10.14639/0392-100X-N2144
Objective. This study aims to provide real-world data on oncologic and functional outcomes of the most modern surgical and non-surgical treatments of locally advanced HPVpositive oropharyngeal cancer. Methods. We reviewed data on patients treated for stage III and IV HPV-positive oropharyngeal squamous cell carcinoma with either endoscopic surgery (Transoral Robotic Surgery, TORS; Transoral Laser Microsurgery, TLM – group A) or intensity-modulated radiotherapy (IMRT – group B). The minimum follow-up required was 6 months. Survival outcomes and toxicities of treatments were evaluated. Results. 30 patients in group A and 66 in group B were eligible for the analysis. 28% of patients in group A underwent a unimodal treatment, while 42% needed trimodal treatment. 90% of patients in group B underwent concurrent chemoradiation. We found no statistically significant difference in survival outcomes (group A: overall survival 97%, progression-free survival 83%; group B: OS 98%, PFS 86%) or toxicities between groups. Conclusions. Both transoral surgery and IMRT provide excellent outcomes in HPV-positive oropharyngeal cancer. Because of the good prognosis, treatments need to be refined to reduce toxicities while preserving oncologic soundness.
text/xml
1827-675X
2144
en
Mohssen Ansarin
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
minimally invasive surgery
Upfront transoral robotic surgery (TORS) versus intensity-modulated radiation therapy (IMRT) in HPV-positive oropharyngeal cancer: real-world data from a tertiary comprehensive cancer center
Text.Serial.Journal
https://www.actaitalica.it/
42
Head and neck
2022-08-08
2022-05-10
2022-10-12
2022-10-12
334-347
1
Mohssen Ansarin
2022/08/08
10.14639/0392-100X-N2144
334
Department of Otolaryngology and Head and Neck Surgery, IEO European Institute of Oncology IRCCS, Milan, Italy;* D. Alterio and M. Ansarin are co-last authors.
1827-675X
minimally invasive surgery
en
347
Upfront transoral robotic surgery (TORS) versus intensity-modulated radiation therapy (IMRT) in HPV-positive oropharyngeal cancer: real-world data from a tertiary comprehensive cancer center
https://www.actaitalica.it/article/download/2144/841
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:334-347; doi: 10.14639/0392-100X-N2144




Head and neck


Upfront transoral robotic surgery (TORS) versus
intensity-modulated radiation therapy (IMRT)
in HPV-positive oropharyngeal cancer:
real-world data from a tertiary comprehensive
cancer centre
Confronto tra chirurgia transorale e radioterapia a intensità modulata
nel carcinoma orofaringeo HPV-positivo
Stefano Filippo Zorzi1, Giovanni Agostini2, Francesco Chu1, Marta Tagliabue1, Giacomo Pietrobon1, Giulia Corrao3,
Stefania Volpe3, Giulia Marvaso3, Francesca Colombo4, Maria Cossu Rocca5, Sara Gandini6, Aurora Gaeta6,
Francesca Ruju7, Daniela Alterio3*, Mohssen Ansarin1*
1
  Department of Otolaryngology and Head and Neck Surgery, IEO European Institute of Oncology IRCCS, Milan, Italy; 2 Section of
Otolaryngology-Head and Neck Surgery, Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy;
3
  Department of Radiotherapy and Adrotherapy, IEO European Institute of Oncology IRCCS, Milan, Italy; 4 Department of Oncology
and Hemato-Oncology, University of Milan, Milan, Italy; 5 Department of Medical Oncology, Urogenital and Head and Neck Tumors
Medical Treatment, IEO European Institute of Oncology IRCCS, Milan, Italy; 6 Department of Experimental Oncology, IEO European
Institute of Oncology IRCCS, Milan, Italy; 7 Department of Radiology, IEO European Institute of Oncology IRCCS, Milan, Italy
*
  D. Alterio and M. Ansarin are co-last authors.


                                                                                                  Received: June 29, 2022
SUMMARY                                                                                           Accepted: July 4, 2022
Objective. This study aims to provide real-world data on oncologic and functional out-            Published online: August 8, 2022
comes of the most modern surgical and non-surgical treatments of locally advanced HPV-
positive oropharyngeal cancer.                                                                    Correspondence
Methods. We reviewed data on patients treated for stage III and IV HPV-positive oro-              Giacomo Pietrobon
pharyngeal squamous cell carcinoma with either endoscopic surgery (Transoral Robotic              Programma Cervico Facciale, Divisione di Otorino-
Surgery, TORS; Transoral Laser Microsurgery, TLM – group A) or intensity-modulated                laringoiatria e Chirurgica Cervico-facciale
radiotherapy (IMRT – group B). The minimum follow-up required was 6 months. Survival              Istituto Europeo di Oncologia, via Ripamonti 435,
outcomes and toxicities of treatments were evaluated.                                             20141 Milan, Italy
Results. 30 patients in group A and 66 in group B were eligible for the analysis. 28% of          Tel. +39 02 57489495
patients in group A underwent a unimodal treatment, while 42% needed trimodal treatment.          E-mail:giacomo.pietrobon@ieo.it
90% of patients in group B underwent concurrent chemoradiation. We found no statistically
significant difference in survival outcomes (group A: overall survival 97%, progression-free        How to cite this article: Zorzi SF, Agostini G,
survival 83%; group B: OS 98%, PFS 86%) or toxicities between groups.                               Chu F, et al. Upfront transoral robotic surgery
Conclusions. Both transoral surgery and IMRT provide excellent outcomes in HPV-posi-                (TORS) versus intensity-modulated radiation
tive oropharyngeal cancer. Because of the good prognosis, treatments need to be refined to          therapy (IMRT) in HPV-positive oropharyn-
                                                                                                    geal cancer: real-world data from a tertiary
reduce toxicities while preserving oncologic soundness.
                                                                                                    comprehensive cancer centre. Acta Otorhi-
KEY WORDS: oropharyngeal cancer, HPV, transoral robotic surgery (TORS), intensity-                  nolaryngol Ital 2022;42:334-347. https://doi.
modulated radiotherapy (IMRT), minimally invasive surgery                                           org/10.14639/0392-100X-N2144

                                                                                                  © Società Italiana di Otorinolaringoiatria
RIASSUNTO                                                                                         e Chirurgia Cervico-Facciale
Obiettivo. Questo studio presenta dati di pratica clinica sui risultati oncologici e funzionali
dei più moderni trattamenti chirurgici e non chirurgici del carcinoma orofaringeo HPV-                           OPEN ACCESS
positivo in stadio localmente avanzato.                                                           This is an open access article distributed in accordance with
Metodi. Abbiamo revisionato i dati dei pazienti affetti da carcinoma squamocellulare              the CC-BY-NC-ND (Creative Commons Attribution-Non-
dell’orofaringe HPV-positivo in stadio III e IV e trattati con chirurgia endoscopica (Chi-        Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
rurgia Robotica Transorale; Microchirurgia Laser Transorale – gruppo A) o radioterapia
                                                                                                  ning the license, but only for non-commercial purposes and
a intensità modulata (IMRT – gruppo B). Il follow-up minimo era di 6 mesi. Sono state             only in the original version. For further information: https://
valutate e confrontate sopravvivenze e tossicità.                                                 creativecommons.org/licenses/by-nc-nd/4.0/deed.en




334
                                                             Transoral robotic surgery versus intensity-modulated radiotherapy in oropharyngeal cancer




Risultati. Sono stati inclusi nell’analisi 30 pazienti nel gruppo A e 66 pazienti nel gruppo B. il 28% dei pazienti del gruppo A ha ricevuto un
trattamento unimodale, mentre il 42% un trattamento trimodale. Nel gruppo B il 90% è stato sottoposto a chemioradioterapia concomitante.
Non abbiamo rilevato differenze statisticamente significative nelle sopravvivenze (gruppo A: overall survival 97%, progression-free survival
83%; gruppo B: OS 98%, PFS 86%) e nelle tossicità.
Conclusioni. TORS e IMRT forniscono risultanti eccellenti nel cancro orofaringeo HPV-positivo. Alla luce della buona prognosi, i trattamenti
devono essere perfezionati per ridurre le tossicità preservando l’efficacia oncologica.
PAROLE CHIAVE: cancro orofaringeo, HPV, chirurgia robotica transorale (TORS), radioterapia a intensità modulata (IMRT), chirurgia mini
invasiva



Introduction                                                              to consider: recent meta-analyses reported tooth decay
                                                                          in 29% 11 and vascular endoluminal narrowing > 50% in
The incidence of oropharyngeal squamous cell carcinoma
                                                                          25% 12 of irradiated patients, with worsening effects over
(OPSCC) has progressively increased in the last years due                 time. IMRT techniques (e.g. Volumetric Modulated Arc
to the diffusion of Human Papilloma Virus (HPV). In 2020,                 Therapy – VMAT and Tomotherapy) allow the delivery
OPSCC was the 23rd cancer by incidence worldwide, affect-                 of more conformed doses to the target volume, hence
ing predominantly males (80%) in their 7th decade 1. The                  sparing healthy tissues and decreasing toxicity, especial-
incidence of OPSCC is expected to increase significantly,                 ly in oropharyngeal cancer tumours 13.
with an estimated number of 22.3 new cases per 100,000                    Nowadays, the role of surgery and IMRT in oropharyngeal
people and a rise of 157% by 2045 compared to present                     cancer is highly debated. Several trials are ongoing world-
data 2.                                                                   wide to assess the superiority of one strategy over the oth-
In contrast with the HPV-negative counterpart, the HPV                    er 14. Meanwhile, the choice between these two approaches
target population is more likely to be younger with a                     is based primarily on the physicians’ expertise, the institu-
greater survival probability and loco regional control.                   tions’ equipment and the patient’s preference.
This is mainly due to both the longer time to relapses                    The aim of the present study is to provide real-world data
and the lower propensity to develop distant metastases 3,4.               on the two most modern conservative treatment approaches
This clinical profile demands less disabling therapies be-                (TOS +/- radiotherapy +/- chemotherapy VS concurrent
cause of patients’ life expectancy 3. The best treatment                  chemoradiation with IMRT) for locally advanced HPV-
option is still debated and is currently based on past find-              positive OPSCC. Oncological outcomes and toxicity pro-
ings and ongoing studies.                                                 files are compared.
The combination of the most modern and minimally-
invasive treatment approaches, such as transoral robot-
ic surgery (TORS) and intensity modulated radiation                       Materials and methods
therapy (IMRT), has been associated with satisfactory                     We retrospectively reviewed patients treated for locally ad-
oncological outcomes and reduced long-term side ef-                       vanced OPSCC between January 2015 and October 2020
fects 5. Specifically, minimally invasive surgical ap-                    at the European Institute of Oncology (IEO) in Milan. All
proaches permit precise removal of the tumour through                     data were retrieved from a dedicated database.
the mouth, thus avoiding trans-mandibular surgical ac-                    Inclusion criteria were as follows: 1) age older than 18
cess. This technique reduces complication rates as well                   years; 2) primary OPSCC of tonsillar lodge (TL), base of
as poor functional and cosmetic outcomes 6. Unfortu-                      tongue (BOT), soft palate (SP), or posterior wall (PW);
nately, it cannot spare possible shoulder impairments due                 3) HPV-DNA or p16 positive tumours; 4) advanced stages
to neck dissection, which should be always taken into                     (clinical stage III and IV according TNM 7th edition of the
account 7. Similarly, before the advent of IMRT, radiation                American Joint Committee on Cancer -AJCC- Staging sys-
treatments were burdened by severe late toxicity, such as                 tem); 5) minimum follow-up of 6 months; 6) availability of
xerostomia and chronic dysphagia. The need for enteral                    written informed consent for the anonymised use of data
feeding via percutaneous endoscopic gastrostomy (PEG)                     for scientific purposes. Consequently, patients were ex-
was frequent: Machtay et al. reported that 43% of pa-                     cluded in case of: 1) non-SCC histology; 2) early stage (I-
tients suffered from high-grade late toxicity, while 10%                  II according AJCC 7th edition); 3) HPV-DNA or p16 nega-
were dependent on PEG 8. Of note, swallowing defects                      tive tumours; 4) previous treatment in the head and neck
were the most relevant determinants of patients’ qual-                    region; 5) need for any open surgical procedure (trans-
ity of life 9,10. Although somehow neglected, dental car-                 cervical, trans-mandibular) in the resection of the primary
ies and carotid stenosis are further long-term toxicities                 lesion; 6) treatment for any malignancy in the previous five



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S.F. Zorzi et al.




years, with the exception of superficial skin tumours; 7) in-    and Weinstein et al. 16. The incision is placed between the
complete medical records; 8) enrollment in clinical trials;      anterior tonsillar pillar and the pterygo-mandibular raphe;
9) indication to surgical reconstruction with free or pedi-      the superior constrictor muscle is sectioned and pulled me-
cled flaps; 10) radiotherapy performed with non-standard         dially to guide further resection on the deeper parapharyn-
fractionation and or non-IMRT technique; 11) personalised        geal fat. An additional en bloc mucosal resection was in-
treatment due to the COVID-19 pandemic.                          corporated to enclose the hard palate, intermaxillary and
Each clinical case was discussed in a weekly-scheduled           buccal mucosa whenever a superficial mucosal involve-
Multidisciplinary Board, which included a dedicated head         ment of the tonsillar pillars into the mobile tongue, soft
and neck radiologist. The indications were based on Na-          palate, or posterior pharyngeal wall was suspected. Base of
tional and International guidelines, and in accordance with      tongue resections were performed using a 30° three-dimen-
patients’ expectations. As a general rule, upfront TransOral     sional robotic telescope with one forceps instrument and
Surgery (TOS) was proposed to smoker patients with T1/           either a spatula or hook cautery instrument, as described by
T2 lesions. Patients were considered “smokers” in case of        O’Malley et al. 17.
exposure greater than 10 pack-years, independently of the        Reconstruction of the surgical defect was performed by
timing 4. All other patients were referred to IMRT (+/- con-     direct closure or with local flap if necessary, as described
current chemotherapy). Upfront TOS was excluded in case          by Almeida et al. 18. However, in the majority of cases pa-
of bilaterally positive neck nodes, radiological evidence of     tients healed by secondary intention, possibly favoured by
extra nodal extension, unresectable neck disease, tumour         a protective layer made of human fibrinogen and thrombin
extension to more than 50% of base of the tongue (BOT)           sponge.
and radiologically-proven infiltration of parapharyngeal fat     The Transoral Laser Microsurgery (TLM) approach adopt-
tissue.                                                          ed is the same described by Steiner et al. 19. The exposure
                                                                 was obtained with either a Kleinsasser laryngoscope (Karl
Pre-treatment staging                                            Storz, Tuttlingen, Germany) or a Steiner’s oropharyngo-
All patients were evaluated with fibre optics under white        scope (Karl Storz, Tuttlingen, Germany). For visualisation
light (WL), “I-scan Chromo Endoscopy system” (Pentax             of the surgical field, we adopted a Zeiss OPMI PENTERO
Medical) and HD Video Rhino-Laryngoscope NBI (Storz).            800 (Carl Zeiss AG, Germany) with applied CO2 laser in
Magnetic Resonance Imaging (MRI) or Computed Tomog-              super pulse modality.
raphy (CT) were used for loco-regional staging, whereas          Surgical margins of the final specimen (superior, inferior,
total body 18-fluorodeoxyglucose Positron Emission To-           lateral, medial, deep) were macroscopically evaluated for re-
mography (18-FDG PET) or, alternatively, total body CT           sidual disease and then inked by the surgeon in the operating
scan were used for systemic staging. In case of suspicious       room. Frozen sections were not used routinely, but reserved
nodal involvement which could influence the therapeutic          only for cases with suspicious intraoperative margins.
choice (such as contralateral or bilateral lymph nodes), an      A therapeutic neck dissection of levels Ib to IV with pres-
ultrasound-guided fine needle aspiration was performed to        ervation of submandibular gland was systematically per-
rule out malignancy.                                             formed at the same time of TOS but ahead of it, so that
HPV positivity was defined by the detection of p16 on immu-      closure of either the lingual or the facial-pharyngeal arter-
nohistochemistry (IHC) of at least 70% of cells of a tumour      ies could provide better haemostasis during the subsequent
sample or on node fine-needle aspiration cytology (FNAC).        oropharyngectomy and also prevent major post-operative
In case of p16-IHC expression lower than 70%, HPV-DNA            bleedings.
was assessed by polymerase chain reaction (PCR).                 A temporary tracheotomy was performed in case of: diffi-
                                                                 cult intubation, high risk of post-operative bleeding because
Surgical procedure                                               of anticoagulant therapy, or increased risk of post-operative
A standardised TORS approach (en bloc removal of the             upper airway oedema after prolonged surgery. In case of
primary lesion) was performed in all surgical candidates.        positive margins after definitive histopathological report,
Surgical steps were as follows: oropharynx exposure was          an additional resection was systematically proposed.
obtained after placing either a Dingman mouth retractor
(Mueller, San Diego, CA, USA) or a Feyh–Kastenbauer re-          Radiation and systemic therapy
tractor (Gyrus ACMI, Southborough, MA, USA) or a Davis           Radiation treatment was proposed for both curative and
Meyer mouth gag (Karl Storz, Tuttlingen, Germany, Eu-            post-operative intent. Indication for postoperative IMRT
rope). A lateral oropharyngectomy was performed accord-          was given for patients with pT3-pT4 tumours, pN ≥ 2a,
ing to the surgical technique described by Holsinger et al. 15   extranodal extension, perineural/lymphovascular invasion,



336
                                                         Transoral robotic surgery versus intensity-modulated radiotherapy in oropharyngeal cancer




or close or positive surgical margins. According to current           treatment completion, 12 months later, and at last follow-up.
indications from international guidelines, concurrent post-           Common Terminology Criteria for Adverse Event (CTCAE)
operative chemotherapy was 100 mg/m2 three-weekly cis-                scale was used for both the acute and late toxicity. Skin ery-
platin for three courses in all eligible patients. The concur-        thema, mucositis, xerostomia and dysphagia were consid-
rent postoperative strategy was offered to patients younger           ered as acute toxicity for patients treated with radiotherapy
than 70 years and with positive surgical margins and/or ex-           alone, while nausea, renal failure and neutropenia were also
tra nodal extension. High-dose cisplatin was the preferred            investigated in case of concurrent systemic treatments. One
regimen even in the curative setting 20,21, in accordance with        year later, skin erythema, xerostomia, dysphagia, laryngeal
the available literature, while cetuximab was considered for          oedema, dysphonia and soft tissue fibrosis were assessed. At
patients unfit for cisplatin 22.                                      last follow-up, we inquired about severe laryngeal and swal-
Radiation treatment was performed with a VMAT technique               lowing dysfunction (defined by the presence of a tracheal
using a SIB (Simultaneous Integrated Boost) schedule. Con-            tube or the need of enteral nutrition and/or oesophageal dila-
ventional fractionation was proposed for all patients. In case        tion) and the presence soft tissue necrosis.
of exclusive treatment, 35 fractions were administered up to
a total dose of 70 Gy (2 Gy/day) on gross tumour volume, 63           Statistical analysis
Gy (1.8 Gy/day) for high risk areas and 58.1 Gy (1.66 Gy/             We compared patients treated with surgery (group A)
day) for low risk volumes. In case of postoperative IMRT,             and IMRT (group B). For this purpose, a Chi-square test
a total dose of 66 Gy (2 Gy/day) was administered in case
                                                                      were used to compare categorical variables and Wilcox-
of extranodal extension (ENE) and/or positive surgical mar-
                                                                      on rank test for continuous variables. Overall survival
gins with 59.4 Gy (1.8Gy/day) and 56.1 Gy (1.7 Gy/day) ad-
                                                                      (OS) and progression-free survival (PFS) curves were
ministered to high and low risk volumes, respectively. In all
                                                                      drawn using the Kaplan-Meier method and log-rank test
other postoperative cases, 30 fractions were administered up
                                                                      was used to assess survival differences among curves.
to a total dose of 60 Gy (2 Gy/day) and 54 Gy (1.8 Gy/day)
                                                                      Overall survival was calculated from biopsy to death
for high and low risk volumes, respectively. All patients were
                                                                      from any cause, or to last contact if alive. Time to pro-
treated with Linear Accelerator and 6 MV energy photons.
A thermoplastic head and shoulders mask was used for all              gression was defined as the time from biopsy to progres-
positioning and setup. An image-guided technique was ap-              sion or death or last contact if alive. All patients alive or
plied with a verification CT performed at 40-50 and 60 Gy.            free from progressions at the last follow-up date were
Clinical evaluation for toxicity assessment was performed at          considered right censored.
least once a week during the radiation course.
                                                                      Results
Follow-up
                                                                      Data on 196 patients were retrieved. Ninety-six met inclu-
A clinical evaluation was planned every three months for the
                                                                      sion criteria and were considered as the present study co-
first two years after treatments. Subsequently, clinical as-
                                                                      hort (Fig. 1). Group A and group B included, respectively,
sessment was performed 4 times/year during the subsequent
two years, then 2 times/year for the fifth year. In case of cura-     30 and 66 patients. Demographic and clinical characteris-
tive IMRT, MRI of the head and neck region was requested 3            tics are summarised in Table I. Age and gender were not
months after the end of treatment to assess tumour response.          significantly different between the two groups (p = 0.49
A total body staging was performed once a year for the entire         and p = 0.14, respectively).
follow-up period with either 18-FDG PET (first choice im-             Staging according to both AJCC 7th and 8th editions is re-
aging modality) or CT. In case of recurrent disease, further          ported in Table I. According to AJCC 8th edition, group
treatment was defined during the weekly multidisciplinary             A had smaller primary tumours (c/pT1-2, p = 0.002) and
discussion. Follow-up of patients was carried out in a dedi-          lower stages (I and II, p < 0.001) compared to group B. In
cated outpatient clinic together with a radiotherapist.               group A, tumours were located mainly in the TL (p = 0.03).
                                                                      Overall, stage IV according to the AJCC 8th edition was
Toxicities                                                            absent in both cohorts. About one-third of patients in group
Postoperative complications were defined as any event re-             B were affected by a stage III disease, whereas patients in
quiring surgical revision (e.g. bleeding or salivary fistula)         group A had stage I or II.
and all local or systemic events with functional impairment           Concurrent chemotherapy was more frequently employed
or unforeseen prolonged hospitalisation (more than 7 days).           in patients treated in the curative setting rather than the
Radiation-related toxicity was assessed immediately after             post-operative one (p < 0.001).



                                                                                                                                            337
S.F. Zorzi et al.




Figure 1. Selection process of patients included in the study.


Group A                                                          and 15 (42%) underwent concurrent chemoradiother-
Surgical procedures and pathologic characteristics are           apy. Despite high risk factors (microscopic ENE, see
summarised in Table II.                                          Table II), chemotherapy was omitted in five patients
Three patients had positive surgical margins and were re-        (5/20) because of age > 70 years (n = 3) or comorbidi-
ferred to adjuvant chemoradiation, which was already re-         ties (n = 2). Thirteen patients received at least 200 mg/
quired because of other adverse biologic features.               m2 cisplatin. Median interval time between surgery and
According to the AJCC 7th edition, the primary tumour            PORT was 50 days (IQR 47-64 days). Median total
clinical stage (cT) was confirmed by pathological examina-       dose to “high dose”, “high risk” and “low risk” volumes
tion (pT) in 48% of cases, while it was upstaged in 16/36        were, respectively, 66, 59.4 and 56.1 Gy. Median treat-
(44%): cT1 to pT2 in 14 cases, and to pT3 and pT4 in one         ment duration was 47.5 days (IQR 44-53 days).
case each. In 3/36 (8%) cases, a downstaging occurred (all       During surgery, tracheotomy was performed in 35/36
cases from cT2 to pT1).                                          cases (97%) and was kept in place until required for air-
Table 3 provides a comparison between pathological T and         way safety. No patients remained tracheotomy-dependent
N stages of the 7th and 8th AJCC editions.                       after TOS. Thirty-five patients (97%) resumed oral in-
Median hospital stay was 8 days. No post-operative salivary      take prior to discharge, except for one patient, who main-
fistulas were recorded. There were no perioperative life-        tained a nasogastric feeding tube and needed a percutane-
threatening complications and no perioperative deaths. Four      ous gastrostomy (PEG) for worsening dysphagia during
patients (11%) suffered bleeding that required surgical revi-    PORT. The gastrostomy tube was removed 22 months
sion (two on the primary site and two on the neck).              later. During PORT, two additional patients suffered dys-
Ten patients (28%) were treated exclusively by surgery           phagia and a nasogastric feeding was temporary placed.
(unimodal treatment), while 11 (30%) received (PORT)             None of the patients required a tracheotomy during the



338
                                                                    Transoral robotic surgery versus intensity-modulated radiotherapy in oropharyngeal cancer




radiation course (Supplementary Table I). One patient                            Group B
died 13 months after PORT (IMRT) due to a pharyngo-                              Median total dose to “high dose”, “high risk” and “low
vertebral fistula. Of note, patients treated with exclusive                      risk” volumes were, respectively, 70, 63 and 58.1 Gy. Me-
surgery did not report any toxicities or dysfunction, ex-                        dian treatment duration was 53 days (IQR 50-56 days). Six
cept for a single shoulder impairment due to a radical                           patients were treated with exclusive radiotherapy, because
neck dissection.                                                                 of age (n = 3), low-risk tumours (n = 2) and comorbidities


Table I. Demographic and clinical characteristics of the study cohort.
                                              Group A                         Group B                        Overall                       p-value
                                          N = 36 (100%)                    N = 60 (100%)                  N = 96 (100%)
 Pack year (%)
   ≤ 10                                         9 (25)                         10 (17)                        19 (20)                        0.09
   10                                           13 (36)                        13 (22)                        26 (27)
   Missing                                      14 (39)                        37 (61)                        51 (53)
 Potus* (%)
   No                                           33 (92)                        55 (92)                        88 (92)                        0.11
   Yes                                           2 (5)                          0 (0)                          2 (2)
   Missing                                       1 (3)                          5 (8)                          6 (6)
 Sex (n %)
   Male                                         30 (83)                        42 (70)                        72 (75)                        0.22
   Female                                        6 (17)                        18 (30)                        24 (25)
 Age at diagnosis
   Median [q1,q3]                            62.0 [53, 68]                  60.0 [55, 66]                  61.0 [54, 67]                     0.66
 Oropharyngeal subsite (%)
   Tonsillar lodge                              28 (78)                       31 (51.7)                       57 (62)                       0.032
   Base of tongue                                8 (22)                       27 (45.0)                       35 (36)
   Soft palate                                   0 (0)                         2 (3.3)                         2 (2)
 cT AJCC 7th edition (%)
   0                                             0 (0)                         1 (1.7)                         1 (1)                       < 0.001
   1                                            26 (72)                       15 (25.0)                       41 (43)
   2                                            10 (28)                       25 (41.7)                       35 (36)
   3                                             0 (0)                         6 (10.0)                        6 (6)
   4                                             0 (0)                        13 (21.7)                       13 (14)
 cN AJCC 7th edition (%)
   0                                             0 (0)                         1 (1.7)                         1 (1)                         0.38
   1                                            18 (50)                       20 (33.3)                       38 (40)
   2                                            17 (47)                       36 (60.0)                       53 (55)
   3                                             1 (3)                         3 (5.0)                         4 (4)
 Stage for AJCC 7th edition (%)
   I                                             0 (0)                          0 (0)                          0 (0)                         0.53
   III                                          11 (31)                        19 (32)                        30 (30)
   IVA                                          25 (69)                        38 (63)                        60 (60)
   IVB                                           0 (0)                          3 (5)                          6 (6)
 Stage for AJCC 8th edition (%)
   I                                            28 (78)                        33 (55)                        61 (64)                       0.002
   II                                            8 (22)                        10 (17)                        18 (19)
   III                                           0 (0)                         17 (28)                        17 (18)
* alcohol consumption.




                                                                                                                                                       339
S.F. Zorzi et al.




(n = 1). Fifty-four (90%) received concurrent chemother-
apy, mainly cisplatin (47/54). In this subset, the majority
(45/47, 98%) reached a total dose of >200 mg/m2. Details
of radiation treatment and concurrent chemotherapy (in
both the postoperative and curative settings) are reported in
Supplementary Table II.
During treatment, three patients needed a nasogastric feed-
ing tube for dysphagia and two were dependent on enteral
nutrition at last follow-up. One patient needed a trache-
otomy and was still tube-dependent at last follow-up (see
Supplementary Table I).

Recurrence and survival outcomes
The median follow-up time was 37 months in group A
and 28 months in group B. The 2-year OS and PFS were
97% and 83% in the former, and 98% and 86% in the latter                          Figure 2. Overall survival by surgery.
(Figs. 2 and 3).
Likewise, local control (LC) and locoregional control
(LRC) were 94% and 94% in group A and 100% and 92%
in group B, respectively. Data relating to relapses (inci-
dence and treatment) as well as incidence of secondary tu-
mours are reported in Table IV.
OS and PFS were not significantly different between the
two groups, as were both the rate of mortality (2 patients in
group A, 1 patient in group B, p 0.29) and relapses (6 vs 8,
p = 0.61). Disease progression was not affected by smoking
exposure (p = 0.93).

Toxicity
We compared toxicities between the two groups only in pa-
tients affected by stage I and stage II disease (8th edition)
due to the lack of stage III in group A and missing data for
patients submitted to exclusive TOS. We did not find any
significant differences in the parameters investigated. Re-
sults are summarised in Table V.
Toxicity related to concurrent chemoradiation is reported                         Figure 3. Progression-free survival by surgery.


Table II. Details on surgical procedures and tumour biological characteristics.
 Characteristics                                                                                                                    N = 36
 Surgical approach                                              Transoral robotic surgery                                           34 (94)
                                                              Transoral laser microsurgery                                           2 (6)
 Lymph node neck dissection                                    Functional neck dissection                                           34 (94)
                                                                 Radical neck dissection                                             1 (3)
                                                             Modified radical neck dissection                                        1 (3)
 Surgical margins                                                   Positive margins                                                 3 (8)
                                                                    Negative margins                                                33(92)
 High-risk pathologic features                                    Extra nodal extension                                             20 (55)
                                                                   Perineural invasion                                               2 (6)
                                                                    Vascular invasion                                                1 (3)




340
                                                                     Transoral robotic surgery versus intensity-modulated radiotherapy in oropharyngeal cancer




Table III. Pathological T and N stage in the surgical cohort according to AJCC 7th and 8th editions.
                      pT_7th edition (%)                                                                            pT_8th edition (%)
 pT1                                          13 (36)                                               pT1                                   13 (36)
 pT2                                          21 (58)                                               pT2                                   21 (58)
 pT3                                           1 (3)                                                pT3                                    1 (3)
 pT4                                           1 (3)                                                pT4                                    1 (3)
 Missing                                        0                                                   Missing                                 0
                       pN_7th edition (%)                                                                           pN_8th edition (%)
 pN0                                            1 (3)                                               pN0                                    1 (3)
 pN1                                          10 (28)                                               pN1                                   30 (83)
 pN2a                                          8 (22)                                               pN2                                   5 (14)
 pN2b                                         15 (42)
 pN3                                           2 (6)                                                pN3                                      0
 Missing                                         0                                                  Missing                                  0



Table IV. Tumour relapses (incidence and treatment) and secondary tumours.
                                                                                     Group A                       Group B                           Total
                                                                                     N = 36                        N = 60                           N = 96
 Overall recurrences (%)                                                           6 (18)                        8 (13)                          14 (14)
    Local                                                                                   2 (6)                            0                             2 (2)
    Locoregional                                                                            2 (6)                         5 (8)                            7 (7)
    Distant metastases                                                                      2 (6)                         3 (5)                            5 (5)
 Treatment of recurrences (%)                                                      6 (18)                        8 (13)                          14 (14)
    Surgery                                                                                 2 (6)                         4 (7)                            6 (6)
    Surgery + postoperative chemoradiation                                                  1 (3)                            0                             1 (1)
    Chemotherapy                                                                            1 (3)                         2 (3)                            3 (3)
    Concurrent chemoradiotherapy                                                            1 (3)                            0                             1 (1)
    Missing                                                                                 1 (3)                         2 (3)                            3 (3)
 Secondary tumours (%)                                                             2 (6)                         3 (5)                           5 (5)
    Kidney                                                                                  1 (3)                            0                             1 (1)
    Lung                                                                                       0                          1 (2)                            1 (1)
    Head and Neck                                                                              0                          2 (3)                            2 (2)
    Skin                                                                                    1 (3)                            0                             1 (1)



in Supplementary Table III. Nausea/vomiting, neutropenia                           rative IMRT are similar in this clinical setting 5,23,24. Our
and renal failure occurred only in patients treated with con-                      analysis confirms this finding, as no differences in OS and
current chemotherapy.                                                              PFS were found between the two cohorts of patients. Ad-
                                                                                   mittedly, comparison between different approaches may be
Discussion                                                                         burdened by several biases. Firstly, patients who underwent
                                                                                   curative IMRT had only clinical disease staging, while sur-
The present study presents real-world data on clinical outcomes                    gical patients had complete pathological assessment. In this
and side effects of two modern strategies (minimally invasive                      latter cohort, an upstage of the primary tumour following
surgery and highly conformed RT+/- systemic treatment) to                          surgery occurred in 44% of cases. Historical series show
treat locally-advanced HPV-related OPSCC. Both approaches                          that T3 and T4 tumours are more frequent in non-surgical
achieved good oncologic outcomes with a favourable toxicity                        cohorts compared to surgical ones 23. Similarly, in the pre-
profile, without significant differences between the two groups.                   sent study stage III was absent in group A, whereas it rep-
Literature data show that results of upfront TORS and cu-                          resented 28% of tumours in group B. Secondly, the absence



                                                                                                                                                           341
S.F. Zorzi et al.




Table V. Toxicity at the end of radiotherapy and after one year for the curative and postoperative settings. ST systemic treatment, TOS transoral surgery.
                                         TOS followed by postoperative                 Curative radiotherapy                   Overall             p-value
                                                  radiotherapy                                (+/- ST)                        (N = 69)
                                                     (N = 26)                                 (N = 43)
                                                                       Early toxicity (%)
 Skin
   G0-G1                                            12 (46.2)                                27 (62.8)                      39 (56.5)              0.45
   G2-G3                                            12 (46.2)                                16 (37.2)                      28 (40.6)
   Missing                                           2 (7.7)                                   0 (0)                         2 (2.9)
 Mucositis
   G0-G1                                            14 (53.8)                                25 (58.1)                      39 (56.5)              0.99
   G2-G3                                            10 (38.5)                                18 (41.9)                      28 (40.6)
   Missing                                           2 (7.7)                                   0 (0)                         2 (2.9)
 Dysphagia
   G0-G1                                            15 (57.7)                                28 (65.1)                      43 (62.3)              0.99
   G2-G3                                            9 (34.6)                                 15 (34.9)                      24 (34.8)
   Missing                                           2 (7.7)                                   0 (0)                         2 (2.9)
 Xerostomia
   G0-G1                                            21 (80.8)                                38 (88.4)                      59 (85.5)              0.70
   G2-G3                                            3 (11.5)                                  4 (9.3)                       7 (10.1)
   Missing                                           2 (7.7)                                  1 (2.3)                        3 (4.3)
 Weight loss
   15 ≤ (sample median)                             11 (42.3)                                24 (55.8)                      35 (50.7)              0.70
   15 > sample median)                              15 (57.7)                                19 (44.2)                      34 (49.3)
                                                                       Late toxicity (%)
 Skin
   G0-G1                                            15 (57.7)                                32 (74.4)                      47 (68.1)              0.33
   G2                                                1 (3.8)                                   0 (0)                         1 (1.4)
   Missing                                          10 (38.5)                                11 (25.6)                      21 (30.4)
 Mucositis
   G0                                               13 (50.0)                                21 (48.8)                      34 (49.3)              0.45
   G1                                                2 (7.7)                                  8 (18.6)                      10 (14.5)
   Missing                                          11 (42.3)                                14 (32.6)                      25 (36.2)
 Dysphagia
   G0-G1                                            15 (57.7)                                33 (76.7)                      48 (69.6)              0.33
   G2                                                1 (3.8)                                   0 (0)                         1 (1.4)
   Missing                                          10 (38.5)                                10 (23.3)                      20 (29.0)
 Xerostomia
   G0-G1                                            16 (61.5)                                24 (55.8)                      40 (58.0)              0.10
   G2                                                 0 (0)                                   7 (16.3)                       7 (10.1)
   Missing                                          10 (38.5)                                12 (27.9)                      22 (31.9)
 Laryngeal dysfunction
   G0                                               14 (53.8)                                28 (65.1)                      42 (60.9)              0.60
   G1                                                2 (7.7)                                  2 (4.7)                        4 (5.8)
   Missing                                          10 (38.5)                                13 (30.2)                      23 (33.3)
 Soft tissue fibrosis
   G0-G1                                            16 (61.5)                                31 (72.1)                     47 (68.1)               0.99
   G2                                                 0 (0)                                   1 (2.3)                       1 (1.4)
   Missing                                          10 (38.5)                                11 (25.6)                     21 (30.4)
 Pain
   No                                                 0 (0)                                  13 (30.2)                     13 (18.8)               0.13
   Yes                                               1 (3.8)                                  1 (2.3)                       2 (2.9)
   Missing                                          25 (96.2)                                29 (67.4)                     54 (78.3)



342
                                                        Transoral robotic surgery versus intensity-modulated radiotherapy in oropharyngeal cancer




of pathological features (extra nodal extension, perineural          submitted to surgery. These encouraging results suggest
and lymphovascular invasion and tumour grading) in the               that candidates for minimally-invasive surgical procedures
non-surgical cohort does not allow analyses on either prog-          should be referred to high-volume centres with dedicated
nostic or predictive factors.                                        equipment and medical expertise. Although toxicities are
Overall, our results confirm that the main advantage of              multifactorial, the employment of highly selective strate-
surgery over RT is comprehensive pathologic assessment.              gies can undoubtedly help in minimising both surgical and
Whether this advantage justifies a trimodal approach (sur-           radiation-related side effects.
gery + radiotherapy +/- chemotherapy) in up to 40% of pa-            An advocated advantage of surgical over non-surgical ap-
tients remains a matter of debate. Ideally, trimodal therapy         proaches is the possibility of unimodal treatment in about
should be offered to high-risk subjects who may benefit              one-third of patients. Of note, in this cohort, swallowing
from more intense treatment. In this scenario, stratifica-           is recovered immediately after treatment and remains sta-
tion granted by surgery is key to refine the treatment strat-        ble over time 38. In their 4-year-long surgical series (2014-
egy. Current studies investigating the role of de-intensified        2018), Huang et al. reported that 70% of patients had re-
PORT after minimally-invasive surgery may provide fur-               ceived adjuvant treatment, and concurrent chemoradiation
ther clinical information and potentially allow a more per-          in almost half of cases 5. Other authors showed that upfront
sonalised approach.                                                  TOS proved successful in sparing RT in 9-27% of cases
Thanks to technological improvements, toxicity rates in              and CRT in 34-45% 34,39,40. Our results agree with literature
this clinical setting are becoming progressively more ac-            data, since about 30% of patients were treated with surgery
ceptable. To date, upfront TOS, and in particular TORS,              only, because of the lack of pathological risk factors.
seems effective in reaching good functional outcomes in              An et al. showed that a trimodal approach, required in about
the treatment of stage III-IV OPSCC 25-29. Compared to               48% of advanced OPSCC, was mainly due to the presence
open surgical approaches, TOS shows significant lower                of ENE and an advanced pN stage 41. According to a re-
complication rates without jeopardising clinical results 6.          cent review by Dhanireddy et al., the addition of concurrent
Similarly, the introduction of IMRT in daily clinical prac-          chemotherapy in patients with ENE does not provide clear
tice has allowed us to improve the long-term toxicity profile        benefit in terms of survival, while it is associated with ad-
(e.g. xerostomia, mucositis, weight loss, oesophageal ste-           ditional costs and increased toxicity 34. Therefore, whether
nosis and osteonecrosis) thanks to the higher conformity of          extra nodal extension demands an intensified approach
radiation doses around target volumes 13,30-32. However, data        (higher radiation doses and concurrent chemotherapy) is
on the comparison between these two approaches (TOS vs               currently being investigated in ongoing trials 41. In our co-
IMRT) are not homogenous. Superior functional outcomes               hort, only 3 patients were referred to postoperative chemo-
of patients treated by TORS were frequently reported in              radiation with positive resection margins, because further
retrospective analyses 8,9,33,34. On the contrary, the prospec-      excision would have delayed the adjuvant treatment, with-
tive randomised clinical trial ORATOR showed equiva-                 out sparing any part of it. Once again, this data agrees with
lence in oncologic and functional outcomes between TOS               similar reports in the literature 5,40.
and CRT, with a trend towards better outcomes in terms of            The impact of smoking in HPV-related tumours is still de-
swallowing in patients treated with IMRT 35,36. The present          bated 38. As a general rule, smoking has a negative impact
analysis clearly showed a favourable and comparable toxic-           on patients diagnosed with OPSCC HPV-positive cancers.
ity profile with both approaches. Interestingly, patients sub-       Ang et al. observed that the mortality risk for OPSCC smok-
mitted to trimodal treatment suffered side effects similar           er patients is similar, regardless of the HPV status 4. Not
to those treated with chemoradiation only, for most of the           only may smoking act as an independent negative prognos-
parameters considered. The expected higher toxicity of an            tic factor, but HPV-positive OPSCC smoker patients have
intensified approach might be balanced by highly selective           worse prognosis compared to non-smokers diagnosed with
treatments (i.e. minimally invasive surgery and postopera-           the same disease 42. However, the mechanism behind the
tive IMRT). Nevertheless, the presence of more advanced              detrimental effect of smoke on outcomes remains unclear.
stages and more frequent use of concurrent chemoradiation            A few hypotheses are currently under evaluation: the in-
could have worsened the toxicity profile in the non-surgical         creased prevalence of comorbidities among smokers; their
cohort.                                                              higher risk of second primaries; the lower effectiveness of
Overall, 11% of patients suffered surgical-related compli-           RT due to smoke-related hypoxia; the lower compliance
cations, and in particular only 2 cases (5.5%) of oral bleed-        due to the increased RT-related toxicity, and possible in-
ing were recorded. This data is in line with other experienc-        terplays with tumour biology 5. In our cohort, surgery was
es 37. No life-threatening events occurred among patients            more frequently proposed in heavy smokers (> 10 pack-



                                                                                                                                           343
S.F. Zorzi et al.




year) and smoking exposure was not clearly associated            related oropharyngeal cancer, who can be treated unimo-
with clinical outcomes, although the results are inconclu-       dally, whereas chemoradiation should be the first option
sive because of missing data in terms of pack-years. This        in high-risk patients. Instead, de-intensification protocols
finding may derive from the alleged mitigating effect grant-     should be proposed to intermediate-risk patients.
ed by a combined approach (surgery followed by RT +/-            Accurate pre-treatment staging and patient selection, to-
concurrent chemotherapy). This hypothesis is supported           gether with referral to high-volume centres, are key in pro-
by some literature data. In 404 patients undergoing exclu-       viding patients with the best chance of survival and pre-
sive chemoradiation, Liu et al. observed that smokers had        served quality of life.
shorter OS and PFS than non-smokers 43. However, Roden
et al. studied 258 patients submitted to TORS and found no       Conflict of interest statement
differences in recurrence-free survival according to smok-       The authors declare no conflict of interest.
ing exposure (pack-year) 25. We can arguably state that the
negative impact of smoke on prognosis could be balanced          Funding
by more intensive treatment, which includes surgery.             This work was partially supported by the Italian Ministry
Of course, our study has some limitations, mainly its retro-     of Health with Ricerca Corrente and 5 × 1000 funds.
spective nature, the presence of unbalanced cohorts and the
lack of a systematic data collection of surgery-related tox-     Author contributions
icity (e.g. scar fibrosis, functional shoulder impairment).      Conceptualisation: MA, SZ, DA . Data and material acqui-
Nevertheless, the strengths of this analysis are represented     sition: GA, FCh, MT, FR, GM, FCo. Data Analysis: SG,
by the prospective data collection of radiotherapy-related       AG. Writing and editing: SZ, GC, DA, MCR, GP. Review-
toxicities, homogeneity of surgical procedures and radia-        ing: MA, DA, SV.
tion technique, and accurate pre-treatment staging and fol-
low-up procedures. Moreover, these real-world data dem-          Ethical consideration
onstrate the feasibility, efficacy and the favourable toxicity   This study was approved by the Ethics Committee of the
profile of TORS and IMRT in HPV-related OPSCC. Fur-              European Institute of Oncology (approval number 3016).
ther efforts are required to define the best treatment options   The research was conducted ethically, with all study proce-
according to the clinical and pathological characteristics in    dures being performed in accordance with the requirements
this subpopulation with good prognosis.                          of the World Medical Association’s Declaration of Helsin-
                                                                 ki. Written informed consent was obtained from each pa-
Conclusions                                                      tient for study participation and data publication.
The incidence of HPV-positive OPSCC has been grow-
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Supplementary Table I. Need for nutritional and respiratory support in                   Supplementary Table II. Technical characteristics of the radiation and
the three cohorts of patients.                                                           systemic treatment.
                           NGT        PEG            Tracheotomy                                             Postoperative radiotherapy
 TOS                   Elective 36/36               0              Elective 35/36                                  (26 patients)
 (N 36)                   (100%)                                  Removed 35/35           Radiotherapy alone                                 11/26 (42%)
                      Removed 35/36                                   (100%)                VMAT                                             10/26 (38%)
                           (97%)*
                                                                                            IMRT fixed-fields                                     0
 IMRT +/- ST            3/26 (11%)             1/26 (4%)*                 0
 post op                                                                                    Tomotherapy                                       1/26 (4%)
 (N 26)                                                                                   Postoperative concurrent                           15/26 (58%)
 IMRT +/- ST             3/60 (5%)             2/60 (3%)              1/60                chemoradiotherapy
 curative                                      Removed 0            Removed 0               VMAT                                             13/26 (50%)
 (N 60)                                                                                     IMRT fixed-fields                                 1/26 (4%)
*
 PEG was performed in the single patient (1/36) who was not able to resume oral intake
                                                                                            Tomotherapy                                       1/26 (4%)
after TOS. The device was removed 22 months after placement. TOS: transoral surgery;
IMRT: intensity-modulated radiotherapy; ST: systemic treatment.                           Chemotherapy schedule
                                                                                            Three-weekly cisplatin                           14/15 (93%)
                                                                                            Weekly cisplatin                                  1/15 (7%)
                                                                                                                     Curative radiotherapy
                                                                                                                         (60 patients)
                                                                                          Radiotherapy alone                                  6/60 (10%)
                                                                                            IMRT                                                  0
                                                                                            VMAT                                              6/60 (10%)
                                                                                            IMRT fixed-field                                      0
                                                                                            Tomotherapy                                           0
                                                                                          Concurrent chemoradiotherapy                       54/60 (90%)
                                                                                            VMAT                                             54/60 (90%)
                                                                                            IMRT fixed-field                                      0
                                                                                            Tomotherapy                                           0
                                                                                          Chemotherapy schedule
                                                                                            Three-weekly cisplatin                           45/54 (83%)
                                                                                            Weekly cisplatin                                  2/54 (4%)
                                                                                            Cetuximab                                         5/54 (9%)
                                                                                            Miscellaneous                                     2/54 (4%)
                                                                                         VMAT: Volumetric Modulated Arc Therapy.




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Supplementary Table III. Adverse effects related to concurrent chemoradiation.
                                                               TOS +                                               Curative CT/RT
                                                        Postoperative CT/RT                                         54 patients
                                                            15 patients
 Nausea and vomiting
   G0                                                         5/15 (33%)                                            31/54 (57%)
   G1                                                        10/15 (67%)                                            11/54 (20%)
   G2                                                             0                                                 10/54 (19%)
   G3                                                             0                                                  2/54 (4%)
 Neutropenia
   G0                                                            0                                                  34/54 (63%)
   G1                                                        6/15 (40%)                                              2/54 (4%)
   G2                                                        8/15 (53%)                                             11/54 (20%)
   G3                                                        1/15 (7%)                                               7/54(13%)
 Renal failure
   G0                                                       14/15 (93%)                                             43/54(80%)
   G1                                                        1/15 (7%)                                              7/54 (13%)
   G2                                                            0                                                   5/54 (7%)
   G3                                                            0                                                       0
CT/RT: chemoradiation; G: grade.




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