Sentinel node biopsy versus elective neck dissection. Which is more cost-effective? A prospective observational study

Accepted Manuscript Sentinel node biopsy versus elective neck dissection. Which is more cost-effective? A prospective observational study Josue Hernando, Pedro Villarreal, Francisco Álvarez-Marcos, Luis García Consuegra, Lorena Gallego, Luis Junquera PII:

S1010-5182(16)00031-7

DOI:

10.1016/j.jcms.2016.01.017

Reference:

YJCMS 2289

To appear in:

Journal of Cranio-Maxillo-Facial Surgery

Received Date: 23 September 2015 Revised Date:

14 January 2016

Accepted Date: 26 January 2016

Please cite this article as: Hernando J, Villarreal P, Álvarez-Marcos F, Consuegra LG, Gallego L, Junquera L, Sentinel node biopsy versus elective neck dissection. Which is more cost-effective? A prospective observational study, Journal of Cranio-Maxillofacial Surgery (2016), doi: 10.1016/ j.jcms.2016.01.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title. Sentinel node biopsy versus elective neck dissection. Which is more cost-effective? A prospective observational study.

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Author names and affiliations.

Josue Hernandoa, Pedro Villarrealb, Francisco Álvarez-Marcosc, Luis GarcíaConsuegrad, Lorena Gallegod, Luis Junquerad

Spain.

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a Department of Oral and Maxillofacial Surgery, Donostia Hospital. San Sebastian, b Oral and Maxillofacial Surgery. Private Practice. Oviedo, Spain c Department of

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Surgery. Central Hospital. Oviedo, Spain

d Department of Oral and Maxillofacial Surgery. Oviedo University, Central Hospital. Oviedo, Spain Corresponding author.

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Josué Hernando

Oral and Maxillofacial Surgery Department. Donostia Hospital. Dr. Beguiristain St, San Sebastián (Spain)

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[email protected]

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Telephone No. +34 675 82 54 82

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INTRODUCTION The oral cavity is one of the most common locations of head and neck primary

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malignancies. Of those, 90% are squamous cell carcinomas (Capote et al. 2007). The most important independent prognostic factor for this type of tumour is the presence of

metastasis in the cervical lymph nodes. Survival is reduced by 50% when there are neck

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metastases, thus adequately diagnosing and treating the neck is of great importance

(Sloan, 2009). In locally advanced disease (T3-T4) or in presence of positive lymph

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nodes (N+), neck dissection is the elective treatment for initial management of the neck (Omura, 2014). However, controversy exists in literature as to early stages (I-II), with clinically negative neck. The risk of occult metastasis during these stages is of 15- 25%, which means that 75-85% of the patients could be receiving an unnecessary neck dissection (Thompson et al., 2008; Melkane A et al., 2012; D’Cruz et al., 2015). Sentinel

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node biopsy (SNB) is nowadays considered as an alternative to elective neck dissection (END) for cervical staging in oral squamous cell carcinoma (OSCC) in stages I-II (Ross et al., 2002; Kuriakose and Trivedi, 2009; Civantos et al., 2010; Broglie et al., 2011).

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American and European multicentre studies have shown SNB to have a high accuracy for

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detecting occult cervical metastases (Alkureishi et al., 2010; Civantos et al., 2010). Identification indexes for sentinel nodes (SN) in OSCC are comparable with other diseases (melanoma and breast cancer), where the SNB is a routine procedure (Morton et al., 2005; Zavagno et al., 2008). Currently, few studies have researched about the economic impact of clinical use of the SNB in OSCC (Govers et al., 2013; O’Connor et al., 2013). O'Connor et al. (2013) conducted a study with patients taking part in the European Sentinel Node Biopsy Trial

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Protocol (SENT trial) and their results suggested that SNB is cheaper than the traditional neck treatment.

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The present study had two objectives: to analyse oncologic safety by comparing neck disease control and survival rates and to assess the relative cost of both staging

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procedures in early OSCC.

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MATERIAL AND METHODS

A prospective not randomized observational study was carried out on 73 patients with OSCC who underwent surgery between 2005-2009, performed by two single surgeons of the same Department of Oral and Maxillofacial Surgery of a tertiary hospital. Patients

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were included in the study consecutively. Clinical stage was determined by computed tomography (CT) and palpation. Eligible patients had 0.5 to 4 cm squamous cell carcinoma with N0 neck on CT (<1 cm or up to 1.5 cm in level II and no atypical

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features) +/- fine needle aspiration cytology. Patients with previous malignant head and neck neoplasm or any disease that might have altered lymphatic drainage were excluded.

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Two types of cervical treatments were assigned: SNB or END. The treatment choice was made by the patients themselves upon receiving detailed information of the advantages and disadvantages of both suggested treatment types. The study was approved by the Ethics Committee of the Principality of Asturias (Spain). When managing the SNB group patients, the SENT trial protocol was followed (Ross et al. 2004). All patients underwent a lymphoscintigraphy (LG) 2 hours prior to the surgery,

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in order to identify the SN. A Tc-99m-marked nanocolloid (Nanocoll/Nanocis®) was injected according to a standardized technique in 4 different points surrounding the tumour. A dynamic study of the first 10 minutes post-injection was conducted; afterwards

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images where obtained at 10-minute intervals during the following 120 minutes. The

position of the nodes was marked on the neck. After resecting the primary tumour, the sentinel node was identified in the neck using a portable gamma probe (Europrobe®).

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The resected sentinel nodes where fixed in 10% neutral buffered formalin. Five serial

sections were cut every 150 µm through the block, and one from the centre of each series

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was stained with haematoxylin and eosin (H-E). In case of metastases had not yet being detected, an adjacent section of each node was marked with anti-pan cytokeratin antibody AE1/AE3 (Dako Corporation, Carpinteria, CA, USA). Patients with positive nodes underwent a neck dissection of levels I-V, over a period of less than one month after the

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first surgery.

A neck dissection of levels I-III was carried out in the END group. The END was uni- or bilateral depending on whether the tumour compromised the midline. Positive lymph

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nodes were identified by standard protocol with H-E (Shah and Andersen, 1994).

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The criteria followed to administer postoperative radiation therapy were: the presence of positive margins after tumour resection, presence of more than one lymph node with neoplastic infiltration or presence of extracapsular spread. Previous cervical treatment, allergies to components of the radiotracer or pregnancy are exclusion criteria for participation in the study. All patients completed a personalized informed consent form.

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Clinical assessment In both groups the variables studied included socio-demographic data (age and gender)

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and the patients' follow-up (months). Log-rank test was used to compare disease-free survival (DFS) and overall survival (OS) between SNB and END groups. Surgical time (ST) (min) quantified the time invested in tumour resection and in cervical surgery.

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Hospital stay (HS) was measured in days. Recurrence rate and false negatives were

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assessed.

Cost information

The cost analysis was performed from a societal perspective. In order to approximately

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compare the costs between SNB and END, a spreadsheet adapted to our patient sample was prepared. Information regarding possible local and distant recurrences was excluded, as it was not related to the used cervical technique.

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The items collected for the SNB group were: scintigraphy, ST, HS, use of gamma probe and pathology analysis. In the event of a positive SN, economic variables arising from the

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neck dissection were collected, including radiotherapy if it had been required. In patients with neck recurrences, the costs of the surgery and/or radiotherapy (if applicable) were included.

For the END group, the following cost variables were analysed: ST, HS, histopathological analysis and reanimation unit admission. Radiation therapy would be included when indicated. In the event of a neck recurrence, the costs derived from

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subsequent surgical treatment and/or radiotherapy would be included Time data were obtained with the average for patients of each group. Volumes for

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hospital stay after the neck dissection were derived from the Hospital’s financial department. Volumes for histological study, specific techniques for SNB and

radiotherapy treatment were obtained by financial data from the specific departments

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involved. Academic unit costs were used for hospital days. Only direct costs derived

were included. Absenteeism, consultation, and physical therapy derived from SNB or

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END were not evaluated.

Statistical analysis

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The statistical analyses were performed using SPSS version 20.0 software (IBM Corp., Armonk, NY, USA). The Student’s t-test was used to compare the results of ST and HS. Log-rank test was used to compare DFS and OS between the SNB and END groups.

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Kaplan-Meier survival curves were obtained. P- values of <0.05 were considered

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statistically significant.

RESULTS

Seventy-three patients were included in our study. Table 1 shows the characteristics of patients in both treatment groups. Average age was 66.4 years (range 40-90) and the average follow-up was at 48.2 months (range 7- 70months). The average ST in SNB was

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of 120 min (range 80-280 min) and 240 min (range 180-360 min) in the END group (p=0.001). The average HS for the SNB was of 7.2 days (range 4-12) and 11 days in the END group (range 7-18) (p=0.001). The average resected SN was of 2.0 (range 1-4

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nodes). No SNs were identified in level IIb for SNB patients. Three patients of the SNB group showed metastases in the SN (9.4%), two of them in level I and the other one in level IIa. Three weeks later an END was performed. In one of those nodes with

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extracapsular invasion was identified, thus requiring postoperative radiation therapy. The patient died due to a cervical recurrence 10 months later. Twenty SN were analysed in

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floor of mouth patients. One node (IB level) was positive for malignancy. Most nodes were located in the IB (10), IA (5) and IIA (4). A SN was found in level IV. There were no problems to identify the SNs. All cervical surgeries of the END group included levels I-III (including level IIb). Four patients from the END group showed positive nodes

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(9.7%) (all of them in levels I and II). No extracapsular spread or metastases were identified in level IIb. Five cervical recurrences developed in the SNB group (range 1121), and 7 in the END group (range 9-16). In patients with pathologically node negative

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(pN0) the index of false negative was of 10.3% in the SNB group and 13.5% in the END group (p=0.65). Six patients died of tumour recurrence in the SNB group. Nine deaths

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were recorded in the END group, all but 3 were due to tumour relapse. Follow-up and patient outcomes from both groups are detailed in Figures 1 and 2. The Kaplan-Meier analysis seemed to show similar regional DFS in both groups, without statistically significant differences (log-rank=0.114, p=0.736). The OS analysis showed no significant differences between both groups (log-rank= 0.180, p=0.671) (Fig. 3). Tables 2 and 3 shows the incurred cost by each of the items of the techniques in their

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possible outcomes. Table 4 shows the absolute value for each type of patient. For this model, outcomes were only taken into account by means of a cervical recurrence. The pN0 patients with a favourable progress incurred in 42% less costs in the SNB group.

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This category was the most frequent for each group (81.3% in SNB group and 78.0% in END group). The costs incurred in patients with false negatives, regardless of the need of radiotherapy or not, was also lower in the SNB group. Patients with histologically

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positive lymph nodes (pN+) generated 33% more costs in the SNB group, although it

entailed a very low percentage of the patients (3.1% and 4.8% respectively). Finally, pN+

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patients who later developed a cervical recurrence incurred in 17% more costs in the SNB group. This subgroup consisted of 6.25% of patients in the SNB group and 4.8% in the

DISCUSSION

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END group.

Nowadays, SNB procedure has a high level of evidence for staging of early stage oral

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squamous cell carcinomas (Antonio et al., 2012; Melkane et al., 2012; Broglie et al.,

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2013; Chung et al., 2015; Hernando et al., 2014). Thompson et al. (2013) published a meta-analysis where they showed sensitivity and negative predictive value for squamous cell oral carcinoma of 94% and 96%, respectively. Out of our work in 32 patients, the SNB detected metastasis in 3 of them. Three pN0 patients later developed a cervical recurrence and were considered a false negative. In OSCC, multiple SNs are usually present, with reported mean numbers of 1.3 to 4 (range 1-11) (Werner et al., 2004). Atula et al. (2008) concluded that it seemed sufficient

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to harvest three of the hottest SNs. In the present study, the average number of SN resected was 2.0 (range 1-4). Three cases presented only one SN identified in LS and

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intraoperatively. None of these patients presented neck relapses during follow-up. SNB, especially in OSCC with tumours of the floor of the mouth (FOM), can be masked due to the close proximity of the injected radiocolloid and the first draining lymph node

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(shine-through phenomenon), which leads to inferior detection rates (Civantos et al., 2010). In FOM cancer it is suggested that the primary tumour is excised before

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performing SNB, in order to reduce the shine-through phenomenon as radioactivity at the primary site may obscure SN located at I first neck level (Vigili et al., 2007). Preoperatively, this limitation may be overcome by the use of single-photon computed tomography/CT (SPECT/CT), which provides higher detection rates and better morphological information (Wagner et al., 2013; Bluemel et al., 2014). However, the

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advantages of SPECT/CT cannot be transferred to the operating room. Intraoperatively, SNB are usually detected using a hand-held acoustic gamma probe. More recently, freehand SPECT (fhSPECT) was introduced for navigational surgery, combining the

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acoustic information of a conventional gamma probe and intraoperative 3-D images with

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real-time visualization of radiotracer distribution within the surgical field. FhSPECT measures the depth of the hotspot within the region o he hotspot within the region of interest to permit navigated surgery (Schilling et al., 2014; Bluemel et al., 2014). In our study, nine patients presented floor of mouth carcinoma in the SNB group. Twenty sentinel nodes were analysed in these patients. One node (IB level) was positive for malignancy. Most nodes were located in the IB (10), IA (5) and IIA (4) levels. A sentinel node was found at level IV. There were no problems to identify the SNs. Metastasis to

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interpositional lymph nodes are referred to as lateral lingual lymph node metastasis when the primary disease affects the tongue, or paramandibular lymph node metastasis when primary disease affects the floor of mouth. They occur when cervical lymph node

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metastasis does not go through level I or II (Han et al., 2008). In this case it is necessary to identify the SN before resection of the primary tumour. The treatment of metastasis to interpositional lymph nodes in floor of mouth carcinoma may require a pull-through

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operation. However, since these lymph nodes are located around the floor of mouth,

identification is difficult due to shine through when using a conventional tracer, which

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may explain the failure to identify these SNs. This may be solved by inserting a lead board in the oral cavity in a scintigraphy scan, but a complete solution to shine through is still required.

Civantos et al. (2010) presented a 26% of occult metastases with a 10% of recurrence in

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their multicenter study. The difference with our work could be due to minor technical refinement acquired with experience. A learning curve for the SNB technique has been established, where sensitivity is increased after 10 treated cases (Morton et al., 1999). It

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also could be due to the inclusion in our study of patients with lip carcinoma, who present

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a lower index of occult metastases. Squamous cell carcinoma is the most common histologic type of lip cancer, usually develops slowly, and presents loco-regional cervical lymph node metastasis in 3-29% of patients (McGregor et al., 1992; Luna-Ortiz et al., 2004; Salgarelli et al., 2009). The management of the cN0 neck in lip cancer is controversial. Whereas some researchers propose a ‘wait and see’ strategy (Califano et al., 1994; Zitsch et al., 1999), others recommend neck dissection in most cases (Medina and Byers, 1989; Bucur and Stefanescu, 2004). Wermker et al. (2015) revealed tumour

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extent, tumour depth and grading as the most important prediction factors for neck recurrence in a large retrospective study. SNB may be relevant in neck treatment of middle line lip cancer patients that may suffer unnecessary morbidity derived from END.

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Otherwise, one major advantage of SNB compared with END is that it reveals

unexpected individual lymphatic drainage, such as that to the contralateral neck. Four lower lip carcinoma patients in each group were recruited in the present study. No

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positive nodes were observed and no neck relapses in follow-up period were identified

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(range 50-70 months) in either group.

A systematic review of 109 studies showed a 13% of cervical recurrences in squamous cell oral carcinomas in stages I-II treated with END (Brown et al., 2012). In the present study, the cervical recurrence index was similar to the SNB group and the END group (15.6% and 17%, respectively). Some potential limitations of our study should be

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discussed. First, we used a relatively small sample and low frequency of cervical metastasis was identified in both treatment groups. Second, histologic protocol regarding lymph nodes used in both groups is different. END pathology is based on inspection-

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palpation-individualization sequence of lymph node and H-E analysis. Although the

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prevalence of occult metastases in nonsentinel lymph nodes after additional step-serial sectioning and immunohistochemistry in cN0 OSCC is low, Christensen et al. (2011) observed 2% patients with tumoral deposits in nonsentinel nodes. The total number of lymph nodes to be found in the human neck is poorly described in the literature (Atula et al., 2009; Christensen et al., 2011). A minimum of six lymph nodes or more is stated to be expected in a selective neck dissection. When assessing the accuracy of SNB with neck dissection as reference, the reliability is based on the assumption that all lymph

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nodes in the defined levels are removed. This again depends on the skills of the surgeon to localize lymph nodes during surgery and the ability of the pathologist to dissect and identify lymph nodes in the neck specimen. In our material the median number of lymph

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nodes removed was 19 per neck-side after selective neck dissection, although with a

substantial range of 9–28 lymph nodes between different patients. Third, patients were not randomly assigned to the SNB and END groups, which could cause a certain

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selection bias. At the time our study began, there was no clear evidence of the advantages of SNB and END was considered the standard neck staging tool in cN0 OSCC. To avoid

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ethical conflict, treatment choice was made by patients themselves after having been offered detailed information of the advantages and disadvantages of both neck staging tools. Fourth, the cost analysis was performed from a societal perspective. In our study only the direct costs of the two techniques were analysed.

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Specific forms of analysis reflect different approaches to evaluating the consequences of health interventions. Health consequences may be estimated from a single analytic (experimental or nonexperimental) study, a synthesis of studies, mathematical modelling,

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or a combination of modelling and study information. Cost-consequences analyses

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examine costs and consequences, without attempting to isolate a single consequence or aggregate consequences into a single measure. In cost minimization analysis, the consequences of compared interventions are required to be equivalent and only relative costs are compared. Cost-effectiveness analysis measures consequences in natural units, such as life-years gained, disability days avoided, or cases detected. In a variant of costeffectiveness analysis measures, often called cost-utility analysis, consequences are measured in terms of preference-based measures of health, such as quality-adjusted life-

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years, or disability-adjusted life years. Finally, in cost-benefit analysis, consequences are valued in monetary units (Husereau et al., 2013).

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Comparison of inherent costs in the application of either staging technique is a complex task, subject to variations depending on the hospital, country, and evolving healthcare policies. Even within our field, information about the cost of particular procedures or

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admissions varied according to the consulted sources. Therefore, the purpose of this study was only limited to the search for a preliminary vision, as objective as possible, about

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cost differences. Independently of the individual value ascribable to each concept (admission to reanimation, operating room per hour, etc.), which is subject to wide variation, but also due to the uniformity of the common application of both procedures, a main and expected conclusion can be drawn: for the majority of the patients, carrying out a SNB is more cost-efficient than the END. However, when there is a positive result for

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malignancy in the sentinel node, the resources devoted to the SNB exceed those committed to the END. To our knowledge, there is little information in the literature about the cost comparison between both forms of evaluation for cervical state in oral

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carcinomas considered free of node metastasis prior to surgery. Kovacs et al. (2004)

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approximately compared two treatment models: computed tomography plus supraomohyoid neck dissection versus positron emission tomography plus SNB. Their results showed a higher cost ratio for the second model, though with clear benefit to the patients.

Other authors deal exclusively with the genuine costs deriving from the SNB technique, which depend on the lymphoscintigraphy and the immunohistochemistry study techniques required to analyse SN (Ferlito et al., 2006). Payoux et al. (2005) pointed out

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the economic benefits arising from the use of SNB and mentioned a Japanese study where the cost reduction is justified with the decrease in the number of performed dissections, thus reducing their inherent cost. Kosuda et al. (2003) assessed differences in

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costs between both procedures according to the number of hours of surgery each of them requires (taking into account surgeons, anaesthetists, nurses, etc.), adding more 3 hours to the END period. The work esteemed from the histopathological and

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lymphoscintigraphical study of the SNB resulted in an average time of 60 minutes. After converting the value of their analysis into dollars (120 yen = 1 dollar), they concluded

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that saving in Japan after implementing SNB to a histologically negative patient is of 1165 dollars, with the same survival period than with the elective neck dissection. Recently, O’Connor et al. (2013) conducted a study with data pertaining to the European multicenter study on SNB which yielded similar results to our work. When the obtained

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result was a true negative (SN negative without relapse during follow-up) using SNB is more cost effective. Nevertheless, patients in stage II generated the most costs due to the fact that all those who had undergone reconstructive microsurgery had been included

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which, evidently, increased the costs. Absolute economic values differ from ours because they represent a high degree of variability depending on the source for consultation.

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Govers et al. (2013) compared several treatment options in patients with stage II oral carcinoma. These authors concluded that the SNB is the most effective option from the economic point of view, compared to molecular techniques (gene expression profiling) or the traditional way.

CONCLUSION

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This is the first study that compares the economic performance in patients operated in a single institution following the same treatment protocols. With limitations arising from the small sample size and observational character of cost data, but with an adequate

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follow-up period, it might be concluded that despite both groups in the comparison

presenting a similar prognosis, the SNB appeared to be more cost effective when the

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relapse, END ensures a cost reduction.

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patient showed a favourable course without neck relapses. In the event of a regional

Previusly presented at Oral communication at Spanish Society of Oral and Maxillofacial Surgeons Congress, Oviedo, 4th-5th 2015.

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Comercial interest disclosure. None.

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Conflicts of interest. None

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carcinoma of the lip. Head Neck 21: 447e453, 1999

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Fig. 1. Follow-up and patients outcomes in sentinel node biopsy group. SNB: sentinel node biopsy; SN+: positive sentinel node; ECS: extracapsular spread; SN-: negative sentinel node; FND: functional neck dissection; RT: radiotherapy; NR: neck recurrence;

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LR: local recurrence; SS: salvage surgery; DD: dead of disease; NED: no evidence of

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disease.

Fig. 2. Follow-up and patients outcomes in elective neck dissection group. END: elective

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neck dissection; pN+: positive nodes; pN0: no positive nodes; RT: radiotherapy; NR: neck recurrence; LR: local recurrence: PM: positive margins. DD: dead of disease; DOC:

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dead of other cause; NED: no evidence of disease.

Fig. 3. Survival analysis, showing no significant difference between groups for diseasefree survival (log-rank=0.114, p=0.736). Elective neck dissection did not demonstrate

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different overall survival compared with sentinel node biopsy (log-rank=0.180; p=0.671).

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Characteristics

ENDb

65.8 (45-81)

66.7 (40-90)

Male Female

23 9

28 13

Tongue Floor of mouth Lower gum Palate Retromolar Trigone Buccal mucosa Lower lip

14 9 3 0 0 2 4

Localization

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Sex

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Age

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SNBa

T1 17 T2 15 a: sentinel node biopsy; b: elective neck dissection.

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T Classification

1

18 9 2 3 1 4 4

19 22

ACCEPTED MANUSCRIPT Table 2. SNB group. Pathway cost.

ST

Min: 120

€a 116,00 732,50

HS

Days: 7.2

6853,00

Time Scintigraphy SNBb

patients

176,00 3178,00 Min: 185 1373,25 STd e HS Days: 9 8811,00 c SN (+) Pathology 1658,00 Intensive care unit stay Days:1 3955,00 Postoperative radiotherapy 1900,00 d ST Min: 200 1526,05 e HS Days: 11 10769,00 Neck Intensive care unit stay Days: 1 3955,00 recurrence Pathology 1658,00 Postoperative radiotherapy 1900,00 a: euros; b: Sentinel node biopsy; c: positive sentinel node; d: surgical time; e: hospital stay.

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ACCEPTED MANUSCRIPT Table 3. END group. Pathway cost. Time Min: 240

HSd

Days: 11

10769,00

Intensive care unit stay Postoperative radiotherapy

Days: 1

3955,00 1900,00

2763,7 STc Min: 205 1564,20 HSd Days: 13 12727,00 Neck Pathology 1658,00 Recurrence Intensive care unit stay Days: 1 3955,00 Postoperative radiotherapy 1900,00 a: euros; b: elective neck dissection; c: surgery time; d: hospital stay.

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ENDb patients

STc

€a 1831,25

3

ACCEPTED MANUSCRIPT Table 4. Related cost by outcome. Neck surgery (€a) SNBc ENDd 11368,57

19466,95

pN0b+Neck recurrence

29276,57

39971,15

31176,57

41271,15

29065,82 pN(+)e RTf

30965,82 46973,82

pN(+)e+Neck recurrence

RTf

48873,82

21366,79

39371,15

41271,15

euros; b: negative limph nodes; c: sentinel node biopsy; d: elective neck dissection; e: positive node; f: radiotherapy.

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a:

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RTf

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pN0b

4

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