN within a previously irradiated field was discouraged due to concerns over excessive normal tissues damage [11]. Nevertheless, modern RT techniques such as Intensity Modulated Radiation Therapy (IMRT), Stereotactic Body Radiation Therapy (SBRT) and particle beam therapy (i.e., proton and heavy ion therapy) can offer at least comparable local control rates with fewer side effects than conventional 2D or 3D techniques [12,13,14]. Finally, favorable long-term survival outcomes are reported in some cases of R/M SCCHN treated with different modalities [15]. In summary, the therapeutic landscape in the locally recurrent SCCHN setting has evolved, thanks to the use of modern radiation treatment planning and delivery and the availability of proton- and heavy ion-based RT. Thus, our aim is to summarize available literature on the current status of RT in locally recurrent SCCHN, and to provide a pragmatic and useful tool for clinical practice.

Methods

A multidisciplinary group composed of Radiation Oncologists, Medical Oncologists and Radiologists dedicated to head and neck cancers proposed a workflow process to indicate reRT for locally recurrent cancer patients. Details on technical aspects of the reRT approach have been reported in a separate work focused on the same setting (Reirradiation of head and neck squamous cell carcinomas: a pragmatic approach. Part II: Radiation technique and fractionations). In the present work, technical aspects of the reRT approach have been presented with a focus on two topics: (1) patients’ selection (prognostic and predictive factors) and (2) dosimetric feasibility. Postoperative reRT and palliative-intent irradiation were considered out of the scope of this work and were therefore not reviewed. A proposal of a pragmatic tool for daily clinical practice data through a stepwise approach which resumes literature data were then shared and discussed among all members. An initial search in the literature for full papers articles written in English, dating from 1995 to 2022 was performed. A combination of the terms “reirraidiation/re-irradiation,” “head and neck radiotherapy,” “prognostic factor,” “patient selection,” “dosimetric study,” “treatment/indication to treatment” was queried. Finally, two clinical use-cases were provided for the application of the proposed approach.

Results

For unresectable recurrent/second primary head and neck tumors, full-dose reRT is the only potentially curative treatment. However, feasibility should be carefully assessed, based on clinical (e.g., patient- and tumor-related factors) and dosimetric factors (e.g., time interval from the primary RT course). Therefore, the analysis of the cost–benefit ratio includes several prognostic and predictive variables, including all previous oncologic treatments [16,17,18,19,20]. Schematically, such considerations can be articulated into three main steps, which are described below.

Accurate tumor staging

Radiological images have to accurately assess local tumor extent (to minimize the target volume that is most likely confined to gross-tumor volume [GTV] only). Staging through different imaging modalities (i.e., computed tomography -CT-, magnetic resonance -MR,—and fluorodeoxyglucose positron emission tomography-FDG-PET) is required to define tumor extension as well as the presence of nodal and/or distant metastases that cannot be detected by the sole physical examination [21,22,23]. Altogether, clinical staging is needed to define the proximity of the tumor to the surrounding healthy tissues (i.e., nervous structures, carotid arteries, skull base bones). Additionally, functional information conveyed by FDG-PET could also be correlated with prognosis, as for metabolic tumor volume (MTV), which has been identified as an independent prognostic factor by Velez et al. [24].

Additionally, biopsy of the suspected tumor recurrence is strongly recommended whenever feasible since surgical scars and/or radiation-related inflammation and fibrotic processes could complicate the interpretation of both clinical findings and radiologic imaging.

Patient selection

Patient selection is the first fundamental step in the decision-making process to define the most appropriate treatment modality. However, factors that support the feasibility of a second RT course are not clearly defined yet. Consequently, decision often relies on the clinical judgment of the Radiation Oncologist within the multidisciplinary tumor board.

Several parameters have been associated with clinical outcome for recurrent and/or metastatic patients [25].

Of these, the most relevant is patient’s prognosis. Indeed, prognosis not only determines indication to reRT, but also influences the choice of the irradiation technique and of the fractionation schedule. Patients with a long-life expectancy can be treated, when feasible, with a full-dose reRT course while patients with a short-life expectancy should rather be evaluated for a palliative reRT.

Additional prognostic and predictive factors have been identified and are summarized in Table 1. Feasibility of surgery was also considered in the analysis as a prognostic factor.

Table 1 Prognostic factors associated with outcomes in patients treated with re-irradiation for local/regional recurrent SCCHN
Full size table

Overall, patients with good performance status, younger age and no or few comorbidities seem to be the best candidates for curative-intent reRT. Considering tumor characteristics, early stage tumor with no bulky disease/no organ dysfunction and location in the nasopharynx have been associated with better outcomes both in terms of overall survival (OS) and loco-regional control (LRC). Finally, among treatment-related factors, higher reRT doses (> 40 Gy) and longer interval between the two radiation courses (> 12 months), seem to be the most important factors associated with patients’ outcomes. Finally, the presence of relevant radiation-related side effects such as osteo/chondro-radionecrosis, carotid artery stenosis, soft-tissue injuries (e.g., severe fibrosis, fistulae), and myelopathies should be considered at least as relative contraindications for a second radiation course (Table 2).

Table 2 Literature data on risk factors correlated to toxicity in patients treated with a second course of RT in head and neck region
Full size table

Overall, the interpretation and clinical application of these data should be taken with caution due to their high heterogeneity, which also limits the possibility of a quantitative synthesis. Indeed, patients submitted to reRT still remain in a setting for which an extremely individualized approach has been offered cite (Table 3).

Table 3 Patients, tumor and treatment prognostic factors
Full size table

To date, some nomograms have been proposed and are briefly presented below. For instance, Tanvetyanon et al. [37] have presented a nomogram integrating several known prognostic factors (namely, comorbidity, organ dysfunction, isolated neck recurrence, tumor bulk and the time interval between the radiation courses) to predict death probability within 24 months after reRT. A recursive partitioning analysis that considered time interval between the two radiation courses, surgical resection and organ dysfunction allowed to identify three prognostic classes (62%, 40% and 17%, for class I, II and III, respectively) [27]. Similarly, Choe et al. found that previous chemoradiation, surgery before reRT, reRT dose > 60 Gy and reRT interval > 36 months may stratify patients into three risk groups according to their overall survival [51]. Riaz et al. proposed a nomogram to predict the 2 year locoregional control including tumor stage (I–III vs. IVA–B), tumor site (nasopharynx vs. oral cavity vs. other subsites), presence of organ dysfunction, presence of surgery prior reRT, RT dose > 50 Gy [34]. A summary of the abovementioned nomograms is provided in Suppl. S1.

A recent meta-analysis showed that IMRT improved both safety and survival as compared to pre-IMRT data [59]. Moreover, the operation rate (proportion of patients who underwent salvage surgery) was the best predictor of 2-year local control rate in patients treated with IMRT.

Other than oncologic outcomes, toxicity predictors have also been investigated. Takiar et al. reported an association between higher toxicity (grade ≥ 3), the volume of the recurrent tumor (> 50 cm3) and the administration of concurrent chemotherapy [32]. Additionally, Lee et al. found that a shorter interval between the two radiation courses and larger tumor volume (> 100 cm3) were independent predictors of severe dysphagia (mainly in terms of feeding tube-dependency). As a general rule, higher dose to different organs at risk have been correlated with higher risk of severe acute and late reRT-related side effects.

In conclusion, several prognostic and predictive factors have been associated to outcomes and toxicity in patients treated with a second RT course. These parameters should be considered to define the cost/benefit ratio for curative-intent reRT.

Dosimetric feasibility

A recently published review has summarized dose constraints for several organs, including nervous structures (i.e., spinal cord, brainstem, optic pathways, brachial plexus, brain), the mandible and carotid arteries [60]. For patients considered at high risk of severe late side effects, the balance between the expected toxicity profile and clinical outcome should be carefully evaluated. Of note, the risk of severe toxicity could be minimized through preventive strategies such as endovascular procedures (carotid artery occlusion and/or stenting) in patients with high risk of carotid blowout syndrome [61].

Therefore, dosimetric analysis is the last step in determining the feasibility of reRT (in terms of total dose and technique) and cost/benefit ratio (expected side effects/efficacy). The total dose of reRT mostly depends on the proximity of the recurrent tumors to organs at risk.

Recently, international recommendations on dosimetric parameters for reRT for both SCCHN and nasopharyngeal cancers have been published [79, 80]. For patients with nasopharyngeal tumors, the PRANCIS (Predicting Radioresistant Nasopharyngeal Carcinoma Survival) prognostic score has also been reported (http://www.prancis.medlever.com/).

For an accurate dosimetric analysis, availability of Digital Imaging and COmmunications in Medicine (DICOM) files of the first radiation course is paramount. Uncertainties deriving from patient’s positioning, altered anatomy and differences in dose calculation algorithms should be carefully considered when interpreting the obtained summed dosimetric profiles, and extra-caution in approving the final reRT plan must be taken accordingly.

The most frequent grade ≥ 3 late toxic effects included radionecrosis, feeding tube dependency and trismus. Mucosal necrosis and carotid blowout are both life-threatening adverse events. Notably, no largely recognized dosimetric constraints for the re-irradiated carotid arteries and mucosal tissues are available. Moreover, it is relevant to note that the dose limit of 120 Gy to the carotid artery suggested by some studies [66, 81] is below the therapeutic cumulative dose that should be given to the tumor for an effective reRT, considering a dose of 70 Gy EQD210 for the first course and a dose of 60–66 Gy for definitive reRT [54]. In this context, to ensure both tumor dose coverage and OARs preservation [72], other strategies such as pre–reRT stenting or embolization of the threatened artery could be evaluated. It is interesting to observe that, in the recent retrospective study by Bagley et al. [82] reviewing the outcomes of patients re-irradiated for oropharyngeal cancer, carotid stenting was performed in only 2/69 cases, and carotid endarterectomy was performed in 5/69 patients (7%). Three oropharyngeal hemorrhages from the lingual artery requiring embolization occurred as late grade ≥ 3 events. To reduce the likelihood of potentially fatal events resulting from major vessels damage, the authors suggest the use of specific avoidance structures during treatment planning. Specifically, the suggested constraints for the lingual vessel avoidance structure are a maximum dose less than 30 Gy to 0.3 cm3 if the artery is outside the target volume (< 5 mm from the target), or to avoid hot spots if the artery is within the target volume.

The risk of soft-tissue necrosis should also be considered as a potential life-threatening adverse event after reRT; likewise, even in this scenario there are no clear dosimetric constraints to apply to the re-irradiated mucosa. Therefore, a careful evaluation of mucosal status pre reRT along with a strict follow-up imaging and SCCHN consultations with endoscopy for diagnosis and early treatment of soft-tissue is mandatory [83].

When using particle therapy, in consideration of the increased biological effectiveness of charged particles at the end of their range in tissues [84], special attention should be paid in treatment planning not to convey the beam distal fall-off toward serial critical structure such as carotid vessels, brainstem, mucosal tissue outside GTV [79].

Pragmatic approach to select patients for reRT

To summarize literature data and organize available information in a manageable tool, we propose a stepwise approach helping to define the best reRT candidate (Fig. 1).

Fig. 1
figure 1

A stepwise approach to help to define the best reRT candidate

Full size image

Of note, given the existence of multiple clinical variables in the lack of well-defined cut-offs related to patients’ prognosis, the definition of a “favorable” or “unfavorable” condition remains at the discretion of the referring Radiation Oncologist.

While reported time intervals between the two radiation courses ranged from 12 to 36 months, we proposed a cautionary threshold of 12 months. Moreover, it is worth reminding that this workflow should be shared and discussed with the patient, to fully understand their needs and expectations.

Below, two clinical cases are presented to provide the reader with a practical overview of how the proposed approach can be applied to real-life situations.

Case 1

Patient: 50-year-old male. Comorbidities: gastritis and kidney stones.

Brief history: In 2007, the patient was diagnosed with a squamous cell carcinoma of the oral cavity (left mobile tongue) and treated with compartmental left hemiglossectomy and bilateral neck dissection. The resulting pathologic stage was pT4N0M0 (AJCC 7th Ed.) Postoperative RT was performed up to a total dose of 60 Gy (2 Gy/fraction) to the surgical tumor bed and 54 Gy to negative neck lymph nodes in February 2008. Three local recurrences occurred in 2009, 2012 and 2016: they were all considered as amenable to surgery, and were staged as rpT1, rpT4, and rpT3, respectively. Adopted approaches were transoral surgery of the amigdaloglossus region and reconstruction with a Bichat’s flap, and hemimandibulectomy, respectively. The last recurrence was finally diagnosed in 2021, at the posterior margin of the pectoralis flap positioned in 2016.

  • Step 1) Diagnostic work up: Clinical Examination: KPS 90, no dysphagia, no dyspnea. No signs of bleeding. Slight headache responsive to paracetamol. Stable body weight (82 kg). No dysfunction from the previous radiation treatment (G1 subcutaneous fibrosis). Fibroscopy: presence of ulcer in the lateral oropharyngeal wall at the posterior edge of the oral cavity flap reaching the ipsilateral hypopharynx. MR: lesion of 16 mm of the left pharyngeal wall infiltrating the parapharyngeal space and the constrictor muscle up to the superior margin of the pyriform sinus. No infiltration of pre-vertebral muscles could be identified. FDG-PET: absence of pathological uptake other than the lesion in the parapharyngeal space. Resulting clinical stage was rcT4 rcN0 rcM0, with a volume of the recurrent tumor of 40 cm3. A biopsy confirmed the histology of squamous cell carcinoma. The mass was judged not suitable for further surgery.

  • Step 2) Prognostic and Predictive Factors for patient’s selection

  • Step 3) Dosimetric analysis

The dosimetric assessment showed that the current recurrence was partially included in the high dose area (60 Gy) of the first RT. Moreover, the ipsilateral carotid artery received the full dose from the previous treatment at the level of the last local recurrence. To maintain a cumulative dose < 120 Gy to the carotid artery, a full course of RT up to a total dose of 60 Gy by IMRT has been proposed. Table 4 summarizes risk factors for long-term toxicity considering the abovementioned characteristics.

Table 4 Risk factors for long-term toxicity. Red, yellow and green emojis stated whether a defined risk factor is present, is borderline or absent, respectively
Full size table

Conclusion: both expected oncologic outcomes at 2 years and long-term toxicity profile seem to be quite favorable for the majority of considered prognosticators. Therefore, based on the available data, it appears reasonable to propose a second RT course.

Case 2

Patient: 57-year-old male, with no reported comorbidities. Brief history: in June 2014 the patient was diagnosed with a non-keratinizing poorly differentiated nasopharyngeal carcinoma, staged as cT1cN1M0 (AJCC 7th Ed). Curative chemoradiation up to a total dose of 70 Gy (2 Gy/day) ended in June 2014. In October 2015 a retropharyngeal lymph node was detected at RM images during the follow-up. A biopsy was not feasible due to the tumor location.

Volume of the recurrent tumor was 20 cm3.

The mass was judged not suitable for surgery.

  • Step 1) Diagnostic work up

    Physical examination: KPS 100. No pain, no dysphagia, no respiratory distress. No dysfunction from the previous radiation treatment (xerostomia G2). Fibroscopy: no signs of local recurrence or mucosa ulcer. MR: pathologic lymph node 11 × 10 × 18 mm in the left parapharyngeal space (pre-styloid space), close to the carotid artery (< 180°). FDG-PET: no other pathologic uptake than in the left parapharyngeal space. Table 5 summarizes predictive and prognostic factor for patients’ selection related to the analyzed case.

    Table 5 Patients, tumor and treatment prognostic and predictive factors
    Full size table

  • Step 2) Prognostic and Predictive Factors for patient’s selection.

  • Step 3) Dosimetric analysis.

The dosimetric assessment showed that the recurrence fell within the high dose area (70 Gy) of the previous treatment. Moreover, carotid artery had received a full dose from the previous treatment at the level of the recent local recurrence. To maintain a cumulative dose < 120 Gy to the carotid artery, a full course of RT up to a total dose of 50 Gy has been proposed. Identified risk factors for long-term toxicity are summarized in Table 6.

Table 6 Risk factors for long-term toxicity
Full size table

Conclusion: overall both expected oncologic outcome at 2 years and long-term toxicity profile seems to be quite favorable for the majority of the considered prognosticators. Therefore, based on available data, it seems reasonable to propose a second course of RT up to a total dose of 50 Gy [12, 34].

Discussion

Several literature data have been provided during the last decades to guide reRT indications [18, 85,86,87,88,89,90,91]. The majority of these works were narrative reviews on several aspects that should be considered in locally recurrent cancers of the head and neck. Cacicedo et al. [18]: in their 2013 work reviewed prognostic and predictive factors for both clinical outcomes and toxicity and provided dosimetric information to estimate the risk of toxicity of a second course of RT in head and neck region. Nevertheless, during the last decades, several new clinical studies (i.e., on the use of particle beam therapy) and international recommendations have been published [79, 80]. Our work, therefore, summarizes current knowledge on the topic providing an updated pragmatic instrument to manage reRT in the setting of SCCHN.

We are aware of the several limitations of this work: (1) the majority of provided literature data derived from mono-institutional analysis and have limited sample sizes, (2) prognostic and predictive factors are often expressed in qualitative terms (e.g., “young” age), and derive from heterogenous populations treated with multiple reRT techniques and fractionation schedules. Indeed, there are no validated prognostic parameters for reRT. While the presence of HPV in RM SCCHN has been associated with improved overall and progression-free survival tumors [92], Nevertheless none of the available nomograms have incorporated this variable. This underlines the need of further studies in this clinical setting. (3) application of provided prognostic and predictive factors on cohorts that differ from the original ones, could produce differences in obtained results [39]. (4) Nomograms could provide different results for the same endpoint due to the different parameters used to build the final prognostic value. (5) Several potentially relevant factors (i.e., stage of the primary tumor, patients’ compliance, supportive care network and logistic arrangements, psychological and rehabilitation aspects, individual tolerance to radiation etc.) have not been specifically reported but should be considered in real-life situations. (6) Not unique cut-off value has been found for several factors (i.e., tumor volume at recurrence, reRT dose, minimum interval between the two radiation courses) (7) the “favorable” vs “unfavorable” setting represented in Fig. 1 can be highly subjective as it was not possible to provide a cut-off to separate the two cohorts in each step of the process (8) the efficacy of the provided tool should be validated and adapted (if necessary) in prospectively enrolled in controlled clinical studies.

Moreover, the use of concurrent systemic treatments has not been detailed in this work. In particular, whether the association of concurrent systemic treatment could lead to dose de-escalation need further investigation.

Results reported in the present work were retrieved from a narrative review of the literature. We chose this approach as it allowed us either to report an overview of the available knowledge on the topic or to gather data provided by different authors. A systematic review generally provides a more robust evidence-based method, but considering the aim of our work as well as the nature of the vast majority of the studies focused on SCCHN reRT (retrospective monocentric analysis obtained from a low number of enrolled patients and with high heterogeneity of reported results) we preferred to proceed with a comprehensive and critical qualitative analysis of the current literature shreds of evidence. However, this approach is prone to criticism, and therefore all reported data need to be considered with caution when applied in daily clinical practice.

Despite the present work focuses on indication to a second course of full-dose RT, it is important to emphasize that a clear cut-off value for considering reRT as curative or cytoreductive intent has not yet been well established. Moreover, in the era of the high-precision RT (stereotactic body/intensity-modulated radiotherapy and hadrontherapy), the trade-off between prescription doses to the target volume and the ability to spare surrounding organs at risk should be carefully considered.

According to results of the present work, several factors should be considered in patients with recurrent/second primary head and neck tumors. However, most authors agree that a minimum interval of 6 months between two radiation courses, absence of severe radiation-related sequalae, limited volume of the recurrent tumor and the dosimetric feasibility should be minimum requirements to consider a patient for a full course reRT.

In conclusion, a reRT remains a personalized approach that can be offered to selected patients only in centers with expertise and dedicated equipment after a multidisciplinary discussion. Results of our work represent the first attempt to standardize the approach providing an evidence-based clinical tool for indication to reRT in SCCHN patients.