10.14639/0392-100X-N1672
Objective. The PRO.M.E.THE.O. study (PredictiOn Models in Ent cancer for anti-EGFR based THErapy Optimization) aimed to develop a predictive model (PM) of overall survival (OS) for patients with locally advanced oropharyngeal cancer (LAOC) treated with radiotherapy (RT) and cetuximab (Cet) from an Italian dataset. Methods. We enrolled patients with LAOC from 6 centres treated with RT-Cet. Clinical and treatment variables were collected. Patients were randomly divided into training (TS) (80%) and validation (VS) (20%) sets. A binary logistic regression model was used on the TS with stepwise feature selection and then on VS. Timepoints of 2, 3 and 5 years were considered. The area under the curve (AUC) of receiver operating characteristic of 2, 3 and 5 year and confusion matrix statistics at 5-threshold were used as performance criteria. Results. Overall, 218 patients were enrolled and 174 (79.8%) were analysed. Age at diagnosis, gender, ECOG performance, clinical stage, dose to high-risk volume, overall treatment time and day of RT interruption were considered in the final PMs. The PMs were developed and represented by nomograms with AUC of 0.75, 0.73 and 0.73 for TS and 0.713, 0.713, 0.775 for VS at 2, 3 and 5 years, respectively. Conclusions. PRO.M.E.THE.O. allows the creation of a PM for OS in patients with LAOC treated with RT-Cet.
text/xml
1827-675X
1672
en
Vincenzo Valentini
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
head and neck tumour
Development of a prognostic model of overall survival in oropharyngeal cancer from real-world data: PRO.M.E.THE.O.
Text.Serial.Journal
https://www.actaitalica.it/
42
Head and neck
2022-04-08
2021-05-06
2022-07-26
2022-07-26
205-214
1
Vincenzo Valentini
2022/04/08
10.14639/0392-100X-N1672
205
Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Università Cattolica del Sacro Cuore, Roma, Italy
1827-675X
head and neck tumour
en
214
Development of a prognostic model of overall survival in oropharyngeal cancer from real-world data: PRO.M.E.THE.O.
https://www.actaitalica.it/article/download/1672/753
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:205-214; doi: 10.14639/0392-100X-N1672




Head and neck


Development of a prognostic model of overall survival
in oropharyngeal cancer from real-world data:
PRO.M.E.THE.O.
Sviluppo di un modello predittivo in pazienti affetti da neoplasia dell’orofaringe:
PRO.M.E.THE.O.
Francesco Miccichè1, Giuditta Chiloiro1, Silvia Longo1, Rosa Autorino1, Mariangela Massaccesi1, Jacopo Lenkowicz1,
Pierluigi Bonomo2, Isacco Desideri2, Liliana Belgioia3,4, Almalina Bacigalupo4, Elisa D’Angelo5, Federica Bertolini6,
Anna Merlotti7, Nerina Denaro8, Pierfrancesco Franco9, Francesco Bussu10, Gaetano Paludetti11,12, Umberto Ricardi9,
Vincenzo Valentini1,12
1
  Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma,
Italy; 2 Department of Radiation Oncology, Azienda-Ospedaliero-Universitaria Careggi, University of Florence, Italy; 3 Radiation
Oncology Department, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 4 Department of Health Science (DISSAL), University
of Genoa, Genoa, Italy; 5 Radiation Oncology, University Hospital of Modena, Italy; 6 Medical Oncology, University Hospital of
Modena, Italy; 7 Department of Radiation Oncology, S. Croce and Carle Teaching Hospital, Cuneo, Italy; 8 Department of Oncology,
S. Croce and Carle Teaching Hospital, Cuneo, Italy; 9 Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy;
10
   Otolaryngology Division, Sassari University Hospital, Sassari, Italy; 11 Dipartimento Scienze dell’Invecchiamento, Neurologiche,
Ortopediche e della Testa-collo, UOC di Otorinolaringoiatria, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy;
12
   Università Cattolica del Sacro Cuore, Roma, Italy


SUMMARY
Objective. The PRO.M.E.THE.O. study (PredictiOn Models in Ent cancer for anti-EGFR
based THErapy Optimization) aimed to develop a predictive model (PM) of overall survival
                                                                                               Received: May 6, 2021
(OS) for patients with locally advanced oropharyngeal cancer (LAOC) treated with radio-
                                                                                               Accepted: October 11, 2021
therapy (RT) and cetuximab (Cet) from an Italian dataset.                                      Published online: April 8, 2022
Methods. We enrolled patients with LAOC from 6 centres treated with RT-Cet. Clinical
and treatment variables were collected. Patients were randomly divided into training (TS)      Correspondence
(80%) and validation (VS) (20%) sets. A binary logistic regression model was used on           Silvia Longo
the TS with stepwise feature selection and then on VS. Timepoints of 2, 3 and 5 years          Diagnostica per Immagini, Radioterapia Oncologica
were considered. The area under the curve (AUC) of receiver operating characteristic of        ed Ematologia, Fondazione Policlinico Universita-
2, 3 and 5 year and confusion matrix statistics at 5-threshold were used as performance        rio A. Gemelli IRCCS, largo A. Gemelli 1, 00168
criteria.                                                                                      Rome, Italy
Results. Overall, 218 patients were enrolled and 174 (79.8%) were analysed. Age at diag-       Tel. +39 06 3015498
                                                                                               E-mail: silvia.longo@guest.policlinicogemelli.it
nosis, gender, ECOG performance, clinical stage, dose to high-risk volume, overall treat-
ment time and day of RT interruption were considered in the final PMs. The PMs were
developed and represented by nomograms with AUC of 0.75, 0.73 and 0.73 for TS and                How to cite this article: Miccichè F, Chiloiro
0.713, 0.713, 0.775 for VS at 2, 3 and 5 years, respectively.                                    G, Longo S, et al. Development of a prognostic
Conclusions. PRO.M.E.THE.O. allows the creation of a PM for OS in patients with LAOC             model of overall survival in oropharyngeal can-
                                                                                                 cer from real-world data: PRO.M.E.THE.O. Ac-
treated with RT-Cet.
                                                                                                 ta Otorhinolaryngol Ital 2022;42:205-214. https://
KEY WORDS: prediction model, personalised medicine, cetuximab, head and neck tumour              doi.org/10.14639/0392-100X-N1672

                                                                                               © Società Italiana di Otorinolaringoiatria
RIASSUNTO                                                                                      e Chirurgia Cervico-Facciale
Obiettivo. L’obiettivo di PRO.M.E.THE.O. è quello di sviluppare modelli predittivi (MP) di
sopravvivenza globale (OS) per pazienti (pz) con neoplasia orofaringea localmente avan-                       OPEN ACCESS
zata (LAOC) sottoposti a radioterapia (RT) e Cetuximab (Cet), provenienti da un dataset        This is an open access article distributed in accordance with
italiano multicentrico.                                                                        the CC-BY-NC-ND (Creative Commons Attribution-Non-
Metodi. Sono stati arruolati pazienti con LAOC trattati con RT-Cet provenienti da 6 centri     Commercial-NoDerivatives 4.0 International) license. The
                                                                                               article can be used by giving appropriate credit and mentio-
italiani, dei quali sono state raccolte variabili cliniche e di trattamento. I pazienti sono
                                                                                               ning the license, but only for non-commercial purposes and
stati suddivisi casualmente in un training set (80%) e in un gruppo di controllo (20%).        only in the original version. For further information: https://
Per la creazione del MP è stata considerata l’OS a 2, 3 e 5 anni. L’area sottesa alla curva    creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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F. Miccichè et al.




(AUC) di ROC (receiver operating characteristic) a 2, 3 e 5 anni e la statistica della matrice di confusione a 5 classi rappresentano i criteri
di performance.
Risultati. 218 pazienti sono stati arruolati e 174 (79,8%) analizzati. I parametri testati per la costruzione degli MP includevano: età alla
diagnosi, sesso, ECOG, stadio clinico, dose del volume ad alto rischio, tempo complessivo di trattamento e giorni di interruzione della RT. I
MP di OS sono stati rappresentati con dei nomogrammi.
Conclusioni. PRO.M.E.THE.O. ha consentito la creazione di MP di OS in pazienti LAOC trattati con RT-Cet.
PAROLE CHIAVE: modello predittivo, medicina personalizzata, cetuximab, tumori della testa e del collo



Introduction                                                             is to develop predictive prognostic models (PPM) of OS
                                                                         at 2, 3 and 5 years for OPC patients treated with RT and
Meta-analyses on chemotherapy (CT) in locally advanced
                                                                         cetuximab (bio-radiotherapy [b-RT]) based on a real-world
head and neck squamous cell carcinoma have demonstrated
                                                                         data collection.
an overall survival (OS) benefit for the addition of CT to ra-
diotherapy (RT) 1-5. Cetuximab is considered a viable treat-
ment option for patients who are unfit for cisplatin, and has            Materials and methods
been shown to significantly improve OS when combined                     The PRO.M.E.THE.O. project involved 6 Italian Radia-
with RT compared with RT alone in a randomised phase III                 tion Oncology Departments. The promoting centre was
trial 3.                                                                 Fondazione Policlinico Universitario A. Gemelli-IRCCS,
Even if squamous cell carcinomas (SCC) of the head and                   Rome. A multidisciplinary team of physicians defined the
neck region share major risk factors and some clinical fea-              project milestones and a teleconference was scheduled eve-
tures, they still have specific characteristics, different treat-        ry two weeks for progress updates. The objective of this
ment options and variable prognosis, depending on the tu-                first phase was to implement a system that can analyse a
mour site and subsite 6.                                                 large heterogeneous dataset which included all available
As new strategies and therapies are being tested, it is be-              data conforming to a standardised ontology collected from
coming apparent that the magnitude of benefit derived from               daily activity. The final aim was to develop reliable PPM
a specific treatment, and the corresponding toxicity profile,            for OS in OPC at 2, 3 and 5 years for use in clinical man-
may vary in different patient groups 7.                                  agement DSS.
Over the last decade, remarkable advances in cancer care
have raised new challenges, leading clinical practice to-                Ontology
wards personalised medicine, although there remains a gap
between evidence from clinical trials and real-world prac-               Creation of an ontology
tice 8.                                                                  The first step was the creation of an ontology, as a de-
Moreover, studies investigating the physicians’ perfor-                  fined data collection model, which is capable of collect-
mance in predicting radiosensitivity and oncological out-                ing, standardising and organising features of patients with
comes are currently lacking 9.                                           OPC treated with cetuximab. The ontology is fundamen-
Since the clinical introduction of cetuximab, the lack of bi-            tal for the data mining process, as it will explicitly declare
omarkers to predict its efficacy have profoundly hampered                the clinical variables involved and their mutual relation-
its routine clinical use. The development of tools that allow            ships. Each variable has four main properties: name, form,
physicians to individualise treatment will facilitate trans-             field type and level. The existing field types are text: some
formation from population-based strategies to personalised               variables are described with a multiple choice option and
medicine with an essential role of decision supporting sys-              someone others with free text option; number: integer or
tems (DSSs) 10,11. The DSS development process necessar-                 decimal number; date; table; files: DICOM and.txt files
ily relies on an ontology that represents knowledge as a set             are the standard file formats chosen for images and data on
of shared concepts within a domain and the relationships                 treatment, respectively.
between them, using a large amount of data with proximity                Initially, a small multidisciplinary team based in the pro-
to daily clinical reality 12.                                            moter centre identified clinical variables to be included in
The PRO.M.E.THE.O. (PredictiOn Models in Ent cancer                      the ontology, and all the six centres validated them. Next, a
for anti-EGFR based THErapy Optimization) project                        technical committee consisting of an engineer, a physicist,
involved several Italian RT centres to implement a system                a physician with experience in data storage, and a software
that is able to analyse large heterogeneous datasets specific            expert was created. This multiprofessional group defined
for oropharyngeal SCC (OPC). The aim of this project                     the characteristics required for the ontology to be accept-



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ed. These requirements included defining the data type for            international consensus recommendations 15). The only ex-
each field, the possible values allowed, the cardinality of           clusion criteria was the presence of metastatic disease.
the entries (i.e., single- or multi-selection field) and the          Cetuximab was administered at an initial loading dose of
range allowed in case of numeric values.                              400 mg/m2 one week before initiation of RT followed by a
After the formal definition of the ontology and its requirements,     weekly dose of 250 mg/m2 for 7 weeks concurrent to RT.
the working group and the technical committee were asked              Patient underwent RT with different techniques such as 3D,
to define the tools to share the ontology among centres via           Intensity-modulated radiotherapy (IMRT), tomotherapy,
a standardised form. To accomplish this task, the “Beyond             volumetric modulated arc therapy (VMAT) with simulta-
Ontology Awareness” (BOA) software was developed to                   neous integrated boost (SIB), or sequential RT boost. Pa-
reproduce the ontology structure, manage the import of                tients underwent weekly physical evaluation during treat-
legacy data and coordinate data sharing activities 13,14.             ment. Acute toxicities, including cutaneous side effects and
                                                                      onset of rash, were graded according to CTCAE version
Ontology implementation
                                                                      4.0. Clinical follow-up consisted of physical examination
From January 2017 to January 2018, we selected more than
                                                                      every three months for 3 years from diagnosis and every 6
200 variables across 16 input forms related to OPC. The
                                                                      months thereafter, and was performed alternatively by the
ontology was organised into three levels:
                                                                      radiation oncologist, otolaryngologist and medical oncolo-
1. registry: with exclusive epidemiologic information (age,
                                                                      gist or in joint consultation.
   gender, ethnicity, height, etc.);
2. procedural: where treatment information and related
                                                                      PM development
   toxicities were reported;                                          Table I shows the clinical and treatment variables that
3. research: where dimensional data, such as radiomics and            were collected. Categorical covariates were dummy field,
   genomics were collected.                                           while numerical covariates were kept in their original ver-
A BOA-Web service platform was created and the centers                sion and binarised at different cut-off thresholds as re-
involved collected data using Case Report Forms (CRFs).               ported in Table II.
A total of 16 CRFs were created for: registry and history;            Overall survival was considered as the time elapsing
blood and serum test pre-treatment and follow-up;                     between the date of diagnosis of the neoplasm and last
histology; staging c, yc, p, and yp; external beam RT; CT;            follow-up date or death from any cause; 2-, 3- and 5-year
brachytherapy; surgery; toxicity Common Terminology                   time points were considered. For PPM development
Criteria for Adverse Events (CTCAE) v4.0, and Radiation               and internal validation, the dataset was randomly split
Therapy Oncology Group (RTOG); follow-up and                          into 80% and 20% 16 for the training and validation
outcomes.                                                             sets, respectively. The covariates selected and the ones
                                                                      engineered from those selected were included within a
Standardised data sharing                                             multivariable logistic regression model on the training set
A network of private connections was implemented                      and further selected with step-wise regression based on
between the various centres and a computer system that                the Akaike Information Criteria (AIC). The model was
automatically translated the various available information            then applied on the testing set to assess the performance
into extractable parameters that conformed to the ontology.           in terms of Receiver Operating Characteristic (ROC) Area
The data was anonymised, encrypted and sent to the central            Under the Curve (AUC). The models were retrained for
repository via a secure https-based web service. The system           each OS time point on the entire dataset to be represented
allowed the data to be aggregated anonymously into a                  in the form of nomograms. Statistical analysis was
single ‘large database’ to proceed with analysis of selected          performed using R version 3.4.4.
patient data.

Patient characteristics                                               Results
We retrospectively collected data on patients with OPC                Patient characteristics and treatment
treated with b-RT from 2006 to 2018 with curative intent.             From February to December 2018, we collected data on 218
Inclusion criteria were: age > 18 years, Eastern Coopera-             OPC patients. We considered clinical and treatment vari-
tive Oncology Group-Performance Status (ECOG-PS East-                 ables, as shown in Table II. The covariates analysed were:
ern Cooperative Oncology Group) 0-2, stage I-IVa, ineligi-            age at diagnosis, gender, ECOG score, smoking status, al-
ble to be treated with cisplatin (due to clinical conditions          cohol consumption, human papilloma virus (HPV)-status
known to contraindicate the use of cisplatin according to             (p16 immunohistochemistry), cT, cN, tumour grading,



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Table I. Clinical and treatment variables collected from February to Decem-        status was not considered because of the not available rate
ber 2018.                                                                          > 25% (Tab. I). Covariates tested that showed a negative
 Patient characteristics                                 Available (%)             impact on 2-, 3- 5-year OS were cN+, ECOG ≥ 1, age, RT
 Gender                                                     174 (100%)             dose < 66 Gy and DRTI > 3. At a median follow-up of 57.6
 Analysed patients/collected patients per RT centre                                months (1.5-142.0), the OS rate at 2, 3, 5 years was 71.5%,
    Rome                                                   77/89 (86.5%)           67.4% and 64.7%, respectively.
    Modena                                                 17/22 (77.3%)           No significant difference was found between the
    Florence                                                48/50 (96%)            distributions of training and validation set covariates.
    Genoa                                                  16/21 (76.2%)           The logistic regression models trained with the covariates
    Cuneo                                                   12/16 (75%)            selected from the previous stepwise selection are
    Turin                                                   4/20 (20%)             summarised in Table III for the three different OS time
 HPV (human papillomavirus) DNA                             Not analysed           points. The performance of these models in terms of
 HPV (human papillomavirus) RNA                             Not analysed           AUC is reported in Table IV, along with their respective
 cT                                                         174 (100%)             ROC curves (Fig. 1). The nomograms built from these
 cN                                                         174 (100%)             models are reported in Figures 2, 3 and 4 and two clinical
 ECOG PS                                                    174 (100%)
                                                                                   examples are reported in Table V.
 RT start date                                               154 (88%)
 RT end date                                                 154 (88%)             Discussion
 Interruption days                                           144 (83%)             In this study, we collected registry and procedural level
 Prescription dose to CTV                                    166 (95%)             variables and prognostic models were developed to pre-
 Dose reached (y/n)                                          166 (95%)             dict 2-, 3- 5-year OS for patients with OPC treated with
 Censor death                                                139 (92%)             b-RT. Specifically, nomograms allowed the integration of
 Last follow-up date                                         104 (94%)             clinical, treatment-related and epidemiological risk factors,
 Smoking status (Pack year)                                  109 (63%)             assessing their interactions and estimating the final effect
 Alcohol consumption                                          41 (23%)             on survival. Most importantly, the PPMs provide personal-
 Acute toxicity                                             Not analysed           ised, patient-specific estimates of OS that can be used for
 Relapse (y/n)                                              Not analysed           risk-stratification and prognosis discussions with patients.
 Cetuximab number of cycles                                 Not analysed           Fundamental to the creation and validation of any PPM is
RT: radiotherapy; HPV: Human Papilloma Virus; ECOG: Eastern Cooperative Oncology   the generation of an ontology that in this study was used as
Group; PS: Performance Status; CTV: clinical target volume.                        a fundamental tool to collect, standardise and organise data
                                                                                   from OPC patients treated with cetuximab.
                                                                                   The collection of data from several Italian centres selected for
dose to high risk clinical target volume (CTV), fractiona-                         accrual and expertise, allowed us to perform an analysis on
tion, overall treatment time (OTT), days of RT interruption                        a large population of OPC based on real-world experience.
(DRTI). DRTI was taken as surrogate of treatment toler-                            Our results are consistent with the literature, showing better
ance. We considered only variables with at least 75% of                            survival rates than those reported in the Bonner studies 17,18.
available values (Tab. II).                                                        The creation of a large database gave us the ability to
A total of 174 (79.8%) patients were analysed. All patients                        predict which variables impact clinical outcomes. In our
underwent combined b-RT with a median OTT of 51 days                               analyses, clinically negative nodal status (p < 0.05), good
(range 6-101) with a median dose of 69.9 Gy (17.6-79.2                             performance status with ECOG 0 and RT dose > 66 Gy
Gy). This wide dose range is due to the discontinuation of                         were protective factors, while DRTI ≥ 3 appeared to be a
RT treatment for patients receiving less than 50 Gy.                               detrimental factor for OS at 2, 3 and 5 year.
                                                                                   The strength of our project is related to the multicentre ori-
PM development                                                                     gin of the data and their quality due to the relative homoge-
The analysis was performed considering several variables.                          neity of the population, including patients with oropharynx
Categorical covariates were dummy field, whereas numeri-                           cancer treated with cetuximab-based RT protocols.
cal covariates were kept in their original version and bina-                       PRO.M.E.THE.O also has the benefit of taking into ac-
rised at different cut-off thresholds (such as total RT dose                       count treatment compliance, which is a key parameter in
to high risk CTV ≥ 66Gy, age at diagnosis > median value,                          patients with OPC, where discontinuation of RT may
DRTI yes/no, DRTI > 2, > 3, > 5, > 7, > 10, > 20). HPV                             affect the overall efficacy of treatment. It indirectly shows



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                                                                           Multicentric prognostic model of overall survival in oropharyngeal cancer: PRO.M.E.THE.O.




Table II. Variables analysed (with at least 75% of available values).
            Covariates tested:                            Training set                                    Validation set                            P-value
                                                       139 patients (%)                                  35 patients (%)
 Age at diagnosis > 65 years                                      70 (50%)                                   13 (37%)                               0.187 a
 Gender
    Male                                                          106 (76%)                                  26 (74%)                                0.826*
    Female                                                         33 (24%)                                   9 (26%)
 Nodal status
    N0                                                            116 (83%)                                  29 (83%)                                  1*
    N+                                                             23 (17%)                                   6 (17%)
 ECOG
    ECOG = 0                                                      55 (39%)                                   20 (57%)                                0.084*
    ECOG = 1                                                      48 (34%)                                    2 (5%)
 Treatment interruption
    Yes                                                           110 (79%)                                  32 (91%)                                0.359*
    No                                                             29 (21%)                                   3 (9%)
 Treatment interrupted
    Interruption days ≥ 2                                          95 (68%)                                  26 (74%)                               0.544*
    Interruption days ≥ 3                                          85 (61%)                                  22 (62%)                                 1*
    Interruption days ≥ 5                                          52 (37%)                                  19 (54%)                               0.084*
    Interruption days ≥ 8                                          40 (29%)                                  16 (46%)                               0.068*
    Interruption days ≥ 10                                         25 (18%)                                  12 (34%)                               0.062*
    Interruption days ≥ 21                                          8 (5%)                                    5 (14%)                               0.140*
 Median OTT in days (range)                                       51 (6-101)                                52 (41-81)                              0.284 a
 Total RT dose ≥ 66 Gy                                            126 (90%)                                  34 (97%)                               0.306 a
OTT: Overall Treatment Time; RT: radiotherapy; ECOG: Eastern Cooperative Oncology Group. a Mann-Whitney test; *Fisher’s Exact Test.



Table III. Logistic regression models trained with the selected covariates for the three different OS time points.
                                                                           OS model
                                               2 years                                            3 years                                        5 years
 Covariate                  Coefficient       Standard          P-value        Coefficient       Standard          P-value        Coefficient    Standard     P-value
                                                error                                              error                                           error
 N=0                          -1.0439           0.6260           0.095           -0.8863          0.5702            0.120             -0.8863    0.5702       0.120
 ECOG PS = 0                  -1.3410           0.4634           0.003**         -0.9209          0.4129            0.025*            -0.9209    0.4129       0.025*
 RT Dose ≥ 66 Gray            -2.0091           0.6714           0.002**         -1.7503          0.6499            0.007**           -1.7503    0.6499       0.007**
 RT Interruption days         0.9058            0.4405           0.039*          1.0223           0.4165            0.014*            1.0223     0.4165       0.014*
 ≥3
OS: overall survival; ECOG PS: Eastern Cooperative Oncology Group Performance Status; RT: radiotherapy. *: p-value < 0.05; **: p-value < 0.01.



Table IV. Performance of logistic regression models in terms of receiver op-                compliance with cetuximab, underscoring its importance 3.
erating characteristic (ROC) of area under the curve (AUC).                                 Unfortunately, we do not have clear data about the main
 OS time point                   AUC training set       AUC validation set                  reasons for treatment interruptions, which would have been
 2 years                                 0.750                       0.713                  interesting and could be a subject of future research.
 3 years                                 0.731                       0.713                  HPV status is a major determinant of the prognosis of
 5 years                                 0.729                       0.775                  patients with OPC with a 60% reduction in the risk of
OS: overall survival.
                                                                                            death. Data from randomised trials highlight the impact of
                                                                                            HPV status on survival, demonstrating a 60% improvement
                                                                                            in HPV-positive patients.



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F. Miccichè et al.




Figure 1. The performances of training (1) and validation (2) model at 2 (A), 3 (B) and 5 (C) year OS in terms of receiver operating characteristic (ROC) curves.


Our retrospective observational case series on a large                             recommended, in this heterogeneous setting, our models,
amount of data lacks HPV status because in the period                              which overcome HPV-status, could be useful as well. In
analysed HPV determination was not part of routine clinical                        addition, the benefit of the present work is that it is based
practice; nevertheless, the model provided has highlighted                         on a real-world data collection and reflects the fact that in
prognostic factors for survival that in our opinion may                            many Italian centres the evaluation of HPV in OPC is still
represent an essential integration in the prognostic framing                       not standardised nor routinely performed.
of patients with OPC.                                                              Nonetheless, our results provide evidence of the feasibility
There is heterogeneity in HPV positive patients due to                             of model building on real-world data also considering that
tumour stage, smoking status and other prognostic factors                          they are in line with the literature, even without considering
such as radiological extranodal extension, matted nodes                            HPV-status. In fact, our models showed a good predictive
and PIK3CA 19. Therefore, even if the integration of HPV                           power with an AUC between 0.73 and 0.75.
status in the nomogram for the clinical use is absolutely                          Some sources of big data already exist in the literature 10,20,



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                                                                         Multicentric prognostic model of overall survival in oropharyngeal cancer: PRO.M.E.THE.O.




Table V. Clinical examples of the nomograms prediction in terms of overall survival modulated in relation to risk factors.
                                Age at diagnosis          N0                ECOG 0                     RT                 Interruption                   Death risk
                                                                                                Dose ≥ 66 Gy              RT days ≥ 3                    at 2 y (%)
 Very Good                                   65                    N-                    Yes                      Yes                      No                2
 OS > 90% at 2 y
                                             65                    N-                    No                       No                       No               3
                                             75                    N-                    Yes                      Yes                      No               3
                                             65                    N-                    No                       Yes                      No               4
                                             65                    N-                    Yes                      Yes                      Yes              5
                                             75                    N-                    No                       Yes                      No               6
                                             65                    N+                    Yes                      Yes                      No               7
                                             75                    N-                    Yes                      Yes                      Yes              7
                                             65                    N-                    No                       Yes                      Yes              11
                                             75                    N+                    Yes                      Yes                      No               11
 Good                                        75                    N-                    No                       Yes                      Yes              15
 OS > 75-85% at 2 y
                                             65                    N+                    No                       Yes                      No               16
                                             65                    N-                    Yes                      No                       No               16
                                             65                    N+                    Yes                      Yes                      Yes              17
                                             75                    N+                    No                       Yes                      No               21
                                             75                    N-                    Yes                      No                       No               22
                                             75                    N+                    Yes                      Yes                      Yes              24
 Poor                                        65                    N+                    No                       Yes                      Yes              33
 OS > 50-70% at 2 y
                                             65                    N-                    Yes                      No                       Yes              33
                                             75                    N-                    No                       No                       No               39
                                             75                    N+                    No                       Yes                      Yes              42
                                             75                    N-                    Yes                      No                       Yes              42
                                             65                    N+                    Yes                      No                       No               43
                                             65                    N-                    No                       No                       Yes              53
                                             75                    N+                    Yes                      No                       No               53
 Very Poor                                   65                    N+                    No                       No                       No               63
 OS > 15-40% at 2 y
                                             75                    N-                    No                       No                       Yes              63
                                             65                    N+                    Yes                      No                       Yes              66
                                             75                    N+                    No                       No                       No               72
                                             75                    N+                    Yes                      No                       Yes              74
                                             65                    N+                    No                       No                       Yes              82
                                             75                    N+                    No                       No                       Yes              87
OS: overall survival; ECOG PS: Eastern Cooperative Oncology Group Performance Status; RT: radiotherapy. Covariates with a negative impact are in bold.


but are constrained by important limitations, including                                     reliability, consistency and accuracy of these calculators
low granularity (i.e. lack of detailed information on                                       in predicting outcomes for individual patients in differ-
RT). Available big data sources are usually at least                                        ent populations remain unclear. These uncertainties are
2-3 years behind current practice due to the time                                           critical in order to optimally implement these tools in
required to collect and assemble the data and perform                                       clinical practice 24.
quality control. Adding the time for data analysis and                                      The present study has some limitations. First, the absence
publication, current studies examining quality of care                                      of external validation and analysis for variables such as
and comparative effectiveness usually report data that is                                   HPV-status, smoking and alcohol habits that may have an
at least 5 years old 22,23. However, to our knowledge, the                                  impact on OS. However, considering the results of De-Es-



                                                                                                                                                                      211
F. Miccichè et al.




Figure 2. The nomogram built from the OS model at 2 years.




Figure 3. The nomogram built from the OS model at 3 years.



212
                                                             Multicentric prognostic model of overall survival in oropharyngeal cancer: PRO.M.E.THE.O.




Figure 4. The nomogram built from the OS model at 5 years.


calate 4 and RTOG 1016 5 trials, it is important to create a                personalised treatment. This could facilitate active partici-
model that bypasses HPV-status and investigate the impact                   pation by patients in decision-making.
of other factors on survival. Another limitation is that we
did not study adherence to cetuximab therapy, as we did not                 Conflict of interest statement
consider cetuximab dose intensity as a potential variable                   The authors declare no conflict of interest.
influencing outcome. We also did not specifically address
the impact of toxicity, as we assumed that toxicity-induced                 Funding
RT discontinuations were too rare to have an impact on OS.                  This research did not receive any specific grant from funding
However, we are planning to investigate this aspect in fu-                  agencies in the public, commercial, or not-for-profit sectors.
ture analyses, where it may be of interest to evaluate the
impact of cetuximab dose intensity and cumulative dose on                   Authors’ contributions
skin toxicity and OS.                                                       All authors have equally contributed to the manuscript.

                                                                            Ethical consideration
Conclusions
                                                                            This study was approved by the Institutional Ethics Commit-
This project represents the first example of a PPM created                  tee of Catholic University of the Sacred Heart (approval num-
specifically for OPC patients treated with b-RT based on                    ber/protocol number 0049309/16). The research was con-
real-world data. The next step of this project will be exter-               ducted ethically, with all study procedures being performed
nal validation of the PPM. We would also like to implement                  in accordance with the requirements of the World Medical
our analysis with HPV, smoking status, alcohol consump-                     Association’s Declaration of Helsinki. Written informed con-
tion, details about toxicity (and in particular compliance to               sent was obtained from each participant/patient for study par-
cetuximab treatment) and radiomics data. Schematisations                    ticipation and data publication.
have been shown to significantly enhance physician-patient                  The local ethics committees of each centre approved the pro-
communication, and nomograms provide a visual picture                       tocol before patient enrolment according to Italian legislation.
of prognostic factors and their relative influence to support               A Collaboration and Data Transfer Agreement was signed



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F. Miccichè et al.




to define the type of data, permitted use and data protection                    12
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