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Radiotherapy for Recurrent/Metastatic Oral Cavity Squamous Cell Carcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13010099

Oral squamous cell carcinoma is the most common malignant epithelial neoplasm affecting the oral cavity. While surgical resection is the cornerstone of a multimodal curative approach, some tumors are deemed recurrent or metastatic (R/M) and often not suitable for curative surgery.

squamous cell carcinoma oral cavity treatment option

1. Introduction

Malignant tumors of the lip and oral cavity are the 16th most common tumors in humans [1]. Oral cancers account for the majority of squamous cell carcinomas of the head and neck (SCCHN). Their prevalence is variable, with rates as low as 5% of all cancers in the United States to as high as 30–45% in India [1]. The survival 5 years after diagnosis is around 40–50%, with the global burden of oral cancer documented to increase between 1990 and 2017 [1][2]. Approximately 2.4 deaths per 100,000 and 64.2 disability-adjusted life years (DALYs) lost per 100,000 people were reported in 2017. This burden of disease is higher in men [2]. Although the quality of care for these patients has been increasing in most countries, global disparities still exist worldwide due to uneven access to healthcare between and within countries [2][3]. Several regional and global exogenous risk factors have been described for oral cancer, where tobacco, either smoked or chewed, is one of the main factors. The prevalence of SCCHN is 5 to 8.4 times higher in tobacco users compared to the general population [4]. Alcohol, another risk factor, is directly harmful to the DNA and acts synergistically with tobacco as a carcinogen [4]. Despite not being considered for treatment selection in international guidelines, human papillomavirus (HPV)16/18 is an acknowledged carcinogen, which will potentially be used as a prognostic and predictive marker in the future [5][6][7]. Genetic studies have uncovered a great variety of alterations associated with these tumors, such as aberrations in the fragile histidine triad gene (probably related to tobacco smoke), co-amplification of EIF3E and RECQL4 (related to alcohol consumption), and PIK3CA mutations (with increased prevalence in HPV-associated disease). Tumor mutations or epigenetic changes may lead to abnormal cell signaling and proliferation, malignant transformation, and evasion from the host immune response [4]. Patient symptoms are usually associated with invasion of adjacent structures (and may include limitation of tongue mobility, trismus, dysphagia, stridor) or treatment side effects. Treatment for localized disease consists of a combination of surgery, radiotherapy, and systemic therapy (either conventional cytotoxic chemotherapy or targeted therapy with cetuximab). Even when it is not operable, localized SCCHN is potentially curable with systemic therapy and radiotherapy. This range of therapeutic options warrants the need for a multidisciplinary approach to these patients, encompassing medical oncologists, radiation oncologists, and surgeons, among other health professionals, within a shared decision process. While the side effects of local (radiotherapy and/or surgery) and systemic therapy have an impact on patients’ quality of life (QoL) in the short term [8][9][10], long-term survivors of localized disease have a good the QoL at 2 to 10 years after end of treatment [11][12], although inferior to controls with no history of cancer [13]. Active smoking at the time of diagnosis and the need to use feeding tube in the long term predict low QoL [11]. In recurrent/metastatic (R/M) disease setting, patients’ QoL decreases rapidly as a result of treatments or disease progression, leading to impairment in activities of daily living and poor health-related QoL, and placing a high burden on formal and informal caregivers [14]. This highlights the need to optimize the management of this patient population.

2. Radiotherapy

The standard of care for locoregional recurrent SCCHN is surgical resection, followed by adjuvant chemotherapy and/or radiotherapy, if indicated according to pathologic risk factors [6].
For patients deemed medically unfit for surgery or for whom surgery would result in adverse functional outcomes, radical radiotherapy, with or without chemotherapy, is an option. The University of Chicago first demonstrated the feasibility of this approach in 1996, after reviewing previously irradiated head and neck cancer patients enrolled in four phase I/II trials [15]. The investigators reported a 2-year overall survival (OS) of ≈20%, which increased to 35% among patients receiving over 58 Gray (Gy). The long-term analysis of this research confirmed initial results, with the reirradiation dose remaining an independent prognostic factor [16]. However, the late toxicity of this treatment was significant, with 19 of 115 patients dying from treatment-related intercurrences, including 5 from carotid artery blowout.
Another series of 169 reirradiated head and neck patients from Institut Gustave Roussy yielded similar results, with a 2-year OS of 20% [17]. However, five patients died from carotid blowout, and late grade 3 toxicities were frequent. The RTOG 96-10 trial investigated a twice-daily radiation schedule with delivery of 60 Gy of radiation to previously irradiated head and neck patients, with comparable results: 1-year OS of 48%, but 7% of treatment-related deaths [18]. In this research, the time between each radiation course and reirradiation for a second primary tumor instead of for local recurrence significantly correlated with survival. This difference in prognosis between second and recurrent primary tumors was already suggested in a series of 100 patients reirradiated with external beam plus brachytherapy [19]. If indicated, radiotherapy and/or chemotherapy should be considered even for patients submitted to surgery for recurrent local disease. A randomized trial from Institut Gustave-Roussy assigned 130 patients with macroscopically resected recurrent head and neck cancers (18% of which were oral primary tumors) to adjuvant chemoradiation or observation [20]. Although adjuvant treatment did not provide a survival advantage (2-year OS 40–50%), locoregional control was significantly improved in the adjuvant treatment group, as well as deaths related to local recurrence. Late toxicity was noticeably higher in the adjuvant group, including grade 3–4 sclerosis, trismus, and osteoradionecrosis, which affected as much as 39% of surviving patients at 2 years. The development of more precise, dose-intensive radiation regimens for other anatomical sites spurred the interest on stereotactic body radiotherapy (SBRT) for locally recurrent head and neck tumors.
A phase I dose-escalation trial including seven patients with recurrent oral cavity cancers explored up to 44 Gy in five fractions [21]. Although no grade 3 toxicities were observed, only a modest interval of 4 months until disease progression was reported. Another study used a median of 30 Gy in five fractions at reirradiation reported more promising results, although 15% of patients died of bleeding due to carotid blowout [22]. Interestingly, the authors found that this outcome was only observed in patients whose tumors completely encased the carotid artery.
The finding that cetuximab conferred a survival benefit versus radiotherapy alone in naïve head and neck patients unfit for platinum-based chemotherapy led investigators from the University of Pittsburgh to conduct a matched case–control study of SBRT in recurrent disease setting [23][24]. Patients treated with concomitant cetuximab had a median OS of ~24 months and no grade 4–5 toxicities. A phase II trial also exploring SBRT (36 Gy in six fractions) and concurrent cetuximab showed a more modest OS of 11.8 months, with one treatment-related death [25]. These results were confirmed in another phase II trial including 29% of patients with recurrent oral cavity cancer, which reported an OS of 10 months and only 6% of grade 3 or higher late toxicities [26].
Radiotherapy with curative intent may not be feasible in head and neck tumors for a variety of reasons, including simultaneous relapse with local recurrence and distant metastases, patients’ unfitness for aggressive treatments (i.e., low performance status (PS)), and/or patient choice. In these cases, radiotherapy may play a relevant role as palliative treatment of these tumors, including those of the oral cavity. The goal of palliative radiotherapy for the primary tumor is local relief with some degree of local control, particularly in patients without indication for curative treatment [27].
Well-established palliative schemes considering patients’ PS and estimated survival are available. The ideal patient candidate should have Eastern Cooperative Oncology Group (ECOG) PS 0–2 (or 3 in selected cases) and an estimated survival over 1–3 months. Patients should tolerate the positioning of the procedure, and its potential benefit (both from a clinical and patient perspective) should outweigh the discomfort it causes. The well-known QUAD-SHOT regimen includes at least one radiotherapy cycle that corresponds to two twice-daily treatments of 3.7 Gy on two consecutive days. An interval of 2–4 weeks is required between each cycle to assess response, toxicity, and the need for replanning. The time interval between the new treatment planning and execution of a new cycle should not exceed 3 days, in order to allow for treatment on consecutive days. Corry et al. assessed 30 eligible cases with the QUAD-SHOT regimen, showing that 43% of patients had oral cavity carcinoma [28]. Although only 16 patients completed three cycles, 16 patients had an objective response (2 cases with complete response) and 7 had stable disease. The median OS was 5.7 months, and the median progression-free survival (PFS) was 3.1 months. Toxicity was assessed in 27 patients, 14 of whom experienced grade 1 radiodermitis, 9 experienced grade 1 mucositis, and 3 experienced grade 2 mucositis. Other schemes can be applied following the recommendations adapted from Grewal et al. Besides PS, the radiation oncologist should consider the previous history of irradiation in overlapping fields [29][30].
In patients with low estimated survival (up to 4 months) unfit for other cancer treatments, the main goal is comfort and symptom relief. Ideally, the duration of the complete radiotherapy scheme should be no longer than two weeks. Possible schemes include QUAD-SHOT, 20 Gy in five fractions (one fraction per day), and 28 Gy in three fractions (in days 0, 7, and 21) [30][31][32][33]. For patients with an estimated survival between 4 and 12 months, QUAD SHOT with or without chemotherapy is an option, as well as 20 Gy in 5 fractions (4 Gy daily), 30 Gy in 5 fractions twice per week, or 40 Gy in 10 fractions twice per week [30][31][32][33]. For patients with an estimated survival over 12 months, more aggressive treatment can be considered. For patients with no indication for other treatments, a hypofractionated regimen with 50 Gy in 16 fractions (3.125 Gy/day) or 52.5 Gy in 15 fractions (3.5 Gy/day) is recommended [30].
The fact that palliative radiation has a primary goal of symptom relief should not hinder the fact that it can also contribute to local control and even survival. The QUAD-SHOT study reported over 50% of objective responses, with a median OS of 5.7 months, which is promising given that those were patients not amenable to curative therapy. “Christie scheme” (3.125 Gy per fraction) reported an OS of 40% at 1 year and a median survival time of 17 months. Even the more modest “0–7–21” regimen showed a median 6-month OS of 51% with a 39% PFS within the irradiated volume [31].
Brachytherapy also has a place in the treatment of head and neck cancer, with oral cavity tumors being the best candidates for this approach. However, its efficacy evidence comes mainly from retrospective studies. New guidelines have been recently published by GEC-ESTRO ACROP for the use of brachytherapy as a reirradiation option in inoperable patients, according to which this approach allows for adequate coverage without serious toxicities, such as bone invasion or fistula. Brachytherapy can also be used as a boost after external beam radiation therapy [32][33][34].
Some currently ongoing trials may uncover new directions for the treatment of R/M SCCHN, as the combination of radiotherapy with immunotherapy, which is currently a hot topic for investigation. The pillar concept for this combination is a synergistic effect, by which neoantigens produced during radiotherapy treatment and the immunotherapy agents (i.e., immune checkpoint inhibitors) promote immunological synapses in order to intensify the host immune system against the cancer cells. This can happen near the area of irradiation, but also over distant metastasis (known as abscopal effect). This combination can be useful for locally advanced disease and metastatic disease, especially if limited oligoprogression is observed while on isolated immunotherapy, promoting the so-called “turning cold tumor to hot tumor” effect [35]. Although more established for the combination of immune therapies, the immune effect produced by radiotherapy can also play a role in this setting.
The concept is feasible but there are still impeding questions beyond the scope of the research that are under investigation: What are the best immunotherapy agents for the combination? Which is the ideal biomarker(s)? Ideal timings for the introduction of each therapy? What are the appropriate RT technique, prescription dose, and treatment volumes of interest to enhance the immunological effect?
Ongoing trials without results for a plethora of cancer diseases and settings are being conducted with very few SCCHN cancers, especially for oral cavity carcinomas. Although not exclusively in oral cavity tumors, the KEYSTROKE/RTOG 3507 phase II trial (NCT03546582) is comparing SBRT alone versus SBRT in combination with pembrolizumab in locoregionally recurrent or second primary head and neck cancers. rEA3191 is another phase II trial seeking to compare reirradiation with pembrolizumab versus re-irradiation plus paclitaxel versus pembrolizumab alone in locally recurrent or second primary SCCHN in a previously irradiated field [36][37].
Potential combinations with novel radioenhancers, such as nanoparticles, are also being investigated. NBTXR3 is a hafnium oxide crystalline nanoparticle compound that is injected directly into tumors to enhance the absorption of ionizing radiation, resulting in increased tumor cell death without adding toxicity to adjacent normal tissues. This approach has shown promising results in soft tissue sarcoma [38][39]. It is being investigated across multiple tumor types and different settings, including inoperable locoregional recurrent SCCHN. A phase II trial with two cohorts of patients with inoperable locoregional recurrent SCCHN is currently active and recruiting patients (NCT04834349). In the cohort I, the aim of the research  is to estimate the PFS and early clinical benefit of NBTXR3 activated by SBRT reirradiation with concurrent pembrolizumab. Cohort II aims to assess the safety profile and estimate early clinical benefit of NBXTR3 activated by dose reduction of intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) reirradiation with concurrent pembrolizumab in patients with locoregional recurrent disease not eligible for SBRT [40].
Keypoints of Radiotherapy section:
  • Patients with R/M oral cavity SCCHN cancers impose a challenge since the impossibility of surgery hampers clinical outcomes.
  • Reirradiation with external beam radiotherapy can be offered, but patient selection is important to decide the treatment intent (curative vs. palliative) because OS is limited and severe cumulated toxicities are increased (e.g., carotid blowout, trismus, and osteonecrosis).
  • In curative reirradiation, the 2-year OS is around 20%, but treatment-related events can reach up to 7–15% of cases. Most data are based on IMRT techniques and very few with stereotactic treatments.
  • There are a wide variety of palliative RT schemes to confer best comfort and symptom relief, with the QUAD-SHOT regimen being the most known.
  • Robust data for brachytherapy techniques are lacking, and ongoing trials are being conducted to search the benefit RT combinations with novel agents, such as immunotherapy or nanoparticles.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Cecília Melo-Alvim
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Maria Eduarda Neves
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Jorge Leitão Santos
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André N. Abrunhosa-Branquinho
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Tiago Barroso
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Luís Costa
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Leonor Ribeiro
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Update Date: 04 Jan 2023
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