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Radiotherapy for Tracheal Squamous Cell Carcinoma: A Review

Article Information

A. Larnaudie1,2*, H. Orliac1, D. Lerouge2, C. Naessens1, N. Deny1, R. Serre1, P. Clavère1

1Department of Radiation Oncology, Dupuytren University Hospital, Limoges, France

2Department of Radiation Oncology, Centre Francois Baclesse, Caen, France

*Corresponding Author: Audrey Larnaudie, Department of Radiation Oncology, Dupuytren University Hospital, Limoges, France.

Received: 27 August 2022; Accepted: 07 September 2022; Published: 24 September 2022

Citation:

A. Larnaudie, H. Orliac, D. Lerouge, C. Naessens, N. Deny, R. Serre, P. Clavere. Radiotherapy for Tracheal Squamous Cell Carcinoma: A Review. Archives of Clinical and Medical Case Reports 6 (2022): 653-659.

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Abstract

Tracheal cancer is a rare localization without official recommendation nether European nor French. This review summarizes the data published about tracheal squamous cell carcinoma treated with radiotherapy in terms of dose and fractionation, techniques, volume, toxicity, overall survival and local control.

Keywords

Tracheal Cancer; Radiotherapy; Squamous Cell Carcinoma

Tracheal Cancer articles; Radiotherapy articles; Squamous Cell Carcinoma articles

Article Details

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].

Series

N

Characteristics

Treatment

Dose and Volume

Toxicity

Local control and Survival

Series published after 2012

Zeng and al

2021

Retrospective

1996-2016

[10]

32 patients

M 72% / F 29%

SCC 56% ACC 31%

Surgery 50%

Adjuvant RT 41%

Definitive RT 56 %

Induction CT 6%

Technique

3DRT 37%

IMRT 34 %

2DRT 28%

Dose (1.8-2Gy)

50-54 Gy with boost if R1 ou R2

60-70 Gy

Late

No toxicity ≥ grade 3

At 5 year :

OS 47%

SSPLR 68% - better if surgery (93 % vs 46%, )

DFS better if at least 68 Gy 68 Gy (44.4% vs 13.0%, )

Jiang and al

2020

Retrospective

2009-2019

[16]

49 patients

M 55%/ F46%

SCC 41 % ACC 21%

Surgery 23%

Definitive RT 26 %

ND

ND

At 5 year

OS 14%

SCC OS 8%

ACC OS 29%

Yusuf and al

2019

Retrospective

2004-2014

[17]

300 patients

M 56%/ F 44%

SCC 43%

ACC 33%

CT 23%

Adjuvant RT

Dose

RT dose superior to 30 Gy

ND

At 5 year

OS

SCC 33%

ACC 98%

Hararah and al

2019

Database NCD

2004-2012

[14]

532 patients

M 64%/ F36 %

Surgery 40%

Definitive RT with CT 26 % ; RT alone 17%

Dose

≥60 Gy for 45% of the patients

ND

At 5 year

0S 25%

Similar in case of surgery and adjuvant treatment versus radiochemotherapy

Prognostic factor : age ≥65 years, ≥1 comorbidities, and palliative treatment 

Agrawal and al

2017

Database SEER

1973-2011

[15]

1144 patients

327 Surgery

M 47%/ F 53%

ACC 28%

SCC 40%

Surgery

Ajuvant RT (nd)

Definitive RT ( nd)

ND

ND

At 5 year

OS 25% in 1973 and 30% in 2006

OS higher if surgery

No difference RT alone versus no treatement

Xie and al

2012

Retrospective

1988-2007

[7]

78 patients

RT M 58%/ F 42%

SCC 42 % ACC 15%

Surgery 61 %

Adjuvant RT 61 %

Exclusive RT 38 %

78 patients : no RT (control)

ND

ND

At 5 year ( RT)

OS 42%

LC 50%

At 5 year ( no RT )

OS 28%

LC 37%

Napieralska and al

2016

Retrospective

[9]

48 patients

SCC 64 % ACC 16%

Adjuvant RT

Exclusive RT

Brachytherapy 17

 CT 29 %

Cisplatin alone or in combination with adriamycin, navelbine, etoposide, mitomycin C or 5-fluorouracil.

1-6 cycle

Technique

RT3D IMRT Tomotherapy

Brachytherapy (HDR) Iridium-192

Dose

palliative RT (2-8Gy) in 2 to 16 fractions of 2 to 8 Gy

Exclusive RT (1.6-3Gy)

42.5 - 82.6 Gy2 (median 66).

Boost 10 - 12 Gy , Adjuvant RT

 42.5 Gy

ND

At 12.7 months

DFS : 14.5 %

At 5 year

SCC OS: 8%

ACC OS 78%

OS Prognostic factors : radiotherapy, PS, haemoptysis

Li and al

2013

Retrospective

[22]

31 patients

M 80 % / F20 %

ACC 68% SCC 10%

Surgery 97%

Adjuvant RT 83%

RT+CT 64%

Dose

60 Gy in 30 fractions

Emergent tracheotomy

mediastinal emphysema and pneumothorax

At a median of 6 year (3-11 year)

LC 77%

Cases reports published after 2012

Hussein and al

2020

[23]

2 patients

Dose

60- 64 Gy

ND

ND

Al Asmar and al

2020

[24]

1 patient

F SCC

Induction CT Cisplatin docetaxel

Then Radiochemotherapy

ND

ND

At the end of Radiochemotherapy partial response

Kovacs and al

2021

[12]

1 patient

M

Exclusive RT with concomitant CT

Cisplatin 100 mg/m2

Dose (2.2Gy)

60 Gy

Mucositis

Tracheitis

Anemia

neutropenia

Pneumonia

ND

Maller and al

2019

[21]

1 patient

M SCC

Adjuvant RT

ND

ND

Reccurent after 5 months

Complete response after immunotherapy

Yathiraj and al

2017

[11]

1 patient

M SCC

Definitive RT with CT weekly cisplatin 40 mg/m2

Technique

3D

Dose (2Gy)

60 Gy in 30 fractions

Acute

Dermatitis grade 1 dysphagia grade 2 Loss of weight 9.5%

Late : hypothyroidism

Complete response at 1 year  

Tan and al

2016

[20]

1 patient

M SCC

After surgery of thyroid and radioiodine treatment

Treatment with RT

ND

ND

ND

Imai and al

2016

[18]

1 patient

SCC associated with HPV18

ND

ND

ND

Paliouras and al

2015

[25]

1 patient

SCC associated with multiple papilloma

Laser ablation then recurrence at 1 week adjuvant radiotherapy and chemotherapy

CT Cisplatin 70 mg/m2

Dose

40 Gy in 20 fractions

ND

At 1 year : complete response

Luo and al

2014

[13]

1 patient

M SCC

With oesophageal SCC

CT carboplatin etoposide

Dose

60 Gy in 30 fractions

Sequential RT

Ventricular tachycardia

Complete response at 1 year

Series published before 2012 (selection)

Urdaneta and al

2011

Database SEER

[26]

1973-2004

578 patients

M 56% / 44%

SCC 45% ACC 16%

Surgery 66%

RT 61%

ND

ND

At 5 year, for localized disease

OS 46%

SCC OS 25 %

ACC OS 90%

Better OS if surgery

No difference in adjuvant RT

Honings and al 2007

[27]

293 patients

M 72% / F 29%

SCC 53 % ACC 7%

Surgery 12 %

RT 53%

ND

ND

A 5 year OS 15%,

OS if surgery 51%, Better prognostic with ACC

Case reports avant 2012 (selection)

Videtic and al

2003

[28]

1 patient

2 induction cycle

Exclusive RT avec

Cisplatin

Dose (2Gy)

60 Gy in 30 fractions

ND

At 6 weeks and 2 year : complete response e

A 3 year : lung and bones metastases

Haresh and al

2010

[29]

1 patient

SCC

Radiotherapy

with carboplatin paclitaxel

Dose

60 Gy in 37 fractions

ND

A 2 year : complete response

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.

Treatment

Modalities

Possible indication

Induction Chemotherapy

Cisplatin associated with another molecule

In case of symptoms 1 retrospective serie

Concomitant Chemotherapy

Cisplatin 100 mg/m2 Cisplatin 40 mg/m2 Cisplatin associated with another molecule Rare : Carboplatin Paclitaxel

In case of incomplete resection or no surgery

Definitive Radiotherapy

Dose : 60-70 Gy in 2 Gy fraction Volumes GTV P : tumour correlated to endoscopic description and CT/ PET-CT exams CTV P : GTV-P +/-3-5cm cranio caudal +/- 1 cm axially, adapted to anatomical barriers CTV N : adjacent nodal areas PTV : CTV-P and CTV-N +/- 1 cm Techniques : IMRT

If no surgery or refusal

Adjuvant radiotherapy

Dose : 50-54 Gy

In case of incomplete resection or risk factors ( extranodal extension, lymphovascular invasion) and if locally advanced tumour

Volumes CTV P : Surgical bed PTV P : CTV P+/- 1 cm CTV N : nodal adjacent areas Techniques : IRMT

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.

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