Exclusive Radio±chemoTherapy versus upfront Surgery in the treatment of HPV-related localized or locally ADvanced Oropharyngeal squamous cell Carcinoma (RT-SHADOC): a tricentric study of efficacy, tolerance and quality of life

doi:10.21203/rs.3.rs-3234987/v1

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Exclusive Radio±chemoTherapy versus upfront Surgery in the treatment of HPV-related localized or locally ADvanced Oropharyngeal squamous cell Carcinoma (RT-SHADOC): a tricentric study of efficacy, tolerance and quality of life

https://doi.org/10.21203/rs.3.rs-3234987/v1

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Background

The treatment of stage I-III HPV + oropharyngeal squamous cell carcinoma (HPV-OPSCC) is based on either surgery ± adjuvant therapy or exclusive radio ± chemotherapy. We sought to compare these two therapeutic strategies in terms of efficacy, tolerance and quality of life (QoL).

Methods

Patients treated for stage I-III HPV-OPSCC from 2010 to 2021in 3 academic centers were included and sorted according to the treatment strategy: surgery or exclusive radio ± chemotherapy. Efficacy and tolerance were retrospectively assessed, and QoL was prospectively evaluated using QoL assessment instruments.

Results

Eighty-three patients were included, 21 underwent surgery and 62 definitive radio-±chemotherapy. 2-year progression-free survival (PFS) and overall survival (OS) were respectively 80% and 86% in the surgical group and 92% and 95% in the non-surgical group, with no significant difference. At the end of treatment, 64.5% of patients presented a grade III symptom, without significant difference between the two groups. No patient had late grade III toxicity at 24 months. Forty-five patients (11 in the surgical group, 34 in the nonsurgical group) participated in the prospective quality-of-life analysis. Patients reported significantly more fatigue and loss of appetite after surgery, whereas patients in the radio ± chemotherapy group described significantly more salivary and oral problems and difficulty swallowing. The global quality of life score tended to be better in the radio ± chemotherapy group (EORTC QLQ-C30 77.6 vs 65.2, p = 0.07).

Conclusion

No significant difference in terms of efficacy, physician-reported toxicity and patient-reported quality of life was found between surgery and radio ± chemotherapy in the treatment of stage I-III HPV-OPSCC.

Oropharyngeal squamous cell carcinoma

human papillomavirus

HPV

Radiotherapy

Upfront surgery

Efficacy

Tolerance

Quality of life

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has substantially increased over the past twenty years and is likely to continue to rise (1). Between 2020 and 2040, projections of the International Agency for Research on Cancer (IARC) estimate an incidence progression of 8% in Europe and up to 15% in North America (2). Mainly due to alcohol consumption and smoking in the past decades, it is now well established that a growing share of OPSCCs is attributable to human papillomavirus (HPV) infection (3): 30–70% of OPSCCs are now HPV-related in Europe and North America (4).

HPV-related OPSCC (HPV-OPSCC) differs from non-HPV-related OPSCC, as they each present different molecular, histological and epidemiological characteristics (1). It has also been demonstrated that HPV infection is an independent prognosis factor regardless of the chosen treatment (5, 6).

To date, no treatment has shown its superiority over another in localized and locally advanced OPSCCs. Irrespective of the HPV status, their management is based on either upfront surgery (uS), followed or not by adjuvant therapies – including radiation therapy (RT) and chemotherapy (CT) – or exclusive radiotherapy (eRT) or radio-chemotherapy (eRCT) (7, 8). The only trial comparing these two strategies in stage III/IV OPSCCs had to be discontinued because it failed to reach the accrual goal (9) and included only 42 patients. In less advanced diseases (T1-2 N0-2), the phase II ORATOR study compared transoral robotic surgery (TORS) with or without adjuvant treatments to eRT ± CT in terms of quality of life but was not designed to assess the efficacy of both strategies (10).

The majority of data on the two options for the treatment of HPV-OPSCC are from monocentric studies (11, 12) or the American National Cancer Database (13). Furthermore, since patients with HPV-OPSCC are younger, healthier and live longer, the impact of treatments on quality of life (QoL) is paramount (14). However, apart from the ORATOR trial, the aforementioned studies did not focus on tolerance (11–13, 15), and data remain sparse.

Hence, the purpose of this multicentric work was to compare surgical and nonsurgical strategies in terms of efficacy as well as toxicity and QoL in localized and locally advanced HPV-OPSCCs.

Patients

This retrospective study was conducted in three French tertiary referral centers in the management of OPSCCs: the Georges-François Leclerc Cancer Center (Dijon), the François Mitterrand University Hospital (Dijon) and the Jean Minjoz University Hospital (Besançon).

It included adult patients treated with a curative intent for stage I-III (T1-4 N0-3 M0) operable and resectable HPV-OPSCC between 2010 and 2021.

Patients were excluded from this analysis if they presented one of the following criteria:

a past medical history of cancer of any kind and/or of radiation therapy in the head and neck region;
75 years old at the onset of treatment;
unresectable or stage IV disease or neck metastases of unknown primary origin;
not fit for surgery;
non-HPV-OPSCC.

The stage of the disease was determined according to the TNM American Joint Committee on Cancer (AJCC) 8th version for HPV-related OPSCCs (16). For patients whose staging was initially performed with the 7th version, a new staging according to the 8th version was retrospectively performed.

Comorbidities were evaluated through the modified Charlson Comorbidities Index (mCCI).

Determination of HPV status

HPV evaluation could be carried out using immunohistochemistry (IHC) staining for p16 or by performing HPV-specific testing (DNA, RNA or in situ hybridization) (7). The carcinoma was considered HPV-related if at least one of the aforementioned tests was positive.

Resectability

Resectability was evaluated by the multidisciplinary tumor board (MTB). If no clear mention of it was found in the medical file of a patient who met the other inclusion criteria, resectability was retrospectively evaluated by a trained head and neck surgeon.

Data extraction

Data were extracted from the medical information department of each facility using the International Classification of Diseases (ICD). A complete medical record search was performed for each included patient, looking for demographic and clinical information.

We identified 898 patients treated for OPSCC. Most of them (n = 815) were excluded after a medical file search because they met the exclusion criteria, leaving 83 patients for analysis (Fig. 1).

Treatments

Patients were treated according to international guidelines (7, 8). The therapeutic strategy was discussed by the MTB and with the patients.

For this study, patients were divided into two groups: those who underwent carcinological surgery followed by adjuvant RT or RCT if needed (uS group) and those who received exclusive RT or RCT (eRT ± CT group).

In patients who underwent upfront surgery, postoperative radio ± chemotherapy was performed if at least one of the following risk factors was identified:

pT3-4;
positive margins;
perineural infiltration and lymphovascular spread;
≥ 2 invaded lymph nodes;
extracapsular node infiltration.

Data collection

Efficacy criteria

We evaluated treatment efficacy through progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS), locoregional progression-free survival (LRPFS) and metastasis-free survival (MFS). PFS was defined as the time from treatment to disease recurrence, progression or death of any cause. OS represented the time from treatment to death of any cause. DSS accounted for the time from treatment to death from OPSCC. LRPFS and MPFS were defined as the time from treatment to local and/or regional recurrence and metastatic relapse, respectively.

We also reported the patterns of relapse.

Tolerance and toxicity assessment

Toxicity was evaluated by physicians during follow-up according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Acute toxicity was defined as toxicity that occurred within 6 months after treatment, whereas late toxicity was assessed at 1 and 2 years.

Data concerning the hospital admissions of patients during treatment, the use of opioids in the management of pain and the need for a feeding tube were also collected.

Quality of life assessment

QoL was prospectively assessed. We used the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (17) and QLQ-H&N35 (18) instruments.

The EORTC QLQ-C30 contains five functional scales (physical, role, cognitive, emotional, and social functioning), a global QoL scale, three symptom scales (fatigue, nausea and vomiting, and pain), and six single items (appetite loss, diarrhea, dyspnea, constipation, insomnia and financial impact). The questionnaire uses a four-point response format (“not at all,” “a little,” “quite a bit,” and “very much”), with the exception of the global QoL scale, which has a seven-point response format. The EORTC QLQ-H&N35 is divided into six scales (pain, swallowing, nutrition, speech, social function, body image, and sexuality) and uses the same four-point response scale as the QLQ-C30.

A high score for a functional scale represents a high level of functioning, a high score for the global health status represents a high QoL, but a high score for a symptom item represents a high level of symptomatology.

These questionnaires were sent by mail in March 2022 to each living patient who was included in the retrospective analysis. Those who did not reply received the questionnaires again in May 2022.

Statistical analysis

Descriptive analyses and QoL scores were performed using means with standard deviations for quantitative variables and percentages for qualitative variables. Comparison between the groups (uS versus eRT ± CT) was performed using Student’s t test, Wilcoxon‒Mann‒Whitney, CHI² or Fisher’s test as appropriate.

Survival rates and medians were determined using the Kaplan‒Meier method. Survival curves were compared with the log-rank test. Median follow-up was determined using the reverse Kaplan‒Meier method.

Tests were 2-sided. P values less than 5% were considered significant. Analyses were performed using SAS 9.4 software.

This study was approved by the patient protection commission of Ile de France VII on January 12, 2022.

Patients

The main characteristics of the patients are reported in Table 1.

Table 1. Demographic and clinical characteristics of the patients

uS: upfront surgery, eRT±CT: exclusive radiotherapy ± chemotherapy, SD: standard deviation, WHO: World Health Organization, N/A: not applicable

Characteristics		All patients n=83	uS group n=21	eRT±CT group n=62	p value
Sex					0,23
	female	19 (22,9%)	7 (33,3%)	12 (19,4%)
	male	64 (77,1%)	14 (66,6%)	50 (80,6%)
Mean age (SD), years old					0,82
		60,6 (9,6)	60,6 (10,9)	60,5 (9,1)
Performance Status (WHO)					0,02
	0	9 (11,1%)	1 (4,8%)	8 (12,9%)
	1	53 (65,4%)	9 (42,9%)	44 (71,0%)
	2	18 (22,2%)	8 (38,1%)	10 (16,1%)
	3	1 (1,2%)	1 (4,8%)	0
Mean modified Charlson comorbidities index (SD)					0,60
		4,2 (2,1)	4,5 (2,60)	4 (1,51)
Tobacco consumption, pack-years					0,45
	< 10	40 (48,2%)	12 (57,1%)	28 (45,2%)
	> 10	43 (51,8%)	9 (42,9%)	34 (54,8%)
Alcohol consumption					1
	Yes	19 (22,9%)	5 (23,8%)	14 (22,6%)
	No	64 (77,1%)	16 (76,2%)	48 (77,4%)
Hypertension					1
	Yes	22 (26,5%)	5 (23,8%)	17 (27,4%)
	No	61 (73,5%)	16 (76,2%)	45 (72,6%)
Diabetes					0,26
	Yes	4 (4,8%)	2 (9,5%)	2 (3,2%)
	No	79 (95,2%)	19 (90,5%)	60 (96,8%)
Ischemic heart disease					1
	Yes	11 (13,3%)	3 (14,3%)	8 (12,9%)
	No	72 (86,7%)	18 (85,7%)	54 (87,1%)
T classification					0,10
	missing	1 (1,2%)	1 (5%)	0
	1	10 (12,0%)	4 (20,0%)	6 (9,7%)
	2	39 (47,0%)	11 (55,0%)	28 (45,2%)
	3	19 (22,9%)	1 (5,0%)	18 (29,0%)
	4	14 (16,9%)	4 (20,0%)	10 (16,1%)
N classification					0,60
	0	12 (14,4%)	4 (19,0%)	8 (12,9%)
	1	54 (65,1%)	15 (71,4%)	39 (62,9%)
	2	11 (13,3%)	1 (4,8%)	10 (16,1%)
	3	6 (7,2%)	1 (4,8%)	5 (8,1%)
Tumor stage					0,002
	I	28 (33,7%)	13 (61,9%)	15 (24,2%)
	II	31 (37,4%)	2 (9,5%)	29 (46,8%)
	III	24 (28,9%)	6 (28,6%)	18 (29%)
Tumoral site					0,45

	palatine tonsil or glosso-tonsillar sulcus	51 (61,4%)	15 (71,4%)	36 (58,1%)
	Base of tongue	24 (28,9%)	5 (23,8%)	19 (30,6%)
	Vallecula	4 (4,8%)	0	4 (6,5%)
	Posterior pharyngeal wall	2 (2,4%)	0	2 (3,2%)
	Lateral pharyngeal wall	1(1,2%)	1 (4,8%)	0
	Soft palate	1 (1,2%)	0	1 (1,6%)
Treatments
Radiotherapy					N/A
	Yes	83 (100%)	21 (100%)	62 (100%)
	No	0	0	0
Chemotherapy					0,17
	Yes	69 (83,1%)	15 (71,4%)	54 (87,1%)
	No	14 (16,9%)	6 (28,6%)	8 (12,9%)

Between 2010 and 2021, 83 patients, 64 (77.1%) male and 19 (22.9%) female patients, were included in this study. The mean age at diagnosis was 60.6 ± 9.6 years. The most frequent localizations were the palatine tonsil or glosso-tonsillar sulcus (61.4%) and the base of the tongue (28.9%).

Notably, patients significantly differed between the treatment groups in terms of performance status (p = 0.02) and overall tumor stage (p = 0.002).

The evaluation of HPV status was carried out using IHC staining for p16 in 70 (84.3%) patients, HPV DNA testing in 5 (6.1%) patients, and both methods in 8 (9.6%) patients.

Treatments

Twenty-one (25.3%) patients received uS, whereas 62 (74.7%) were treated with eRT ± CT.

In the uS group, 10 (47.6%) had histologically complete resection (R0), 11 (53.2%) had R1 resection, and none had R2 resection. Lymphatic emboli and perineural neoplastic invasion were found in 6 (29%) and 7 (33%) patients, respectively. Sixteen (76%) patients underwent lymphadenectomy. Among them, 4 were pN0, 10 were pN1, 2 were pN2 and 5 had at least one adenopathy with capsular rupture features. All patients received adjuvant treatments following surgery: 15 (71.4%) had RCT, and 6 (28.6%) received RT alone.

In the nonsurgical group, 54 (87.1%) patients received CT in addition to RT, and 8 (12.9%) received eRT.

In both groups, all patients received intensity-modulated radiation therapy, either volumetric-modulated arc therapy (89.2%) or static step-and-shoot IMRT (10.8%).

When given, CT was mostly concurrent with RT (95.5%), and cisplatin was the most commonly used drug (85.6%), followed by carboplatin plus 5-fluorouracil (8.7%).

Efficacy outcomes

All stages

The median follow-up in the cohort was 37.0 months. PFS, OS, DSS, LRPFS and MPFS are presented as Kaplan‒Meier curves in Fig. 2 and as survival rates in Table 2.

Figure 2. Kaplan‒Meier estimates of PFS (A), OS (B), DSS (C), LRPFS (D) and PFS (E)

All stages (I-III)

PFS: progression-free survival, OS: overall survival, DSS: disease-specific survival, LRRFS: locoregional progression-free survival, MFS: metastasis-free survival

PFS did not significantly differ between the treatment groups (p = 0.20). PFS at 2 and 3 years was 80% and 67% in the uS group and 92% and 84% in the eRT ± CT group. Predictive factors for PFS are available in supplementary table 1. Alcohol consumption (HR = 3.07, p = 0.03, 95% CI [1.139;8.272]) and stage III disease (versus stage I-II, HR = 5.563, p = 0.001, 95% CI [1.996;15.506]) were significantly associated with a worsening PFS contrary to tobacco consumption, Charlson index, age and treatment strategy.

Likewise, OS did not significantly differ between the surgical and nonsurgical groups (p = 0.38): the 2- and 3-year OS rates were 86% and 73% in the uS group and 95% and 86% in the eRT ± CT group, respectively.

We did not find any significant difference in terms of DSS, LRPFS or MPFS depending on the treatment groups.

Table 2. Oncological outcomes at 2 and 3 years

PFS: progression-free survival, OS: overall survival, DSS: disease-specific survival, LRPFS: locoregional progression-free survival, MPFS: metastatic progression-free survival, uS: upfront surgery, eRT±CT: exclusive radiotherapy ± chemotherapy, N/A: not applicable

Tumor stage	Therapeutic strategy	2-year rates
		PFS	OS	DSS	LRPFS	MPFS
All stages (I-III)
	uS	80%	86%	91%	90%	95%
	eRT±CT	92%	95%	96%	95%	85%
Early stages (I-II)
	uS	87%	100%	100%	87%	100%
	eRT±CT	95%	98%	100%	97%	93%
Advanced stage (III)
	uS	67%	56%	67%	100%	78%
	eRT±CT	84%	87%	87%	100%	68%
		3-year rates
		PFS	OS	DSS	LRPFS	MPFS
All stages (I-III)
	uS	67%	73%	78%	90%	80%
	eRT±CT	84%	86%	89%	95%	85%
Early stages (I-II)
	uS	87%	100%	100%	87%	100%
	eRT±CT	90%	92%	97%	97%	93%
Advanced stage (III)
	uS	37%	56%	56%	100%	40%
	eRT±CT	58%	75%	62,2%	100%	58%

Early stages (I-II)

No significant difference was found in PFS (p = 0.55), OS (p = 0.39), DSS (p = 0.65), LRPFS (p = 0.20) or MPFS (p = 0.32). Data are presented in Table 2.

Advanced stage (III)

No significant difference was found in PFS (p = 0.61), OS (p = 0.23), DSS (p = 0.54), LRPFS (p = 1) or MPFS (p = 0.39). The data are shown in Table 2.

Patterns of relapse

During the follow-up period, 16 (19%) patients presented a relapse. Patterns of relapse are presented in Fig. 3.

In patients with local or locoregional recurrence in the eRT ± CT group, 2 underwent salvage surgery, and 1 was reirradiated. Two patients developed locoregional failure after uS. The first patient underwent reirradiation, and the second patient underwent chemotherapy because of concurrent metastatic relapse.

In patients with a metastatic relapse, 2 presented an oligometastatic pulmonary progression treated by stereotactic ablative radiotherapy (SABR), 9 had chemotherapy and 1 received supportive care.

Figure 3. Flow diagram outlining patterns of relapse in both groups

uS: upfront surgery, eRT ± CT: exclusive radiotherapy ± chemotherapy, SABR: stereotactic ablative radiotherapy

Tolerance and clinician-reported toxicities

Treatment tolerance and discontinuation

There was no treatment-related death in either group. One patient presented postoperative bleeding requiring a surgical revision.

In both groups, every patient received full-dose RT as planned.

Among those with an indication for CT, 37 (54%) received the treatment as planned, and 32 (46%) prematurely discontinued it. Causes for discontinuation were chemotherapy-related toxicity (88.4%), sepsis (7.8%) and patient refusal to continue CT (3.8%). We did not find any significant difference in CT discontinuation between the groups (uS group: 8 (53%); eRT ± CT group: 29 (54%), p = 1).

Acute toxicities

At the end of treatments, 52 (63.4%) patients presented at least one grade III side effect: 15 (75%) after uS and 37 (59.7%) in the eRT ± CT group. The main grade III symptoms were dysphagia (47 (57.3%)) and oral mucositis (12 (14.6%)). Notably, patients presented significantly more oral mucositis in the surgical group, with 17 (85.0%) presenting grade II-III oral mucositis versus 33 (53.2%) in the nonsurgical group (p = 0.009). There was no significant difference between the treatment groups concerning other symptoms and all-type toxicity. Data are reported in Table 3.

At 6 months, one patient still reported grade III pain after uS and adjuvant RCT. No patient in the nonsurgical group had any grade III toxicity. The main grade II symptom was xerostomia (7). No significant difference was found between the surgical and nonsurgical groups in terms of overall toxicity at 6 months (supplementary table 2), but dysphagia was more frequently reported in the surgical group, although it did not meet statistical significance (grade I-II, 25% vs 14.5%, p = 0.06).

Late toxicities

No grade III toxicity was reported by physicians at 1 and 2 years after treatment. At 2 years, 2 (22.2%) patients had grade II toxicity in the uS group, and 4 (8.7%) in the eRT ± CT group. Grade II side effects were xerostomia (4), dysphagia (1), and pain (1). No significant difference was found in late toxicity between each group. Data at 2 years are shown in supplementary table 3.

Nutritional support

At the end of treatment, a higher proportion of patients had a feeding tube in the uS group, although this difference was not significant (14 (66.7%) vs 35 (56.4%), p = 0.28). At one year, 1 patient in the surgical group and 4 patients in the eRT ± CT group still needed a feeding tube.

Table 3. Physician-reported toxicities at the end of treatments

uS: upfront surgery, eRT±CT: exclusive radiotherapy ± chemotherapy

Toxicity		uS		eRT±CT			p value
	Grade	n=20	%		n=62	%
All-type maximum toxicity								0.15
	0	1	5,00%		0	0,0%
	1	0	0,0%		1	1,6%
	2	4	20,00%		24	38,7%
	3	15	75,00%		37	59,7%
Dysphagia								0.48
	0	0	0,0%		1	1,6%
	1	1	5,00%		10	16,1%
	2	4	20,00%		18	29,0%
	3	14	70,00%		33	53,2%
	missing	1	5,00%		0	0,0%
Odynophagia								0.22
	0	0	0,0%		1	1,6%
	1	4	20,00%		25	40,3%
	2	12	60,00%		31	50,0%
	3	2	10,00%		2	3,2%
	missing	2	10,00%		3	4,8%
Xerostomia								0.08
	0	1	5,00%		1	1,6%
	1	15	75,00%		18	29,0%
	2	3	15,00%		36	58,1%
	3	0	0,0%		5	8,1%
	missing	1	5,00%		2	3,2%
Oral mucositis								0.009
	0	0	0%		2	3,2%
	1	1	5,0%		24	38,7%
	2	14	70,0%		24	38,7%
	3	3	15,0%		9	14,5%
	missing	2	10,0%		3	4,8%
Dysgueusia								0.40
	0	1	5,0%		7	11,3%
	1	6	30,0%		20	32,3%
	2	9	45,0%		16	25,8%
	missing	4	20,0%		19	30,6%
Trismus								1
	0	17	85,0%		56	90,3%
	1	0	0%		3	4,8%
	missing	3	15,0%		3	4,8%
Pain								0.85
	0	1	5,0%		3	4,8%
	1	8	40,0%		22	35,5%
	2	8	40,0%		32	51,6%
	3	2	10,0%		5	8,1%
	missing	1	5,0%		0	0%
Radiodermatitis								0.60
	0	0	0%		0	0%
	1	4	20,0%		21	33,9%
	2	13	65,0%		36	58,1%
	3	2	10,0%		5	8,0%
	missing	1	5,0%		0	0%

Patient-reported quality of life

Forty-five patients answered both QoL questionnaires: 11 from the uS group and 34 from the nonsurgical group. One patient who received eRCT returned a completed EORTC QLQ-C30 but not the QLQ-H&N35. Data are presented in supplementary tables 4 and 5.

The median time between the end of treatments and the response to the questionnaires was 38.4 (Q1 25.67; Q3 56.2) months.

Fatigue (34.3 vs 21.0, p = 0.03), appetite loss (33.3 vs 8.6, p = 0.005) and the need for nutritional supplements (36% vs 6%, p = 0.02) were found to be significantly greater in patients who underwent surgery. However, patients in the eRT ± CT group reported more swallowing issues (80.1 vs 59.8, p = 0.008), sticky saliva (54.9 vs 30.3, p = 0.05), and mouth and teeth problems (80.4 vs 57.6, p = 0.04 and 79.4 vs 48.5, p = 0.02, respectively).

Role functioning was better in the eRT ± CT group, close to statistical significance (91.4 vs 80.3, p = 0.06). Physical, cognitive, emotional and social functioning, pain, speech, social function, body image, and sexuality were not significantly different in either group. Finally, the global health status from the QLQ-C30 instrument was better in the nonsurgical group, although it did not reach statistical significance (77.6 vs 65.2, p = 0.07).

The purpose of this study was to assess the efficacy, tolerance and impact on quality of life of two therapeutic strategies in the treatment of localized and locally advanced HPV-OPSCCs: upfront surgery followed or not by adjuvant RT ± CT and exclusive RT ± CT.

Both study groups were quite homogeneous but differed from each other, as patients from the uS group had a higher performance status and those from the eRT ± CT group presented a higher tumor stage. However, the proportion of stage III OPSCC was the same in both groups. Tumors that developed within the palatin tonsils or the glosso-tonsillar sulcus were more likely to be treated surgically, even though this was not significant. These elements should be taken into account, as they are likely to affect the efficacy outcomes of both treatment groups even if they did not seem to impact PFS in the predictive factor analysis.

We found no significant difference in PFS, OS, DSS, LRPFS and MPFS between uS and eRT ± CT in the whole population, neither in early stages nor in more advanced diseases. Both strategies appeared to be effective in the treatment of stage I-III HPV-OPSCC.

Our results seem consistent with the sparse data available in the literature. Kelly et al. found no difference in OS between a surgical approach and eRCT in a retrospective study of over 3,000 patients with stage I-II HPV-OPSCC (13), as did Kim et al. more recently (19). In more advanced tumors - stage III-IV according to the AJCC 7th version - Kamran et al. reported an OS benefit from surgery over RT-CT (20). This retrospective study did not focus only on HPV-OPSCC, although clinical characteristics were not available for the 5,037 patients with an HPV-related tumor. Additionally, OS was not significantly different between the treatment groups in the multivariate analysis, suggesting that confounding factors might have explained the difference in OS in the univariate analysis. These results came from American databases, and although they allow us to obtain data on large populations, they only provide information on overall survival, and data about other relevant oncological outcomes are missing.

Recently, the GETTEC (Groupe d’Étude des Tumeurs de la Tête Et du Cou) group conducted a study on 382 patients with HPV-OPSCC in 7 French centers (15). There was no difference in OS at 5 years (89.2% and 84.2% in the surgical and nonsurgical groups, respectively), but DSS and RFS were found to be improved in the surgical group in the multivariate analysis. In our study, we found similar survival rates and patterns of relapse to those published by Culié et al. (19% of relapse in our study vs 20%) (15). However, we did not show differences of any kind in terms of efficacy between our 2 groups. Although this might be caused by a low number of events and the presence of confounding factors, it could also be related to good outcomes in our eRT ± CT group. Indeed, Lacau St Guly et al. found no difference in RFS either at 2 years after uS or eRT ± CT in 92 patients with HPV-OPSCC (21).

A meta-analysis attempted to evaluate both strategies in the treatment of OPSCC, irrespective of HPV status (22). Authors showed a significant heterogeneity between studies, and concluded that OS after surgical and nonsurgical treatments was not significantly different. However, this meta-analysis mostly included unicentric single-modality studies with a low number of patients, highlighting the importance of data from well-conducted large retrospective and prospective studies.

Because patients with HPV-OPSCCs have better outcomes than those with non-HPV-related tumors (5, 23), survival is longer, and treatment tolerance and QoL have become an increasing issue (24). Notably, all patients from our study received IMRT, as it was proven to reduce the incidence of xerostomia and improve saliva-related QoL compared to 3D RT (25, 26).

In our study, overall acute and late toxicities did not significantly differ between the treatment groups, and tolerance remained acceptable in both groups, as no grade IV-V side effects were reported.

Interestingly, the phase II ORATOR study, which compared QoL after transoral robotic surgery (TORS) with or without adjuvant treatments to eRT ± CT in the treatment of T1-2 N0-2 OPSCCs (10), found a trend for more grade III dysphagia in the surgery group (26% vs 18%), as in our study, even though the surgical technique was mini-invasive and only 74% of patients received adjuvant RT in the surgical group (10). However, the ORATOR 2 phase II trial comparing TORS ± 50–60 Gy RT and 60 Gy RT plus weekly cisplatin in Ti-2 N0-2 tumors was prematurely discontinued because of excessive toxic effects in the surgical arm (27). Long-term outcomes are awaited with this surgical approach, but caution is required outside expert centers.

Since it is well established that QoL and toxicity assessment by physicians leads to lower incidence and severity of symptoms compared to patients’ reports (28), we decided to prospectively collect patient-reported outcomes in addition to data retrospectively extracted from medical files. We used the multi-item multidomain EORTC QLQ-C30 and QLQ-H&N35 instruments, as they are considered reliable and valid measurement tools of QoL and are used in many international clinical trials (29–32). We observed a trend for a better global QoL (77.6 vs 65.2, p = 0.07) and for a higher role functioning score (91.4 vs 80.3, p = 0.06) according to the QLQ-C30 questionnaire after eRT ± CT. Patients in the nonsurgical group also reported more swallowing issues and sticky saliva, whereas fatigue and appetite loss scores were higher in the uS group. These results are relevant since the global health status from the QLQ-C30 instrument as well as the scores related to the loss of appetite and fatigue are known to be predictive of OS in many cancer types (33–36), including head and neck cancers (37).

OPSCC survivors face clinically important deteriorations in QoL mostly centered on xerostomia, dysphagia and chewing (24, 38). It has been prospectively proven that patients with an HPV-positive tumor have their own course of QoL during and after treatment (39), but studies comparing surgical and nonsurgical strategies are scarce in this particular population. Similar to our findings, Yin et al. showed a worse QoL after surgery alone or upfront surgery followed by RT compared to eRT at 3 and 6 months after treatment (40). Unfortunately, no long-term data were available. In parallel, longitudinal swallowing QoL according to the MD Anderson Dysphagia Inventory (MADI) score was significantly better with RT in the ORATOR trial, contrary to our results (10, 41). However, this difference did not meet the predefined threshold of a clinically relevant change in QoL and was no longer significant at 2 and 3 years.

In our study, no patient underwent surgery without any adjuvant treatment, possibly due to a selection bias. Thus, our findings cannot be extrapolated to pT1-2 pN0-N1 tumors with negative margins and no criteria for adjuvant treatments. Nevertheless, 97% of the patients in the GETTEC study (15) and two-thirds of the patients in the ORATOR trial (10) received adjuvant therapies, suggesting that only a small number of patients are treated by surgery alone. This implies that patients treated by surgery are likely to need a multimodal approach that may increase the risk of toxicity and deteriorate QoL. Patients must be carefully informed of the oncological outcomes of uS and eRT ± CT and of the high rate of adjuvant treatments after surgery. Again, selecting the population that might benefit from surgery alone as well as finding effective treatment de-escalation are consequently paramount.

Our work has several limitations. First, oncological data and physician-reported toxicities were retrospectively obtained, leading to inherent flaws in retrospective studies. Moreover, because of a lack of power due to very few events, only a univariate analysis could be performed. Therefore, our results might have been impacted by some confounding factors. However, our study population was quite homogeneous between the treatment groups and did not differ in terms of alcohol consumption and stage III disease, the only two variables that were found to impact PFS, suggesting that the effects of potential confounding factors are limited. Another weakness is related to the QoL assessment. Although data were prospectively collected, each patient completed the questionnaires at a unique time point after treatment. Consequently, this QoL survey should be examined carefully.

This work also has strengths. It is indeed, to the best of our knowledge, one of the largest European studies in this field of research and one of the rare to focus not only on efficacy but also tolerance and QoL. We present here a multicentric study, thus reducing the center effect on our outcomes. Additionally, data were collected in three academic centers with expertise in the management of OPSCC and that follow international guidelines, leading to meaningful results.

Therefore, our findings contribute to new insights into the management of HPV-OPSCC in the era of therapeutic de-escalation and might help physicians find the most suitable treatment strategy for each individual. Phase III trials comparing surgery and radiotherapy might never exist because of recruitment issues. However, large, international, prospective studies could clarify the debate between surgery and radiotherapy and even determine predictive factors for one strategy or the other.

We found comparable oncologic outcomes between upfront surgery and exclusive radiotherapy or radiochemotherapy in the treatment of stage I-III HPV-OPSCC. Notably, all patients who underwent surgery received adjuvant treatments. Acute and late toxicity were not significantly different between the treatment groups. Prospective quality of life assessment showed different tolerance profiles between the treatment groups.

These results must be validated through further prospective studies. In the meantime, patients should be informed of these elements by physicians before choosing one treatment strategy over another.

OPSCC oropharyngeal squamous cell carcinoma

IARC International Agency for Research on Cancer

HPV human papillomavirus

HPV-OPSCC HPV-related oropharyngeal squamous cell carcinoma

uS upfront surgery

RT radiotherapy

CT : chemotherapy

eRT : exclusive radiotherapy

eRCT : exclusive radiochemotherapy

eRT±CT : exclusive radiotherapy ± chemotherapy

QoL Quality of life

AJCC : American Joint Committee on Cancer

mCCI modified Charlson comorbidities index

IHC immunohistochemistry

MTB multidisciplinary tumor board

ICD International Classification of Diseases

PFS progression-free survival

OS overall survival

DSS : disease specific survival

LRPFS locoregional recurrence-free survival

MFS metastasis-free survival

CTCAE : Common Terminology Criteria for Adverse Events

EORTC : European Organization for Research and Treatment of Cancer

WHO World Health Organization

IMRT intensity-modulated radiation therapy

SABR stereotactic ablative body radiotherapy

GETTEC : Groupe d’Etude des Tumeurs de la Tête et du Cou

RFS relapse-free survival

TORS transoral robotic surgery

MADI MD Anderson Dysphagia Inventory

Ethic Approval and consent to participate

This study was approved by the patient protection commission of Ile de France VII on January 12, 2022. Each patient participating in the quality of life evaluation signed a written consent.

Consent for publication

Not applicable

Availability of supporting data

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

None

Authors’contribution

All listed collaborators performed the following: 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; 2. Drafting the work ; 3. Final approval of the version to be published; Specific additional individual cooperative effort contributions to study/manuscript design/execution/interpretation, in addition to all criteria above are listed as follows:

Conceptualization: JBa, DT, GT, CC

Investigation and data collection: JBa, CG

Formal analysis: JBa, GC, AB

Methodology: JBa, AB, NV, DT, CC

Supervision: CC

Validation: SL, GT, CC

Writing: JBa

Review: CG, DT, NV, MF, CD, JBo, SL, GT, CC

Acknowledgment

Hannah McIndoe (HM), Sarah McIndoe (SM) and Christopher McIndoe (CM) revised the manuscript for grammar and syntax.

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No competing interests reported.

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Exclusive Radio±chemoTherapy versus upfront Surgery in the treatment of HPV-related localized or locally ADvanced Oropharyngeal squamous cell Carcinoma (RT-SHADOC): a tricentric study of efficacy, tolerance and quality of life

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Abstract

Figures

Background

Methods

Patients

Determination of HPV status

Resectability

Data extraction

Treatments

Data collection

Efficacy criteria

Tolerance and toxicity assessment

Quality of life assessment

Statistical analysis

Results

Patients

Treatments

All stages

Early stages (I-II)

Advanced stage (III)

Patterns of relapse

uS: upfront surgery, eRT ± CT: exclusive radiotherapy ± chemotherapy, SABR: stereotactic ablative radiotherapy

Tolerance and clinician-reported toxicities

Treatment tolerance and discontinuation

Acute toxicities

Late toxicities

Nutritional support

Patient-reported quality of life

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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