Introduction
Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in the developed world. Human papilloma virus (HPV) is the leading cause of this, especially HPV genotype 16, and has overtaken the traditional risk factors such as smoking or excess alcohol.Reference Mehanna, Beech, Nicholson, El-Hariry, McConkey and Paleri1 HPV-related OPSCC, particularly the early-stage tumours, are highly curable, with long-term survival of more than 82 per cent; whereas typical survival in non-HPV OPSCC is around 52 per cent.Reference Ang, Harris, Wheeler, Weber, Rosenthal and Nguyen-Tân2 Moreover, HPV-related patients are likely to be younger and more often non-smokers with fewer competing morbidities.Reference Ringash3 There is much research interest in the de-escalation of treatment in this group of patients, who may face decades living with the consequences of successful treatment.
With the increased availability of minimal-access transoral approaches, there has been a shift towards offering patients upfront surgery with the hope of avoiding the potential toxicities of radiotherapy/chemoradiotherapy for early-stage HPV-positive OPSCC. One particular focus has been in patients’ long-term swallow outcomes, specifically the avoidance of enteral feeding dependence.Reference Cracchiolo, Baxi, Morris, Ganly, Patel and Cohen4 Transoral techniques vary depending on centre expertise and equipment. Techniques include transoral laser, monopolar and direct endoscopic approaches and transoral robotic surgery (TORS).Reference Homer, Winter, Abbey, Aga, Agrawal and Ap5 These minimal access procedures have drastically improved access to the oropharynx and reduced the morbidity compared to open approaches.
The current management options for early-stage HPV positive OPSCC are: (1) primary radiotherapy (pRT) or concurrent chemoradiotherapy (pCRT) and (2) transoral surgery and neck dissection (TORS) followed by pathologically directed adjuvant radiotherapy (aRT) or concurrent chemoradiotherapy (aCRT).Reference Homer, Winter, Abbey, Aga, Agrawal and Ap5
The survival outcomes in either treatment modalities for early-stage HPV positive OPSCC are similar.Reference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6 This has allowed patients to have a choice in determining their treatment, leading to a more personalised treatment. With the introduction of minimal access transoral techniques, many trials are in the process of determining if surgery allows for safe de-escalation of radiation therapy dose or omission of chemotherapy. Current randomised trials such as the Post-operative Treatment for HPV-positive Tumours (PATHOS) trialReference Owadally, Hurt, Timmins, Parsons, Townsend and Patterson7 or E3311Reference Ferris, Flamand, Weinstein, Li, Quon and Mehra8 will report on the survival and functional outcomes of surgery alone for low-risk patients, lower-dose adjuvant radiotherapy in intermediate-risk OPSCC and the omission of chemotherapy in high-risk OPSCC following primary transoral resection. As these trials all require patients to have primary surgery first, there is no direct comparison of these trial arms with standardised CRT. The determination of which primary modality leads to better functional outcomes are yet to be resolved.Reference Lin, Sharbel and Topf9
The ORATOR trial, which randomised between TORS and pRT/pCRT reported slightly better functional outcomes with pRT/pCRT at one-year post-treatment. However, the authors emphasised that conclusions regarding long-term functional outcomes cannot yet be drawn.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran11 Whilst we wait for the results of the multi-centre randomised trials, we present a retrospective series of surgical versus non-surgical treatment of HPV-positive OPSCC at a local centre, with minimum two years of oncological and functional outcomes.
Materials and methods
Data collection
Retrospective analysis of patient notes was conducted at a single centre, University Hospitals Dorset NHS Foundation Trust, UK. Patients treated with primary TORS with or without adjuvant therapy were identified from the robot database between 01/01/2017 and 21/05/2021, and patients treated with pRT/pCRT were identified from the head and neck cancer multidisciplinary database between 01/01/2019 and 21/05/2021. Different dates were screened for each group to ensure an equivalent number of patients were included in each group. Patient selection was based on the criteria outlined in Figure 1 (TNM 8th Edition12). Pre-treatment staging was determined by our multidisciplinary tumour board. Radiotherapy records were reviewed to determine treatment doses and radiotherapy fields, if the treatment fields covered the ipsilateral or bilateral neck.
Inclusion and exclusion criteria for the patient selection (TNM Eighth Edition12). Abbreviations: aRT = adjuvant post-operative radiotherapy; aCRT = adjuvant post-operative concurrent chemoradiotherapy; OPSCC = oropharyngeal squamous cell carcinoma; pCRT = primary chemoradiotherapy; pRT = primary radiotherapy.
Outcome measures
The primary outcome measures were the two-year disease-free survival (DFS) and overall survival (OS) rates. DFS was defined as the time between confirmed residual disease or recurrence and the initial OPSCC diagnosis, while OS was the time between diagnosis and death. For deceased patients, the date and cause of death were obtained from hospital records. Patient survival was confirmed via the latest follow-up or by checking the general practitioner’s records. For those treated with primary surgery, data on surgical margin status, hospital stay duration and complications were also collected.
Functional Oral Intake Scale (FOIS) scoresReference Crary, Mann and Groher13 and gastrostomy dependence rates were measured to determine the swallow outcomes at baseline and at more than two years post-treatment. FOIS scores were evaluated by head and neck speech and language pathologists.
Statistical analysis
With the nature of this study being a retrospective observational study, descriptive statistics were used with the accompanying 95 per cent confidence intervals (CI).
Ethical consideration
No ethical approval was required as the Health Research Authority decision tool determined the study to fall under the remit of audit (available at: http://www.hra-decisiontools.org.uk/research/).
Results
A total of 86 eligible patients were identified; 44 patients were treated with TORS and ipsilateral selective neck dissection with or without adjuvant therapy (“Surgery group”). Within the Surgery group, 6 patients received surgery-only with no adjuvant treatment, 23 patients received unilateral aRT and 15 patients received aCRT (unilateral treatment). A total of 42 patients were treated with pRT/pCRT (“Oncology group”), with 17 patients receiving pRT (7 unilateral and 10 bilateral) and 25 patients receiving pCRT (6 unilateral and 19 bilateral). The median age was 62 years for the Surgery group (range 43–85 years) and 60 years for the Oncology group (range 37–87 years). Baseline characteristics, primary tumour sites and TNM staging are shown in Table 1. The median follow-up period was 3.49 years for the Oncology group (range 2.04–5.68 years) and 5.59 years for the Surgery group (range 2.54–7.32 years)
Patient demographics
Abbreviations: aCRT = adjuvant post-operative concurrent chemoradiotherapy; aRT = adjuvant post-operative radiotherapy; BoT = base of tongue; DFS = disease-free survival; GT sulcus = glossotonsillar sulcus; OS = overall survival; pCRT = primary chemoradiotherapy; pRT = primary radiotherapy.
* The final pN staging was used for the Surgery group: there were two patients in the Surgery group who were cN1, however, the final histology showed pN2.
Procedures
In the Surgery group, the primary tumour was surgically resected via TORS using the da Vinci surgical robot (Intuitive Surgical Inc). Standard en bloc lateral oropharyngectomy being performed for tonsil tumours and lingual tonsil resection for tongue base tumours.Reference O’Malley, Weinstein, Snyder and Hockstein14, Reference Weinstein, O’Malley, Snyder, Sherman and Quon15 Ipsilateral selective neck dissection (levels 2–4) was conducted concurrently. All cases were pre-discussed and approved by our multidisciplinary tumour board and followed the PATHOS trial protocol for the adjuvant treatment regimen.Reference Owadally, Hurt, Timmins, Parsons, Townsend and Patterson7
In the Oncology group, pRT was delivered using volumetric arc radiotherapy (VMAT) techniques with the prescribed dose of 65 Gy in 30 fractions over six weeks to gross disease and 54 Gy to elective regions in the neck. Concurrent chemotherapy primarily involved cisplatin, administered weekly or three-weekly, with carboplatin used for cisplatin-ineligible patients. Following pRT or pCRT response was assessed at three months with positron emission tomography-computed tomography (PET-CT) as per local institutional standards.
Oncological outcome
The two-year DFS rate for the Oncology group was 88 per cent (n = 37/42). Three patients experienced residual neck disease, and two patients developed distant metastases within two years. Three patients with residual neck disease underwent salvage neck dissection and are all currently disease-free. These patients had 4/16, 14/66 and 1/11 positive nodes for residual SCC, respectively. Of the two patients with distant metastases, one presented with a solitary lung lesion, which was treated with stereotactic ablative radiotherapy and remains disease-free. The other patient developed liver and bone metastases and died due to disease progression 3.42 years post-treatment. Additionally, one patient with disease-related death was due to major oropharyngeal haemorrhage four months post-pRT. The two-year OS rate for the Oncology group was 98 per cent (n = 41/42) (Table 2A).
Oncological outcome
Abbreviations: aCRT = adjuvant post-operative concurrent chemoradiotherapy; aRT = adjuvant post-operative radiotherapy; DFS = disease-free survival; OS = overall survival; pCRT = primary chemoradiotherapy; pRT = primary radiotherapy.
A: Two-year DFS and OS.
B: Five-year DFS and OS of the 30 patients in the Surgery group who had follow-up length of five or more years.
* One patient died from major haemorrhage from the oropharynx four months post-radiotherapy.
The two-year DFS rate for the Surgery group was 95 per cent (n = 42/44). Two patients experienced recurrence after primary surgery plus aRT. One patient developed mediastinal metastasis at six months and died from disease progression at 2.92 years. The second patient developed contralateral neck disease at 1.17 years and died at 2.83 years. Both were treated with palliative chemotherapy followed by immunotherapy. The two-year OS rate for the Surgery group was 100 per cent (n = 44/44). Amongst 30 patients with available five-year follow-up data, DFS and OS rates were both 93 per cent (n = 28/30). Five patients who underwent surgery without adjuvant treatment remained disease-free at five years (Table 2B).
Functional outcome
The mean pre- and post-treatment (at more than two years) FOIS scores have been illustrated in Figure 2. All patients in the Surgery group received ipsilateral treatment only. For the Oncology group, 13 patients received ipsilateral treatment, and 29 patients received bilateral treatment.
The mean pre-treatment and the more than two-year post-treatment Functional Oral Intake Scale (FOIS) scoresReference Crary, Mann and Groher13 with 95 per cent confidence interval. (A) Table representation of results. (B) Graphic representation of results. Abbreviations: aCRT = adjuvant post-operative concurrent chemoradiotherapy; aRT = adjuvant post-operative radiotherapy; CI = confidence interval; pCRT = primary chemoradiotherapy; pRT = primary radiotherapy.
In the Oncology group, the mean FOIS score decreased from 6.95 pre-treatment to 6.3 post-treatment (median follow-up 2.98 years; range 2–5.36 years). In the Surgery group, the mean FOIS score decreased from 6.98 pre-treatment to 6.54 post-treatment (median follow-up 4.24 years; range 2–6 years). The Surgery plus aCRT subgroup showed the worst mean post-treatment FOIS score of 6.2 (median follow-up 4 years; range 2–4.83 years) (Figure 2). Surgery-only with no adjuvant treatment subgroup showed the best functional outcome with no decrease in their post-treatment FOIS score at more than two years (median follow-up 5.04 years; range 2.92–5.42 years) (Figure 2). No patients had gastrostomy tube at two years post-treatment. Two patients in the Oncology group developed osteoradionecrosis of the mandible.
Surgical complication
The mean length of hospital stay for patients treated with surgery was 10 days (median 8 days; range 4–38 days). A total of 18.2 per cent (n = 8/44) of patients who underwent TORS plus neck dissection experienced a surgical complication in the first 14 days post-operatively: hospital-acquired pneumonia (n = 3), neck haematoma (n = 1) and post-TORS bleed (n = 4). The post-TORS bleed rate in our cohort was 9 per cent (n = 4/44). Three patients returned to theatre for arrest of bleeding. No patients had tracheostomy at any point, and no patients died in the Surgery group.
Discussion
We report our experience of treating patients with T1-2 N0-1 p16 positive OPSCC with either primary surgery with TORS and ipsilateral neck dissection with or without adjuvant treatment (“Surgery group”) or pRT/pCRT (“Oncology group”).
A systematic review conducted to evaluate the outcomes after Oncology treatment versus Surgical treatment for early OPSCC showed that oncological outcomes were similar with both modalities with a two-year OS to range from 84 per cent to 96 per cent for the Oncology group and 82–96 per cent for the Surgery group.Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16 This was following the review of 20 case series (8 intensity-modulated radiation therapy [IMRT] studies, 1287 patients; and 12 TORS studies, 772 patients).Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16 The ORATOR study, a randomised trial evaluating the outcomes between the Surgery group (n = 34) and the Oncology group (n = 34) for treating T1-2 N0-2 (TNM 7th edition17) OPSCC, also showed that there were no significant differences in the oncological outcomes between the two groups with both groups showing excellent OS.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 More recently, a national multicentre cohort study was conducted from the US evaluating the outcomes of 726 patients with T1-2 OPSCC.Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18 They showed that patients in the Oncology group had worse five-year OS compared to the Surgery group.Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18 However, this was unmatched populations for cancer stage or HPV status.Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18 Our experience supports the findings of the systematic review and the ORATOR study for the oncological outcomes, showing good clinical outcomes, with no clinically significant difference in the two-year DFS and OS between the two groups (Table 2A).
With the recent movement towards treatment de-escalation, and data emerging to confirm oncological outcomes appearing to be similar between the Surgery group and the Oncology group, functional swallowing outcomes have been an area of key interest. A previous systematic review concluded that, although oncological outcomes were similar with both modalities, the Surgery group appeared to achieve better functional outcomes.Reference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6 More recent systematic review concluded that the MD Anderson Dysphagia Index (MDADI) scoreReference Chen, Frankowski, Bishop-Leone, Hebert, Leyk and Lewin19 at one year were not significantly different between the two groups and were both impaired.Reference Campo, Iocca, De, Mazzola, Mercante and Pichi20 The ORATOR study, however, showed that the Oncology group had superior swallowing-related quality of life (QOL) scores, both the MDADI score and the FOIS score, at one-year after treatment, compared to the Surgery group.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 The difference did not represent a clinically meaningful change.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 Recent national multicentre cohort study from the US also concluded that the Surgery group experienced clinically meaningful increased risk of dysphagia at six months and at one year post-treatment compared with the Oncology group, although the Surgery group was less likely to be gastrostomy tube dependent at six months, and at five years post-treatment compared to the Oncology group.Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18 All studies to date have shown progressive worsening of swallow outcomes amongst survivors of OPSCC, whether treated with radiotherapy or TORS.Reference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran11, Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16, Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18, Reference Campo, Iocca, De, Mazzola, Mercante and Pichi20, Reference Achim, Bolognone, Palmer, Graville, Light and Li21 Our experience also showed that the functional swallowing outcome was no different clinically between the overall Oncology and Surgery groups at more than two years (Figure 2). The post-treatment FOIS scores were 6.3 and 6.55, respectively, and our results support the findings from the previous studies that there is no difference in the functional swallowing outcomes between the two groups.Reference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran11, Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16, Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18, Reference Campo, Iocca, De, Mazzola, Mercante and Pichi20, Reference Achim, Bolognone, Palmer, Graville, Light and Li21
All studies assessing oncological and functional outcomes of TORS have treated the Surgery group as a single cohort, despite the existence of three distinct subgroups: Surgery alone, Surgery plus aRT and Surgery plus aCRT.Reference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran11, Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16, Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18, Reference Campo, Iocca, De, Mazzola, Mercante and Pichi20, Reference Achim, Bolognone, Palmer, Graville, Light and Li21 This is relevant as the current trend is on treatment de-escalation for early-stage OPSCC patients, trying to minimise treatment-related patient morbidity. The Surgery-only subgroup, and the Surgery plus reduced-dose aRT subgroup, reflect the true treatment de-escalation population, whereas the Surgery plus aCRT subgroup does not, and centres try to avoid this treatment escalation.
By analysing the distinct subgroups within the Surgery group, we gained valuable insights. Although the sample size is small, the Surgery-only subgroup (n = 6) was the only group in our entire cohort that showed no decline in swallowing function at more than two years with post-treatment FOIS scores remaining at 7 (median follow-up 5.04 years; range 2.92–5.42 years) (Figure 2). In contrast, patients who received triple therapy (TORS + ipsilateral neck dissection + aCRT) (n = 15) had the poorest swallowing outcome at more than two years (Figure 2). Four patients in our cohort were randomised to Arm B2 of the PATHOS trial and received a reduced aRT dose of 50 Gy in 25 fractions.Reference Owadally, Hurt, Timmins, Parsons, Townsend and Patterson7 Their pre-treatment FOIS scores were 7, and post-treatment scores 5, 6, 7 and 7, respectively (median follow-up 4.8 years; range 2.25–5.25 years). In our cohort, the swallow outcome between patient subgroups within the Oncology group who received unilateral treatment and those who received bilateral treatment did not differ (Figure 2).
It is expected that patients undergoing Surgery-only would have the best functional outcomes, as they avoid the toxicity associated with radiotherapy whilst benefiting from minimally invasive TORS. Conversely, those receiving triple therapy had the worst outcomes, likely due to treatment escalation and unnecessary surgery, which could have been avoided with primary pRT/pCRT. By combining these surgery cohort subgroups, the overall swallow outcomes are comparable to the Oncology group (Figure 2).
True treatment de-escalation would mean minimising patient morbidity whilst not compromising the patients’ oncological outcome. Our data and the current literatureReference Yeh, Tam, Fung, MacNeil, Yoo and Winquist6, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10, Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran11, Reference de Almeida, Byrd, Wu, Stucken, Duvvuri and Goldstein16, Reference Amin, Philips, Bertoni, Mastrolonardo, Campbell and Agarwal18, Reference Campo, Iocca, De, Mazzola, Mercante and Pichi20, Reference Achim, Bolognone, Palmer, Graville, Light and Li21 show that there is no difference in the oncological outcome between the Oncology group and the Surgery group, if the subgroups are not analysed individually (Table 2A). However, it is the Surgery-only subgroup, and also the Surgery plus reduced aRT subgroup, that need to be scrutinised. In our cohort, the number is very small to have any meaning (n = 6); however, it is encouraging to see that five patients in this subgroup had five-year DFS and OS available, which were both 100 per cent (Table 2B). The sixth patient in this subgroup has been followed up for 3.5 years and remains disease-free to date. Four patients who received reduced aRT following their Surgery all remain disease-free to date, with three patients having follow up of more than five years, one patient followed up for more than five years and one patient for 2.9 years.
One alarming finding from the ORATOR study was the safety profile of TORS.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 They reported a higher than previously-reported post-TORS bleed rate of 12 per cent, and worse, one patient experienced death caused by post-TORS bleed.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 Following this mortality, the recommendation of an elective tracheostomy at the time of the surgery was newly introduced.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran10 This could be considered an unacceptable risk considering the existence of IMRT. A recent systematic review has shown the post-TORS bleed rate to be 8.8–10.7 per cent.Reference Poupore, Chen, Nguyen, Nathan and Newman22 In our cohort, the post-TORS bleed rate was 9 per cent (n = 4/44). Furthermore, no patients had tracheostomy at any point, and no patients died in our Surgery group.
We acknowledge that this study presents a relatively small dataset from a single-centre retrospective observational study. However, it offers unique insights into the oncological and functional outcomes of the surgical subgroups, which are often under-represented in the literature. The primary oncological outcome measures were two-year DFS and OS rates, given the most recurrences in HPV-positive OPSCC occur within this timeframe.Reference Cracchiolo, Baxi, Morris, Ganly, Patel and Cohen4 Nonetheless, assessing five-year DFS and OS rates would be ideal for a more comprehensive evaluation.
For functional swallowing outcomes, we used the FOIS score measured beyond two years post-treatment. However, as a retrospective study, the timing of FOIS assessments was inconsistent across patients. A more accurate evaluation of long-term swallowing outcomes would require a 5- or 10-year endpoint to account for the delayed toxic effects of radiotherapy.Reference King, Dunlap, Tennant and Pitts23–Reference Tengku, Lohi, Connelly, Slaven, Sloane and Herity25 Current endpoints of one to two years are insufficient to capture the long-term impact on swallowing function.Reference King, Dunlap, Tennant and Pitts23–Reference Tengku, Lohi, Connelly, Slaven, Sloane and Herity25
Additionally, since this is not a randomised controlled trial, there is inherent bias in patient selection. Nonetheless, we believe our study provides a valuable real-world experience in treating early-stage HPV-positive OPSCC, and we hope to provide insights that may guide the design of future randomised controlled trials for more robust conclusions.
• With the increased availability of minimal-access transoral approaches, there has been a shift towards offering patients upfront surgery for early-stage HPV positive oropharyngeal squamous cell carcinoma (OPSCC) to avoid the potential toxicities of radiotherapy/chemoradiotherapy (pRT/pCRT)
• However, current literature had shown the functional swallowing outcomes to be no different between TORS and pRT/pCRT for early-stage HPV positive OPSCC
• In our experience, although the overall functional outcomes were similar between the T1-2 N0-1 (TNM v8) p16-positive OPSCC patient group treated with TORS and the patient group treated with pRT/pCRT, subgroup analyses had shown patients treated with surgery-only with no adjuvant treatment had the best functional outcome without compromised oncological outcome whilst patients treated with surgery followed by post-operative chemoradiotherapy had the worst functional outcome
• Although our sample size is limited and no definitive conclusions can be drawn, our data support the hypothesis that surgery alone without adjuvant treatment leads to better functional outcomes
• Ongoing trials such as PATHOS will provide a definitive answer on this topic in the future
Conclusion
Our experience suggests that, with careful patient selection, oncological and functional swallowing outcomes at two years post-treatment are comparable between T1-2 N0-1 p16-positive OPSCC patients treated with TORS plus neck dissection plus adjuvant treatment and those treated with primary radiotherapy with or without chemotherapy. The critical question remains whether surgery alone, or surgery with reduced adjuvant radiotherapy doses could lead to better long-term outcomes. Although our sample size is limited and no definitive conclusions can be drawn, our data support the hypothesis that surgery-alone without adjuvant treatment leads to better functional outcomes. The ongoing PATHOS trial data will provide a definitive answer on this topic in the future.Reference Owadally, Hurt, Timmins, Parsons, Townsend and Patterson7
Acknowledgement
Chang Woo Lee is currently a Royal College of Surgeons of England Surgical Research Fellow.
Conflict of interest disclosure
None to declare.
Funding
None.
Authorship
C.W.L., W.J., F.H., O.D. and E.V.K. were involved with the conception and design of the study. All authors were involved with the acquisition and analysis of data. C.W.L., W.J., R.N., A.D., S.S. and F.H. were involved with the drafting of the article. M.F., J.D., O.D., J.B., N.D.Z. and E.V.K. gave critical revision. All authors approved the final manuscript.
