1. Introduction

Tracheal cancers are a rare primary tumour location, estimated at less than 0.1 cases per 100,000 inhabitants [1]. No staging classification exists specifically dedicated to tracheal tumours. Clinically, initial symptoms such as haemoptysis, dyspnea, cough, or even stridor are encountered and guide the initial assessment [2,3]. Due to the low incidence, there is neither French nor European recommendation for management of these tumours. Several histological varieties are described: squamous cell carcinomas, adenocarcinomas as well as adenoid cystic carcinomas. The history and age at diagnosis are different amongst these histologies. Smoking, male predominance and rapid progression are associated with tracheal squamous cell carcinoma. A contrario, the male to female ratio is similar, with little or no history of smoking and slow progression in case of adenoid cystic carcinoma [3]. Squamous cell carcinomas are reputed to be more radiosensitive and more lymphophilic than adenoid cystic carcinomas. Thus, the doses and fractionations, margins and volumes recommended in radiotherapy are different according to the histologies, as realised for lung and head and neck cancers [4–6]. In case of tracheal cancer, there is no consensus dedicated to radiation therapy. Tracheal cancer treatment can use endoscopic resection if limited lesion, surgery – realised in first intention, radiotherapy and systemic treatment [3]. Several elements may contraindicate surgery, in particular if impossibility of adequate margin or extension to adjacent organs or metastatic disease. Radiotherapy can be done as an adjuvant treatment as well as an exclusive treatment, associated or not with systemic treatment. This review summarizes the main elements published about squamous cell carcinoma of the trachea treated with radiotherapy, in terms of modalities, therapeutic regimens, local control and survival, acute and late side effects

2. Material and Methods

A review of the literature was made on the pubmed database in French and English from 2012 to April 2022 over the last ten years, due to the change in radiotherapy techniques, in particular use of intensity modulation techniques, reference in lung and head and neck cancers. Series with only brachytherapy have been excluded due the high level of specialization necessary for this technique.

1. The series and case reports were selected if inclusion of squamous cell carcinoma of the trachea with radiotherapy treatment. The MESH words used were “tracheal cancer”; “squamous cell carcinoma” and “radiotherapy”, “radiation therapy”
2. From 2012 to 2022: 125 articles were found, 18 were selected based on title and abstract, 17 were selected after reading the full text.

For comparison, the largest series or case reports detailing the radiotherapy treatment performed, published before 2012 were selected.

3. Results

Several publications have studied radiotherapy in tracheal cancers, the 17 articles selected include 9 case reports and 8 retrospective series published after 2012. Squamous cell carcinomas accounted for more than half of the histologies. Table 1 summarizes the data found in terms of treatment, toxicity and prognostic. Concerning indications and systemic treatment modalities, surgery was the first treatment, exclusive radiotherapy being performed only in case of surgical or anaesthetic contraindication or patient refusal. Systemic treatments were realised as neoadjuvant or concomitant with radiotherapy. Almost all the studies found after 2012 used a platinum salt derivative, in the form of cisplatin. Cisplatin was delivered either at a dose of 100 mg/m² every three weeks or at a dose of 40 mg/m² weekly and/or in combination with other molecule. Only one serie include brachytherapy in the radiotherapy treatment [7]. Regarding radiotherapy, the techniques included 3D and IMRT in most of the cases, in photon. The dose varied between 64 and 70 Gy using an equivalent of 2 Gy by fraction (EQD2). Some series detailed volumes of radiotherapy. More specifically, 2 studies detailed the macroscopic volume of the GTV-P tumour based on imaging and endoscopy as well as the margins for the CTV without help of PET [8,9]. The CTV-P clinical volume was made with a margin of 3-5 cm craniocaudally and 1-2 cm axially. Yathiraj used a 1 cm extension for CTV P and N [9]. The adjacent CTV-N areas were taken in some cases, especially if initial involvement [7] and at least areas IV and V [9]. A margin of 0.5-1 cm was used for PTV. In terms of toxicities, radiotherapy was well tolerated [8–10] with no grade more or equal to 3. The early effects found included low-grade mucositis and dermatitis. Late side effects included hypothyroidism and a case report mentioned ventricular tachycardia [11]. Regarding prognostic, overall survival at 5 years was about 40-50% for all histologies and all treatment combined [8,12]. Two registry studies showed a survival improvement over time with more surgery realised [13,14]. A benefit in terms of overall survival was found in several registry analyses by the addition of radiation therapy [12]. Brachytherapy has been used as a curative treatment but also in palliative case for symptoms [15]. In the case of squamous cell carcinoma, the prognosis was worse, around 8-14% at 5 year comparatively to other histologies [7,16,17] . Among the prognostic factors, adenoid cystic carcinoma histology was associated with better local control and survival [8,16] . A dose-effect of radiotherapy greater than 68 Gy was found on progression-free survival in Zeng's series [8]. Performans status (PS), primary surgery, adjuvant radiotherapy and haemoptysis were significantly associated with survival – on the contrary of the use of systemic treatment in Napieralska's series [7]. The incidence was similar between locoregional progressions (17-28%) and pulmonary and bone metastatic progressions (21%) [7,8]. Age≥65 years, ≥1 comorbidities, and palliative treatment have been found as prognostic factors [13]. Other risk factors have also been reported in recent case reports such as HPV 18 [18], previous treatment with radiotherapy [19] or radioactive iodine [20]. A complete response after post radiotherapy progression had been induced by immunotherapy in another case [21].

Table 1: Summary of series and case reports on squamous cell carcinoma of the trachea.

Legend : SCC- Squamous Cell Carcinoma; ACC- Adenoid Cystic Carcinoma Carcinoma; ADK- Adenocarcinoma; F- Female; M- Male; RT- Radiotherapy; CT- Chemothérapie; OS- Overall Survival; DFS- Disease Free Survival; LRPFS- Locoregional Progression Free Surival; ND- Not Described; IMRT- Intensity Modulated Radiation Therapy

4. Discussion

Few data have been published on squamous cell carcinoma of the trachea. Table 2 summarizes the main elements proposed for radiotherapy and systemic treatment in this context, found in the selected studies. In terms of treatment, surgery remains the treatment offered as first-line due to a much more pejorative prognosis in terms of survival if not operable. Exclusive radiotherapy remains for cases of refusal or contraindication to surgery. The better prognostic associated with surgery is described for locally advanced squamous cell carcinoma in other localisation such as larynx-hypopharynx, oesophagus and lung. Adjuvant radiotherapy must be discussed particularly in the case of insufficient margin, extra nodal extension and for some authors if locally advanced tumours [8]. In case of a high volume impossible to adequately cover, an induction treatment before could be discussed. A few cases of induction chemotherapy in the retrospective series have been described without information on their effect. Systemic treatments most often included cisplatin 100 mg/m² or weekly – which seems analogous to lung and HNT cancers. Among the other combinations, a case report used carboplatin paclitaxel [22]. No association with immunotherapy was found in case of early stage. A phase II is currently open for rare tumours with a combination of Nivolumab-Ipilimumab (NCT02834013). Radiotherapy was performed using intensity modulation (IMRT) in most series and in photon. No series or cases with proton therapy have been found. A 5-point mask seems the most suitable for the treatment. The dose and fractionation were mostly around 60-70 Gy; a dose higher than 68 Gy could be discussed in view of its association with better local control in Zeng's series [8]. For the volumes, at the level of tumour involvement, the trachea is located under the larynx, with the glottic plane cranially and above the carina. The cricoid and thyroid cartilage represent an anatomical barrier to extension in squamous cell carcinoma of the larynx [23]. It does not necessarily seem appropriate to extend the tumour volume above the latter unless affected. Facilitated diffusion into the tracheal cylinder suggests a cranio-caudal margin larger than the axial one [8]. The integration of adjacent or invaded areas was described in the different series – locoregional recurrences being not uncommon. Few data were found in terms of acute and late toxicity apart from thyroid and respiratory involvement [8,9]. Compared to squamous cell carcinoma, other histologies have different prognoses, notably adenoid cystic carcinomas. Data proposed in this review do not apply to these histologies due to their different extensions, their even rarer incidence, and their response to treatment comparatively to squamous cell carcinoma. Concerning prognostic, local control and survival were relatively low if no surgical treatment despite high doses. Smoking appearsed as a factor of poor prognosis in some series. Given the relatively young age and the difference in terms of survival between surgical treatment or not, the opinion of an experienced center seems essential. Two nomograms were developed based on a cohort of 405 patients treated between 1988 and 2015 [24]. Other factors of good prognosis had been considered - (young age, female sex) - allowing aggressive treatments. Lymph node involvement, with a poor prognosis “should justify a more aggressive therapeutic approach. This review presents relatively recent results with description of treatment protocols. Only scarce and heterogeneous data was available, due to the rareness of tracheal carcinomas. The description of the diagnostic work-ups and the place of some imaging methods such as PET that may have revealed lymph node involvement are not detailed. Main data part is ether is in the form of case report or registry study without exhaustive modalities description. Benefits of brachytherapy in terms of survival, local control and toxicities have not been discussed in this review.

Table 2: Synthesis proposal on tracheal squamous cell carcinoma radiotherapy.

Legend: GTV- Gross Tumour Volume; CTV- Clinical Target Volume; PTV- Planned Target Volume; P- Primary Tumour; N- Nodes; IMRT- Intensity Modulated Radiotherapy

5. Conclusion

Few data have been published on radiotherapy treatment in squamous cell carcinoma of the trachea. Overall survival was approximately 14-50% at 5 years depending on histology and treatment performed. The most common extensions are in the oesophagus and thyroid. In the absence of surgical treatment, the prognosis is poorer. Exclusive radiotherapy, preferably with intensity modulation techniques at doses of 60 to 70 Gy, can be associated with systemic treatment. The doses varied between 50 and 54 Gy in the case of adjuvant radiotherapy. The main systemic treatments included a platinum salt mainly administered concomitant to irradiation. The opinion of a specialized center seems important given the rare incidence, the absence of consensual treatment.

Conflict of Interest

None.

References

1. Junker K. Pathology of Tracheal Tumors. Thorac Surg Clin 24 (2014): 7-11.
2. Sherani K, Vakil A, Dodhia C, et al. Malignant tracheal tumors: a review of current diagnostic and management strategies. Curr Opin Pulm Med 21 (2015): 322-326.
3. Madariaga MLL, Gaissert HA. Overview of malignant tracheal tumors. Ann Cardiothorac Surg 7 (2018): 244-254.
4. Khalifa J, Lerouge D, Le Péchoux C, et al. Radiotherapy for primary lung cancer. Cancer/Radiothérapie 26 (2022): 231-243.
5. Grégoire V, Evans M, Le Q-T, et al. Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines. Radiother Oncol J Eur Soc Ther Radiol Oncol 126 (2018): 3-24.
6. Larnaudie A, Marcy PY, Delaby N, et al. Radiotherapy of salivary gland tumours. Cancer/Radiothérapie 26 (2022): 213-220.
7. Napieralska A, Miszczyk L, Blamek S. Tracheal cancer – treatment results, prognostic factors and incidence of other neoplasms. Radiol Oncol 50 (2016): 409-417.
8. Zeng R, Wang H, Cai X, et al. Radiotherapy for Primary Tracheal Carcinoma: Experience at a Single Institution. Technol Cancer Res Treat 20 (2021): 153303382110342.
9. Yathiraj PH, Ail S, Singh A, et al. Unresectable squamous cell carcinoma of upper trachea with long-term survival after concurrent chemoradiotherapy. BMJ Case Rep (2017): bcr-2017-221284.
10. Kovacs AC, Vodanovich D, Mogridge EK, et al. A case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis, with a complete response to concurrent chemoradiotherapy. SAGE Open Med Case Rep 9 (2021): 2050313X2110546.
11. Luo W, Luo G, Gong Y, et al. Synchronous primary cancers of trachea and esophagus and ventricular tachycardia. Chin J Cancer Res Chung-Kuo Yen Cheng Yen Chiu 26 (2014): 345-350.
12. Xie L, Fan M, Sheets NC, et al. The Use of Radiation Therapy Appears to Improve Outcome in Patients With Malignant Primary Tracheal Tumors: A SEER-Based Analysis. Int J Radiat Oncol 84 (2021): 464-470.
13. Hararah MK, Stokes WA, Oweida A, et al. Epidemiology and treatment trends for primary tracheal squamous cell carcinoma. The Laryngoscope 130 (2020): 405-412.
14. Agrawal S, Jackson C, Celie KB, et al. Survival trends in patients with tracheal carcinoma from 1973 to 2011. Am J Otolaryngol 38 (2017): 673-677.
15. Nguyen NTA, Timotin E, Hunter R, et al. Endotracheal brachytherapy alone: An effective palliative treatment for tracheal tumors. Brachytherapy 14 (2015): 543-548.
16. Jiang M, Lei Q, Lv X, et al. Clinical features and prognosis analysis of 57 patients with primary tracheal tumors. Transl Cancer Res 9 (2020): 613-619.
17. Yusuf M, Gaskins J, Trawick E, et al. Effects of adjuvant radiation therapy on survival for patients with resected primary tracheal carcinoma: an analysis of the National Cancer Database. Jpn J Clin Oncol 49 (2019): 628-638.
18. Imai H, Takahashi T, Taira T, et al. Papillary Squamous Cell Carcinoma of the Trachea Associated with Human Papillomavirus-18 Infection. Intern Med 52 (2013): 2785-2788.
19. Mori M, Detterbeck FC. Rare case of radiation-induced primary tracheal carcinoma. Gen Thorac Cardiovasc Surg 66 (2018): 549-551.
20. Tan TH, Lee BN. Primary Squamous Cell Carcinoma of Trachea Arising 4 Years after Radioiodine Treatment of Papillary Carcinoma of Thyroid. Clin Nucl Med 41 (2016): e259-e260.
21. Maller B, Kaszuba F, Tanvetyanon T. Complete Tumor Response of Tracheal Squamous Cell Carcinoma after Treatment with Pembrolizumab. Ann Thorac Surg 107 (2019): e273-274.
22. Haresh K, Das P, Kumar R, et al. Unresectable basaloid squamous cell carcinoma of the trachea treated with concurrent chemoradiotherapy: A case report with review of literature. J Cancer Res Ther 6 (2010): 321.
23. Lapeyre M, Bailly C, Toledano I, et al. Cancer de l’hypopharynx et du larynx?: proposition de sélection et délimitation des volumes cibles microscopiques péri-tumoraux (aires ganglionnaires exclues). Cancer/Radiothérapie 14 (2010): S43-51.
24. Wen J, Liu D, Xu X, et al. Nomograms for predicting survival outcomes in patients with primary tracheal tumors: a large population-based analysis. Cancer Manag Res 10 (2018): 6843-6856.