Article 1

Impact of Treatment Delay on Prognosis in Pharyngeal Cancer: 2

A Single Institution Analysis 3

Andreea Mihaela Kis1,2, Gheorghe-Emilian Olteanu1,2,3,*, Lazar Chisavu4, Marioara Poenaru5, Claudia Borza6,7, An- 4
drada Iftode1,2, Oana Silvana Sarau8, Cristina Dehelean1,2, Roxana Buzatu9 5

1 Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Eftimie Murgu 6
Square No. 2, 300041, Romania. 7
2 Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of 8
Medicine and Pharmacy, Timisoara, Romania. 9
3 Center for Research and Innovation in Personalized Medicine of Respiratory Diseases, “Victor Babes” Uni- 10
versity of Medicine and Pharmacy, Timisoara, Romania. olteanu.gheorghe@umft.ro 11
4 Department of Nephrology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania. 12
5 Department of ENT, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania. 13
6 Department of Functional Sciences–Pathophysiology, “Victor Babeș” University of Medicine and Pharmacy, 14
Timisoara, Romania. 15
7 Centre for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Phar- 16
macy, Timisoara, Romania. 17
8 Department of Hematology, “Victor Babeș” University of Medicine and Pharmacy, Timisoara, Romania. 18
9 Department of Dental Aesthetics, Faculty of Dental Medicine, “Victor Babes” University of Medicine and 19
Pharmacy Timisoara, Timisoara, Romania. 20
* Correspondence: olteanu.gheorghe@umft.ro 21

Abstract: Background: Pharyngeal cancer, particularly head and neck carcinoma (HNC), poses a 22
significant challenge due to its rapid growth in critical anatomical regions, affecting essential func- 23
tions like breathing, speech, and swallowing. With advancements in radiation therapy, specifically 24
Intensity-Modulated Radiation Therapy (IMRT), treatment outcomes have improved. However, the 25
impact of treatment delay on patient prognosis remains a critical area of investigation. Methods: 26
This study was conducted at Timisoara Municipal Emergency Clinical Hospital to assess the effects 27
of time-diagnosis-to-treatment intervals (TDTIs) on the survival outcomes of pharyngeal cancer pa- 28
tients. It focused on individuals undergoing chemotherapy or radiotherapy, evaluating the influ- 29
ence of delayed Diagnosis on Treatment Interval (DTI) and Treatment Package Time (TPT) on prog- 30
nosis. The study population included patients with nasopharyngeal, oropharyngeal, and hypopha- 31
Citation: To be added by editorial
ryngeal cancers. Results: The findings highlight the detrimental impact of prolonged DTIs on pa- 32
staff during production.
tient survival in HNC. Rapid tumor progression in anatomically and functionally delicate regions 33
Received: date necessitates prompt and individualized treatment approaches. The study emphasizes the signifi- 34
Revised: date
cance of timely care delivery in oncology, particularly given the advancements in therapeutic tech- 35
Accepted: date
niques such as IMRT. Conclusion: Delayed treatment initiation in HNC significantly affects patient 36
Published: date
survival. This study underscores the urgency of reducing DTIs and TPTs in managing pharyngeal 37
cancer. The findings advocate for streamlined diagnostic and treatment processes, emphasizing the 38
need for timely interventions in HNC care to improve survival outcomes. 39
Copyright: © 2023 by the authors.
Submitted for possible open access
Keywords: time to treatment; pharyngeal cancer; overall survival; delayed diagnosis 40
publication under the terms and con-
41
ditions of the Creative Commons At-
tribution (CC BY) license (https://cre-
ativecommons.org/licenses/by/4.0/).
1. Introduction 42
In recent years, there have been improvements in the prognosis of patients with phar- 43
yngeal cancer, especially of oropharyngeal cancer patients with HPV positive, due to the 44
understanding of the biological mechanism, tumor progression, and the early identifica- 45
tion of head and neck cancer with the administration of appropriate treatment [1, 2]. The 46

Curr. Oncol. 2024, 31, Firstpage–Lastpage. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/curroncol

Curr. Oncol. 2024, 31, FOR PEER REVIEW 2

challenge is that the period from diagnosis to the beginning of curative therapy (DTI) for 47
head and neck carcinoma (HNC) becomes longer [3], and these tumors are distinguished 48
by their quick growth in a vitally crucial anatomic region. Therefore, malignant tumors 49
and their treatment frequently significantly influence vital processes like breathing, 50
speech, and swallowing. Because diagnosis and treatment are so complicated, a high skill 51
level and a multidisciplinary approach are needed [3]. 52
Due to the complexities of diagnosing and treating HNC, care must be centralized, 53
leading to more patients being referred to specialist facilities [4]. While time-diagnosis-to- 54
treatment intervals (TDTIs) can vary in their effects on overall survival, extensive studies 55
have shown that longer TDTIs have detrimental impacts. [5] 56
Oncology care quality is assessed using the time of care, a key determinant of health 57
prognosis. From the time of the first symptom to consultation, referral to consultation, and 58
diagnosis to the start of treatment (Diagnosis to Treatment Interval, DTI), and from the 59
specialist to the end of postoperative radiotherapy (Treatment Package Time, TPT), timely 60
HNC care has been evaluated [3, 6, 7]. Delays are frequent, a significant cause of avoidable 61
mortality, and a factor in subpar survival across the continuum of HNC care delivery. [8, 62
9] 63
As radiation therapy advances and more complex treatment methods are available, 64
there is a tendency for ever explicit and expensive external support for delivering care. 65
Most centers currently employ conformal radiation treatment (CFRT), and intensity-mod- 66
ulated radiation therapy (IMRT) is also becoming more widespread [10]. The radiation 67
community is aware of the benefits of cobalt units, including their meager maintenance 68
costs and low requirement for engineering support [11]. Many innovative radiotherapy 69
techniques have been applied to reduce the toxicities caused by radiation. One such tech- 70
nique is intensity-modulated radiation therapy (IMRT), a novel variation of 3-dimensional 71
conformal radiation therapy (3D CRT) that allows for the modification of radiation inten- 72
sity across each beam. In contrast, 3D CRT delivers radiation to the target with a minimal 73
radiation dose to the surrounding tissues. Due to its ability to precisely target the primary 74
site and lymph node regions at risk, by lowering the dose to the healthy adjacent tissues, 75
IMRT has become a popular technique for the treatment of HNC patients over the past 20 76
years. This has improved the therapeutic index by lowering acute and chronic morbidity 77
and enhancing target volume coverage with loco-regional control [12]. It is typically used 78
for the nasopharynx and oropharynx, avoiding vital tissues such as the parotid salivary 79
gland, brain, brain stem, and optic nerve, and it was found that it has significantly less 80
xerostomia associated with IMRT when compared to 3D CRT [13]. For locoregional con- 81
trol and laryngeal preservation, concurrent radiation and cisplatin are frequently utilized 82
[14]. The pathologic findings determine the optimal radiation fields, dose, fractionation, 83
the extent of the primary tumor, and the neck lymphadenopathy of different subsites. Per- 84
sonalized approach or “customization” of the therapeutic methods are necessary. One of 85
the primary therapeutic choices for both early and advanced tumors is radiation therapy 86
(RT), which is provided with doses ranging from 54 to 70 Gy according to a typical frac- 87
tionation schedule of 2 Gy/fraction, one fraction/day, and five fractions/week. Further- 88
more, the usual nonsurgical strategy in high-risk situations is to combine RT with concur- 89
rent cisplatin (100 mg/m2 every three weeks [15, 16]. 90

1.1. Region-Specific General Management of Cancers 91

1.1.1. Nasopharynx 92
Nasopharyngeal carcinoma is complicated to treat surgically because of its anatomic 93
position and early tendency to invade retropharyngeal lymph nodes. The cornerstone of 94
treatment is radiation, with intensity-modulated radiation gradually replacing traditional 95
radiation. Therefore, IMRT is the recommended technique for locally advanced nasopha- 96
ryngeal and sinonasal tumors. The deep step gradient dose of IMRT, as opposed to 2D 97
and 3D RT, approaches, enables a better tumor control rate for cancers close to essential 98
Curr. Oncol. 2024, 31, FOR PEER REVIEW 3

structures without raising the toxicity profile. Thus, locally progressed nasopharyngeal 99
cancers have been effectively treated with IMRT [16- 18]. 100

1.1.2. Oropharynx: soft palate, tonsils, and base of the tongue. 101
In soft palate tumors in early stages, local control has been effectively achieved 102
through surgery or definitive radiation. Because the functional outcome is likely better 103
and the treatment results are satisfactory, radiotherapy is typically selected. Patients with 104
locally advanced lesions typically have postoperative radiation therapy after surgical ex- 105
cision/biopsy. Surgery or curative radiation therapy are two treatment options for tonsil- 106
lar tumors in the early stages. Primary radiation therapy is the recommended and final 107
course of treatment for most tonsillar area T1, T2, and exophytic T3 cancers. Because it 108
produces a better functional result, radiotherapy is favored. The contralateral parotid 109
gland should not be exposed to radiation to lower the incidence of xerostomia. Surgery, 110
together with postoperative radiotherapy, is advised for locally advanced tonsillar lesions. 111
Radiotherapy or surgery may be implemented for early lesions at the base of the tongue. 112
Definitive radiation therapy is typically used to treat most patients due to its enhanced 113
quality of life and functional outcomes. Surgery and postoperative radiation are advised 114
for advanced stage. As an alternative to surgery, a nonsurgical strategy such as concurrent 115
chemotherapy and radiotherapy for organ preservation may be considered [19]. 116

1.1.3. Hypopharynx 117

Preserving swallowing function and optimizing control rates are the main objectives 118
of treatment for hypopharyngeal carcinoma; for piriform sinus carcinomas classified as 119
T1 or T2, radiation therapy or surgery alone is recommended. For T1 and T2 lesions, the 120
final local control rates in patients receiving radiation therapy alone and surgical salvage 121
were 95% and 91%, respectively [19, 20]. The usual course of treatment for locally ad- 122
vanced diseases involves a mix of radiotherapy and major surgery. Certain establishments 123
favor the use of irradiation and save drastic surgery for situations where the larynx needs 124
to be preserved. The European Organization for Research in Cancer Therapy (EORTC) 125
conducted a randomized trial of larynx-conserving treatment, which involved induction 126
chemotherapy followed by definitive radiotherapy for patients who showed a complete 127
response to chemotherapy or surgery for those who did not respond well. The trial results 128
showed that the larynx-preserving procedures allowed two-thirds of the survivors to keep 129
their larynxes and provided survival rates comparable to those of conventional treatment 130
[19, 21]. 131
Improving the timeliness of care delivery is one way to increase patient survival for 132
those with HNC. Time-to-treatment intervals are crucial for HNC patients because, as al- 133
ready indicated, these tumors grow quickly in an anatomically and functionally complex 134
environment. This article aims to present data regarding the relationships between three 135
measures of timely HNC care (DTI and TPT) and oncological outcomes for patients with 136
HNC who finished oncological treatment [22]. Although reports on the impact of DTIs on 137
overall survival have been inconsistent, recent extensive studies, including those men- 138
tioned, have shown the detrimental consequences of lengthy DTIs, with longer gaps lead- 139
ing to noticeably reduced survival in HNC patients [23, 8]. Prior research looked at the 140
time between diagnosis and treatment (DTI), postoperative recovery, and radiation recov- 141
ery but did not consider all these factors. While delays in each interval may harm progno- 142
sis, their relative significance and impact size are still unclear. Furthermore, the influence 143
of treatment interval lengthening has a complex, multifaceted association with survival, 144
which is rarely considered [23, 25- 27]. 145
This study aimed to evaluate the impact of increasing DTTIs on patient survival at 146
Timisoara Municipal Emergency Clinical Hospital, focusing on those undergoing chemo 147
or radiotherapy. 148

2. Materials and Methods 149

Curr. Oncol. 2024, 31, FOR PEER REVIEW 4

2.1. Study design 150

This study is a retrospective analysis of medical records from the Timisoara Munici- 151
pal Emergency Clinical Hospital. We reviewed records of patients over 18 years of age 152
who underwent primary surgical interventions (biopsies) for pharyngeal malignant tu- 153
mors between 1 January 2014 and 31 December 2018. 154

2.1.1. Inclusion Criteria: 155

• Patients with previously untreated pharyngeal carcinoma that were located on 156
the nasopharynx, oropharynx, and hypopharynx. 157
• Those who completed curative-intent surgery and full-course adjuvant radia- 158
tion. 159
• Patients who received definitive surgical management and had a 48-month fol- 160
low-up (or until death). 161

2.1.2. Exclusion Criteria: 162

• Insufficient documentation or medical records that did not meet quality stand- 163
ards. (170 patients were excluded for this reason.) 164
• Patients who received treatment for their tumor elsewhere (different center). 165
• Those with a previous history of HNC. 166
• Absence of evidence of treatment or follow-up. 167
• Prior (chemo) radiotherapy in the head and neck area. 168
• Uncertain, zero, or negative time intervals from diagnosis to therapy, surgical 169
recovery, and radiation treatment. 170

171
Figure 1. Study design. 172

2.1.3. Definitions: 173

• Diagnosis to Treatment Interval (DTI): Time from histopathological diagnosis 174
to the start of treatment. 175
• Treatment Package Time (TPT): Time from the first day with the specialist to 176
the end of curative treatment. 177
Curr. Oncol. 2024, 31, FOR PEER REVIEW 5

The final group selected for the study comprised 180 patients with previously un- 178
treated HNC. 179

2.2. Diagnosis process 180

All patients underwent a comprehensive diagnostic evaluation: 181

2.2.1. Medical Examination: 182

• Detailed medical history. 183
• Physical examination. 184

2.2.2. Imaging and Pathological Procedures: 185

• Chest radiography or chest CT (performed in cases of suspicious low cervical 186
lymph nodes or bilateral cervical lymph nodes). 187
• Head and neck imaging using computed tomography (CT) and/or magnetic 188
resonance imaging (MRI). 189
• Biopsy of lymph nodes suspected of harboring metastases. 190
• Positron emission tomography (PET)-CT for unidentified primary tumors. 191

2.2.3. Tumour Staging: 192

• Tumours were categorized based on the date of diagnosis using the TNM Clas- 193
sification of Malignant Tumours (either the sixth or the seventh edition). 194

2.3. Data collection 195

The study focused on data related to patients diagnosed with pharyngeal cancer and 196
treated at Timisoara Municipal Emergency Clinical Hospital. Specific data recorded in- 197
cluded: 198
• Initial diagnostic tumor pathology. 199
• Age at diagnosis. 200
• Gender. 201
• Residency environment (rural or urban). 202
• Tumour localization (nasopharynx, oropharynx, hypopharynx). 203
• Retroactively determined TNM staging (using the extent of disease and collab- 204
orative staging codes for tumor sizes and locations, following the classification protocol 205
developed by the American Joint Committee on Cancer). 206
• Type of hospitalization (emergency or routine). 207
• Surgical intervention details. 208
• Biopsy type and histological diagnosis. 209
• Details of the patient's first admission to the ENT ward and oncological treat- 210
ment. 211
• Details on adjuvant treatments and anti-neoplastic therapies, along with the 212
prognosis considering the timing of initiation for chemotherapy/radiotherapy and the sta- 213
tus of patients (alive or deceased). 214

2.4. Time Intervals Defined: 215

• First presentation-to-diagnosis Interval: Time between the first consultation at 216
the Timisoara Municipal Emergency Clinical Hospital and the final histopathological di- 217
agnosis. 218
• Diagnosis-to-Treatment Interval (DTI): Time between the final diagnosis and 219
the start of treatment (either the surgery date or the first fraction of chemo-radiotherapy). 220
Curr. Oncol. 2024, 31, FOR PEER REVIEW 6

221
Figure 2. Analysis design of the time intervals included in the study. 222

2.5. Outcome Measurements 223

The primary endpoints of this study encompassed: 224
• Oncological Outcomes: An assessment of the disease's progression, status, and 225
prognosis. 226
• Impact of Delays: An evaluation of how delays influence oncological outcomes. 227
• Time Intervals: Measurement of the duration between the initial consultation 228
to diagnosis and subsequent treatment initiation. 229
For calculating follow-up, recurrence rates, and disease-specific survival, we relied 230
on the findings from the most recent outpatient examinations conducted by the consultant 231
head and neck surgeon or radiation oncologist. Overall survival was determined based on 232
the date of the last contact with the patient or the date of their death. 233

2.6. Ethical statement 234

The current study was evaluated and approved by the Scientific Research Ethics 235
Committee of Victor Babes University of Medicine and Pharmacy, Timisoara (Approval 236
No. Nr. 53/28.09.2018 (2023) 237

2.7. Statistical analysis 238

• Survival functions were estimated with the Kaplan-Meier method, and differ- 239
ences were assessed using a log-rank test. 240

2.7.1. Data Handling and Software: 241

• Data were collected and analyzed using R (version 3.6.3). 242
• Packages employed include tidyverse, final-fit, mcgv, survival, stringdist, jan- 243
itor, and Hmisc. 244

2.7.2. Data Presentation: 245

• Continuous variables with Gaussian distribution: Means ± standard deviation. 246
• Continuous variables without Gaussian distribution: Medians and inter-quar- 247
tile range. 248
• Categorical variables: Percentages. 249

2.7.3. Statistical Tests Used: 250

• For Gaussian populations: Student’s t-test or analysis of variance for means. 251
• For non-Gaussian populations, use the Mann–Whitney U test or Kruskal Wallis 252
test for medians. 253
• For proportions: χ^2 tests. 254
• Continuous variable distributions were assessed for normality using the 255
Shapiro–Wilk test and for equality of variance using Levene’s test. 256
Curr. Oncol. 2024, 31, FOR PEER REVIEW 7

• Association strength between non-Gaussian continuous variables was gauged 257

using Spearman’s correlation coefficient. 258

2.7.4. Significance Level: 259

• A p-value of <0.05 was set as the threshold for statistical significance. 260
Data availability 261
All data used for statistical analysis is available upon request. 262

3. Results 263
3.1. Patient Retrospective Observational Study 264
Out of 515 patients evaluated between 2014 and 2018, 350 were diagnosed with a 265
malignant pharyngeal tumor. Among these, only 180 met the study criteria. The follow- 266
up: median of 6.21 years, iQR: 4.62-7.66 years. The average age of the patients receiving 267
post-biopsy treatments was 59.0 years, with a standard deviation of 9.2 years, and their 268
ages ranged from 31.0 to 81.0 years. Most patients were males, accounting for 94.4%, while 269
females constituted 5.6%. 270
In terms of histopathological diagnosis and treatments, squamous cell carcinoma 271
(SCC) was identified in 67.2% of the patients (121 in total). Of these, 67.8% were treated 272
with radiotherapy (RxT), 24 patients with chemoradiotherapy (CRT), and 15 patients with 273
chemotherapy (ChT). Keratinizing squamous cell carcinoma (KSCC) was diagnosed in 274
16.1% of the patients (29 in total), with 17 undergoing RxT, 7 receiving CRT, and five 275
treated with ChT. The N staging revealed that 53.9% of the patients were at the N0 stage, 276
71 out of 121 undergoing RxT. For the T2 and T3 stages, 44.6% (54 patients) and 20.7% (25 277
patients) were treated with RxT, respectively. The detailed clinical characteristics of the 278
population are displayed in Table 1. 279

Table 1. Entire patient retrospective study description (from demographics to treatment). 280

ChT RxT CRT Total

P value
N= 23 N= 121 N=36 N=180
Age 0.2041
Mean (SD) 57.6 (9.5) 59.9 (9.2) 57.1 (8.6) 59.0 (9.2)
Range 42.0 - 78.0 31.0 - 76.0 40.0 - 81.0 31.0 - 81.0
Gender 0.6152
M 21.0 (91.3%) 114.0 (94.2%) 35.0 (97.2%) 170.0 (94.4%)
F 2.0 (8.7%) 7.0 (5.8%) 1.0 (2.8%) 10.0 (5.6%)
Histopathologic di-
0.8482
agnosis

SCC 15.0 (65.2%) 82.0 (67.8%) 24.0 (66.7%) 121.0 (67.2%)

KSCC 5.0 (21.7%) 17.0 (14.0%) 7.0 (19.4%) 29.0 (16.1%)
SCC IN SITU 1.0 (4.3%) 4.0 (3.3%) 2.0 (5,6%) 7.0 (4.1%)
UCNT 2.0 (8.7%) 12.0 (9.9%) 3.0 (8.4%) 17.0 (8.4%)
OTHER CANCERS 0.0 (0.0%) 7.0 (5,6%) 0.0 (0.0%) 7.0 (4.1%)
Time from symp-
tom recognition
0.3752
and seeking medi-
cal care
Unspecified 15.0 (65.2%) 56.0 (46.3%) 14.0 (38.9%) 85.0 (47.2%)
Under three
4.0 (17.4%) 39.0 (32.2%) 13.0 (36.1%) 56.0 (31.1%)
months
Curr. Oncol. 2024, 31, FOR PEER REVIEW 8

Over three
4.0 (17.4%) 26.0 (21.5%) 9.0 (25.0%) 39.0 (21.7%)
months
N category 0.3292
N0 12.0 (52.2%) 70.0 (57.9%) 15.0 (41.7%) 97.0 (53.9%)
N1 1.0 (4.3%) 19.0 (15.7%) 7.0 (19.4%) 27.0 (15.0%)
N2 3.0 (13.0%) 8.0 (6.6%) 5.0 (13.9%) 16.0 (8.9%)
N3 7.0 (30.4%) 24.0 (19.8%) 9.0 (25.0%) 40.0 (22.2%)
T Stage 0.0712
T1 8.0 (34.7%) 39.0 (32.2%) 13.0 (36.1%) 60.0 (33.4%)
T2 9.0 (39.1%) 54.0 (44.6%) 10.0 (27.8%) 73.0 (40.6%)
T3 5.0 (21.7%) 25.0 (20.7%) 9.0 (25.0%) 39.0 (21.7%)
T4 0.0 (0.0%) 3.0 (2.5%) 2.0 (5.6%) 5.0 (2.8%)
This 1.0 (4.3%) 0.0 (0.0%) 2.0 (5.6%) 3.0 (1.7%)
Surgery 0.1372
Minor Surgery (Bi-
20.0 (80.9%) 108.0 (89.3%) 32.0 (88.9%) 160.0 (89.0%)
opsy)
Major surgery (Tra-
cheotomy, Cervi-
5.0 (21.7%) 11.0 (9.1%) 4.0 (11.2 %) 15.0 (11.1%)
cotomy, laryngec-
tomy)
1 Legend: Squamous Cell Carcinoma (SCC), Keratinizing Squamous Cell Carcinoma (KSCC), Squa- 281
mous Cell Carcinoma In Situ (SCC IN SITU), and Undifferentiated Carcinoma of Nasopharyngeal 282
Type (UCNT). The counts and percentages of patients with each histopathologic diagnosis are pro- 283
vided for each treatment modality group - Chemotherapy (ChT), Radiotherapy (RxT), Chemoradi- 284
otherapy (CRT), and the aggregated total retrospective study. Table 1 provides a detailed portrayal 285
of the patient cohort's retrospective demographics, histopathologic diagnosis, intervals from symp- 286
tom recognition to seeking medical care, the extent of lymph node involvement, tumor staging, and 287
surgical interventions. The table facilitates a thorough understanding of the patient and the diverse 288
treatment pathways. However, the P values suggest that the differences across treatment modality 289
groups may not be statistically significant. This comprehensive table is a reference for analyzing the 290
treatment modalities and outcomes in the context of demographic and clinical parameters. 291

3.2. Treatment intervals 292

The time from a patient's first appointment with a specialist to receiving their histo- 293
pathological diagnosis, the specialist-to-diagnosis interval, they had a median duration of 294
9 days. We set up a reference level of 14 days for this interval, and no significant detriment 295
was observed when comparing intervals exceeding this reference. 296
The median DTI was 33 days. Furthermore, the median TPT was 100 days, ranging 297
from 28 to 2217 days, with a standard deviation of 271 days. The mean days from diagno- 298
sis until the end of treatment were notably higher for the nasopharynx group, but this 299
difference was not statistically significant. In the multivariable analysis of this retrospec- 300
tive study, DTI did not show a significant impact (Table 3). 301

Table 2. Patients’ interval evaluation. 302

Media (Stand-
Median 95% CI for Median
ard deviation)
The first presentation to diag-
15.47 (40.08) 9 8-9 180 patients
nosis
Diagnosis to treatment (DTI) 68.21 (134.35) 33 29.05-37 175 patients
Radiation interval 112.78 (184.06) 50 48-51.6 180 patients
Treatment package time
114.06 (186) 50 48-52 176 patients
(TPT)
Curr. Oncol. 2024, 31, FOR PEER REVIEW 9

The first presentation to diag-

15.47 (40.08) 9 8-9 180 patients
nosis
1Table 2. Intervals of patients' medical journey, with statistical measures including the mean, stand- 303
ard deviation, median, and 95% confidence interval for the median provided. 304

Regarding treatment modalities, chemotherapy was administered to 32.8% of the pa- 305
tients, while 87.8% underwent radiotherapy. The overall mortality rate stood at 16.66%, 306
with only one patient from the nasopharynx group succumbing to the disease. The rate of 307
disease recurrence was 26.1%. Most patients were at the N0 stage when assessing ade- 308
nopathy classifications, accounting for 54.4%. The nasopharynx group showed the highest 309
incidence of N3 adenopathy, at 38.5%. In this retrospective study, 42.2% of patients began 310
treatment within 30 days post-diagnosis. (Table 3) 311

Table 3. Nasopharynx, Oropharynx, and Hypopharynx subgroups evaluation. 312

Nasopharynx N=26 Oropharynx N=69 Hypopharynx

Parameter Total N=180 P value
(14.4%) (38.3%) N=85 (47.2%)
Days diagnostic-end of treatment
211 (423.46) 162.36 (177.19) 178.01 (272.15) 0.232
M+SD
Chemotherapy 7 (26.9%) 21 (30.4%) 31 (36.5%) 59 (32.8%) 0.576
Radiotherapy 23 (88.5%) 62 (89.9%) 73 (85.9%) 158 (87.8%)
Treatment duration group (Rxt;
CRT, ChT)
<40 days 8 (30.8%) 11 (15.9%) 25 (29.4%) 44 (24.4%)
40-70 days 10 (38.4%) 41 (59.4%) 34 (40%) 85 (47.2%) 0.1162
>70 days 8 (30.8%) 17 (24.6%) 26 (30.6%) 51 (28.3%)
Diagnosis to treatment group
(DTI)
<30 days 14 (53.8%) 31 (44.9%) 31 (36.5%) 76 (42.2%)
≥30 days 12 (46.2%) 38 (55.1%) 54 (63.5%) 104 (57.8%)
1Table 2. Legend: M=mean, SD=standard deviation, N=number. Statistical tests: ANOVA for contin- 313
uous variables, Chi-square test for categorical ones. 314

3.3. Oncological treatment 315

The retrospective group of 180 patients who underwent various treatment modalities 316
is categorized as follows: 317
• ChT (Chemotherapeutic Treatment): This group received combination therapies 318
which included: 319
Single-agent regimens: Carboplatin, Docetaxel, and Methotrexate. 320
Dual-agent combinations: Paclitaxel with Carboplatin; Cetuximab with Carboplatin; 321
Docetaxel with either Cisplatin or Carboplatin; and 5-Fluorouracil with Cisplatin. 322
Triple-agent combinations: Paclitaxel combined with Carboplatin and Cetuximab or 323
Epirubicin; and Docetaxel combined with Carboplatin and Cisplatin or Cetuximab. 324
• RxT (Radiotherapy): Patients in this category were treated with cobalt therapy, often 325
in conjunction with Cisplatin, intensity modulated radiation therapy (IMRT), and 3- 326
dimensional con-formal radiation therapy (3D CRT) 327
• CRT (Chemoradiotherapy): This group received a combined chemotherapy and ra- 328
diotherapy treatment. 329
The detailed clinical characteristics of this patient cohort can be found in Table 3— 330
Kaplan-Meyer analysis Figure 3, Figure 4, and Figure 5. 331
Curr. Oncol. 2024, 31, FOR PEER REVIEW 10

332
Figure 3. 333

In the Kaplan-Meier survival curve (Figure 3. ) in the risk of death stratified by the 334
location of the neoplasia, the p-value of the Log-rank test is 0.126. There seems to be a 335
trend in increased mortality in the oropharynx (HR=6.21, 95%CI=2.1-18.3) compared to 336
the nasopharynx and hypopharynx (HR=4.61 95%CI=1.61-13.14) compared to the naso- 337
pharynx. 338

(a) (b)
Figure 4. (a). In the Kaplan-Meier survival curve on the risk of death for treatment duration groups. 339
P = 0.129, no statistical differences among groups, but there is a trend of increased mortality between 340
the group with more than 70 days treatment duration compared with the ones with 40-70 days 341
HR=2.26 (95%CI: 0.96-5.33).; (b) In the Kaplan-Meier survival probability for diagnostic to treatment 342
days groups. P value of 0.537, no statistical differences in the risk of death. 343
Curr. Oncol. 2024, 31, FOR PEER REVIEW 11

344
Figure 5. 345

In Figure 5. hypopharynx and oropharynx increased the risk of death by 4.59 (95%CI: 346
1.55-13.55) and 5.49 times (95%CI: 1.79-16.81) compared to nasopharynx location. 347
In the Cox regression analysis regarding mortality risk, after adjustment for adenopa- 348
thy, radiotherapy, sex, age, localization, diagnostic to treatment duration categories, only 349
chemotherapy increased the risk of death by 3.11 times (95%CI: 1.51-6.41, p=0.0021) with 350
a Harrell’s C-index by 0.638 (95%CI: 0.552-0.723) (Figure 6). 351

352
Figure 6. 353

4. Discussion 354
Curr. Oncol. 2024, 31, FOR PEER REVIEW 12

Our study evaluated the influence of treatment intervals on overall outcomes in head 355
and neck cancer patients, from diagnosis to the conclusion of therapy. Few studies focus 356
on time delay in HNC patients. Schutte et al. reported that even after accounting for vari- 357
ables like comorbidities, age, and stage, a specialist-to-treatment gap exceeding 30 days 358
adversely impacted overall survival [5]. Murphy et al. and van Harten et al. both assessed 359
the diagnosis-to-treatment continuum's impact on survival and found that prolonged in- 360
tervals correlated with reduced overall survival [5, 3, 24]. Specifically, Murphy et al. doc- 361
umented diminished patient survival rates when treatment extended beyond 61 days 362
from diagnosis [3, 5]. Ho Allen et al. discussed that postoperative interval and radiation 363
interval significantly impacted mortality rates, with notable increases in risk after specific 364
thresholds [28]. Their findings suggest these delays can be surrogate markers for a poor 365
prognosis. Overgaard's retrospective analysis offered a compelling illustration of the im- 366
portance of overall treatment time (OTT) in the DAHANCA research. In cases when the 367
mean potential doubling time (T pot) of a tumor is four days, such as HNC, it illustrated 368
the importance of OTT in the local control of rapidly growing tumors [29]. Withers ini- 369
tially demonstrated in the 1980s that extended OTT results in the loss of local control and 370
that an additional 0.6 Gy/day is needed to offset the faster repopulation of tumor tissue, 371
which indicates that an increasing time delay also affects the treatment dosage, which in- 372
fluences the side effect of radiation treatment [30]. Head-neck radiation often causes mu- 373
cositis, dermatitis, dysgeusia, dysphagia, and odynophagia, which can lead to poor oral 374
intake and weight loss. In rare cases, this can even cause therapy to be interrupted or 375
stopped too soon, which could hurt results [31]. 376
The landmark trials for the best radiation-alone protocol are RTOG 90-03, EORTC 377
22791, and DAHANCA. These trials are used to guide the appropriateness of the RT com- 378
ponent of various chemo-radiation arms. Still, the improvements in locoregional control 379
achieved by these newer radiation protocols were only 7 to 10% [29, 32, 33]. Moreover, no 380
agreement exists on the best radiation dose fractionation scheme [34]. Our retrospective 381
study group showed that survival analysis in the risk of death stratified by the therapy 382
regimen, the p-value of the treatment with chemotherapy alone group presented a higher 383
mortality rate compared to radiotherapy alone. This coincides with other study groups 384
that demonstrate that in head and neck cancer, the most effective treatment represents 385
radiotherapy concomitant systemic chemotherapy, where necessary, is the current stand- 386
ard of therapy for treating head and neck squamous cell carcinoma to cure cancer [29, 32, 387
33]. 388
However, most head and neck cancer cases were found in the oropharynx and hypo- 389
pharynx. Pharyngeal cancer treatment aims to eradicate tumors while minimizing adverse 390
effects and preserving the quality of life. Treatment choice is multifaceted, factoring in 391
tumor characteristics and patient profiles. Platinum-based chemotherapy, especially Cis- 392
platin, remains the mainstay. Various regimens exist, from single-agent therapies like cis- 393
platin or carboplatin to multi-drug combinations, each with its efficacy profile [36- 40]. 394
Definitive radiation is preferred for oropharynx tumors due to superior functional out- 395
comes [20]. Hypopharynx tumors often involve a combination of radical surgery and ra- 396
diotherapy [41, 42]. 397
A good predictive marker for HPV detection in oropharyngeal squamous cell carci- 398
noma (OPSCCs) has been identified as p16 immunohistochemistry (IHC). p16 is overex- 399
pressed due to HPV carcinogenesis, and significant IHC staining for p16 strongly corre- 400
sponds with the presence of DNA from HPV-16, the HPV subtype most frequently linked 401
to OPSCC. P16 is a reliable predictive marker, according to numerous research. Further 402
evidence that the oropharynx was the leading site of the tumor comes from metastatic 403
SCC with HPV-positive cervical lymph nodes (LNs) from an unidentified primary tumor 404
[44-46]. In addressing the observed limitations within the study, it is essential to mention 405
the non-performance of p16 analysis on any of the samples, which precludes a precise 406
quantification of the number of tumors driven by HPV. The lack of p16 analysis is a sig- 407
nificant shortfall as HPV and p16 are acknowledged for their prognostic importance in 408
Curr. Oncol. 2024, 31, FOR PEER REVIEW 13

oropharyngeal squamous cell carcinoma (OPSCC). The presence of HPV has notably been 409
recognized as a favorable prognostic indicator in OPSCC, with research indicating a broad 410
variance in HPV-associated cancers constituting 38% to 64% of OPSCC cases [44]. In com- 411
parison, a lesser 13% to 29% of hypopharyngeal squamous cell carcinoma (HPSCC) cases 412
are identified as HPV-positive. This distinction is further underscored by a meta-analysis 413
encompassing 37 studies, which revealed a 28% reduction in mortality risk among pa- 414
tients with HPV-positive OPSCC compared to their HPV-negative counterparts [42, 43]. 415
However, the genuine impact of the findings on this subgroup remains ambiguous due to 416
the study's limitations. Notably, the exclusion of patients with aggressive disease who 417
were unable to complete treatment, along with the unavailability or potential undeter- 418
mined influence of several variables, such as smoking status, chemotherapy type, peri- 419
neural invasion, and recurrence status, might have skewed the outcomes. Consequently, 420
the limitations, chiefly the absence of p16 analysis, render the quantification of HPV- 421
driven tumors indeterminate, thus potentially impacting the interpretative validity and 422
comprehensive understanding of the study's findings. 423

5. Conclusions 424
Avoiding treatment delays is crucial. Delays can arise from various challenges, in- 425
cluding logistical issues, post-surgical recovery, treatment complications, lack of auxiliary 426
support, and patient health status. Such delays can impact survival by fostering tumor 427
radioresistance and decreasing radiation efficacy. For patients with HNC, the timely ini- 428
tiation of treatment, prompt postoperative radiotherapy, and TPT are crucial for survival 429
outcomes. Our study highlighted that chemotherapy is linked to a heightened risk of re- 430
lapse and mortality. Among the three subsites examined, oropharyngeal cancer presented 431
the most unfavorable prognosis. 432
Future research should aim to standardize definitions related to delay for DTI and 433
TPT, as current inconsistencies hamper comparability across studies. Additionally, further 434
investigations should focus on designing interventions to enhance the timeliness of HNC 435
care and understanding barriers that impede prompt care throughout the cancer care jour- 436
ney. 437

Author Contributions: Conceptualization, C.D. and M.P.; methodology, A.M.K.; formal analysis, 438
L.C., and A.M.K; investigation, A.M.K.; data curation, L.C.; writing—original draft preparation, 439
A.M.K, G-E.O, M.P., C.B., A.I., O.S.S, R.B.; writing—review and editing, A.M.K, G-E.O., O.S.S, R.B.; 440
visualization, L.C, G-E.O, A.M.K.; supervision, C.D., R.B.; project administration, C.D., R.B. All au- 441
thors have read and agreed to the published version of the manuscript. 442

Funding: The APC for this study was supported by “Victor Babes” University of Medicine and 443
Pharmacy, Timisoara, Eftimie Murgu Square No. 2, 300041, Romania. 444

Institutional Review Board Statement: The study was conducted following the Declaration of Hel- 445
sinki and approved by the Ethics Committee of The University of Medicine and Pharmacy, 446
Timisoara, Romania – ethical approval number 53/28.09.2018. 447

Informed Consent Statement: Informed consent was not sought due to the study's retrospective 448
nature, with no impact on the patient's identity or treatment decisions. 449

Data Availability Statement: All data used for statistical analysis can be acquired from the corre- 450
sponding author. 451

Conflicts of Interest: The authors declare no conflicts of interest. 452

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