Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

Vanessa Milani; Ana Laura de Sene Amâncio Zara; Everton Nunes da Silva; Larissa Barbosa Cardoso; Maria Paula Curado; Rejane Faria Ribeiro-Rotta

doi:10.1371/journal.pone.0246475

. 2021 Feb 17;16(2):e0246475. doi: 10.1371/journal.pone.0246475

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

Vanessa Milani ^1,^#, Ana Laura de Sene Amâncio Zara ^1,^#, Everton Nunes da Silva ^2,^‡, Larissa Barbosa Cardoso ^3,^‡, Maria Paula Curado ^4,^‡, Rejane Faria Ribeiro-Rotta ^1,^*,^#

Editor: Gabriel A Picone⁵

PMCID: PMC7888595 PMID: 33596233

Abstract

The efficiency of public policies includes the measurement of the health resources used and their associated costs. There is a lack of studies evaluating the economic impact of oral cancer (OC). This study aims to estimate the healthcare costs of OC in Brazil from 2008 to 2016. This is a partial economic evaluation using the gross costing top-down method, considering the direct healthcare costs related to outpatients, inpatients, intensive care units, and the number of procedures, from the perspective of the public health sector. The data were extracted from the Outpatient and Inpatient Information System of the National Health System, by diagnosis according to the 10^th Revision of the International Classification of Diseases, according to sites of interest: C00 to C06, C09 and C10. The values were adjusted for annual accumulated inflation and expressed in 2018 I$ (1 I$ = R$2,044). Expenditure on OC healthcare in Brazil was I$495.6 million, which was composed of 50.8% (I$251.6 million) outpatient and 49.2% (I$244.0 million) inpatient healthcare. About 177,317 admissions and 6,224,236 outpatient procedures were registered. Chemotherapy and radiotherapy comprised the largest number of procedures (88.8%) and costs (94.9%). Most of the costs were spent on people over 50 years old (72.9%) and on males (75.6%). Direct healthcare costs in Brazil for OC are substantial. Outpatient procedures were responsible for the highest total cost; however, inpatient procedures had a higher cost per procedure. Men over 50 years old consumed most of the cost and procedures for OC. The oropharynx and tongue were the sites with the highest expenditure. Further studies are needed to investigate the cost per individual, as well as direct non-medical and indirect costs of OC.

Introduction

Oral cancer (OC) is a term used to classify a comprehensive group of neoplasms that can affect the lip, oral cavity, and oropharynx. OC is a current issue worldwide. Inequalities in the access to diagnostic and treatment services aggravate the prognosis and compromise the survival of individuals affected by this disease, especially in lower middle- and upper middle-income countries, including most of the countries in South America, such as Argentina, Bolivia, Colombia, Peru and Brazil. In Brazil, around 15,190 new OC cases are estimated for 2021, making it the fifth most frequent cancer in men and the thirteenth in women, with incidence rates that increase with age, reaching a peak between 60 and 70 years old [1–7].

The world’s demographic transition calls attention to the increase in noncommunicable diseases, such as OC, as it has a direct impact on the budget planning of health care [8]. The search for efficiency of public policies includes measurement of the health resources used and their associated costs [9]. Despite this, there is a large gap in the scientific literature in terms of studies evaluating the economic impact of OC [2].

Cost-of-illness studies on OC have gained increasing importance, since despite its low incidence this disease is often detected in advanced stages, when treatment is more complex and costlier. OC has been considered a disease with high mortality rates and high economic and social impact [10–12]. In the United Kingdom, the cost of treating an individual with OC can range from U$3,343 (I$6,133) in the early stages to U$24,890 (I$45,664) in advanced stages [13].

A cost-of-illness study on OC would be important to draw the attention of managers to the need for more assertive strategies, aimed at prevention, focusing on risk factors and detection of OC in the early stages, in order to reverse the current status: advanced disease as the most frequent diagnosis.

This study aims to estimate healthcare costs related to lip cancer (LC), oral cavity cancer (OCC) and oropharyngeal region cancer (OPC) in Brazil from 2008 to 2016.

Materials and methods

Study design

We conducted a prevalence-based cost-of-illness study from the perspective of the public healthcare system (Ministry of Health), with a top-down approach, from January 2008 to December 2016. We defined prevalence-based as all OC patients were included, regardless of the level of severity or onset of the disease. A top-down approach was used because our estimates consist of allocating total national health care expenditures by type of care (inpatient and outpatient) among the OC sites by using the ICD-10 codes for each site of OC (i.e. we identified the portions of the total health expenditure due to OC sites).

All codes related to OC according to the 10^th Revision of the International Classification of Disease [ICD-10]) were included. Three anatomical regions were considered, as follows: lip (C00—malignant neoplasm of the lip), oral cavity (C02—malignant neoplasm of other and unspecified parts of the tongue, C03—malignant neoplasm of the gums, C04—malignant neoplasm of the floor of the mouth, C05—malignant neoplasm of the palate, and C06—malignant neoplasm of other and unspecified parts of the mouth) and the oropharyngeal region (C01—malignant neoplasm of the base of the tongue, C09—malignant neoplasm of the tonsil, and C10—malignant neoplasm of the oropharynx) [14].

Brazilian health system

Brazil has the largest territorial extension of Latin America, made up of 27 Federation Units, subdivided into five regions (North, Northeast, South, Southeast and Midwest). The Brazilian population is covered by a Unified Health System popularly called SUS, which is the official Brazilian health system, in force since 1988. This system is based on the principles of universality, equity and integrality to provide full access to health at all levels of care, and considers health as a fundamental human right of the human being, which must be guaranteed by the State. About 167 million people, 80% of the Brazilian population, depend exclusively on SUS for healthcare assistance [15].

Data sources

Two important Brazilian health information systems are the Inpatient Information System (SIH-SUS) and the Outpatient Information System (SIA-SUS), tools used to record all hospitalisation and outpatient information, respectively, within the scope of SUS. Health facilities (hospitals, urgent care, clinics, pharmacies, etc.) included all procedures delivered to a patient during an outpatient or inpatient after his/her discharge, including health workers services. Each procedure is valued based on a fixed value defined by the Ministry of Health of Brazil. The sum of all procedures during as an outpatient or inpatient is sent to the Ministry of Health by means of reimbursement. On this basis, it represents the actual amount reimbursed to the health care providers for each outpatient procedure or inpatient stay. It is worth noting that each patient may have a different combination of procedures depending on disease severity.

Both systems use the ICD-10 and were conceived and implemented, initially, as a means of administrative financial control for the payment of services hired by SUS [16]. Despite this, these systems bring together demographic, geographic and diagnostic information and the consumption of healthcare resources for millions of users, at a low operating cost, which increases the possibilities for use in health evaluation, research, planning and management, besides providing information on the epidemiological profile of the population and the place of origin and care [16,17].

Data analysis

The data were extracted and processed using Tab Win^® software, version 4.15, an open access data tab, from the public health system. The expenses were classified by year (2008–2016), OC site (LC, OCC, OPC), outpatient and inpatient unit, sex (male or female), age group (≤ 40 years, 41–50 years, 51–60 years, 61–70 years, and > 70 years) and Brazilian region. Individual patient data were not available, and the expenses were aggregated and associated with the inpatient/outpatient admission documents.

For inpatient care expenses, the following direct healthcare costs were obtained: hospitalisation (e.g. daily rate, room fees, food, personal hygiene, bed support, hospital supplies, allied healthcare professional service costs, medications, and diagnostic and therapeutic auxiliary services), medical professional service costs, intensive care unit (ICU) costs (including the use of all equipment for the ICU, technical teams and 24h patient monitoring). We identified just one direct non-healthcare cost related to companion daily stay. As all expenses are aggregated within the inpatient system, the discrimination of each category was not possible.

For outpatient care expenses, resource use (quantity) and costs were considered for all direct healthcare costs such as ambulatory services and procedures, such as diagnostic imaging and laboratory tests (e.g. computed tomography, scintigraphy, magnetic resonance, biopsy, mammography, immunohistochemistry of malignant neoplasms, etc.), clinical procedures (e.g. chemotherapy, radiotherapy, cobalt therapy, radiotherapy imaging verification, radiotherapy and collimation planning, etc.), surgical procedures, orthoses and prostheses, complementary actions (e.g. food) and other procedures registered in the system. We also included non-direct healthcare costs related to transport for patients and/or companion.

Total expenditure was calculated in the Brazilian currency (Real [R$]) and converted into international dollars (I$) using the World Bank exchange rate for 2018 (1 I$ = R$2,044) [18], according to World Health Organization (WHO) recommendations [19]. Costs were updated to 2018 by applying the official rates of annual accumulated inflation (IPCA—Broad Consumer Price Index). Data were analysed using Microsoft^® Excel^® 2018.

The trend analysis of OC costs, by anatomical site, was performed using the Prais-Winsten method of linear regression, considering the trend analysis to model the seasonality that is present in the time series data of this study. The Prais-Winsten method is recommended in this type of analysis, especially to deal with the serial autocorrelation present in these cases. The serial autocorrelation can induce misinterpretation resulting from undue significance of minor variations. The smaller the number of points included in the series, the more sensitive this effect will be [20].

A critical p-value of 0.05 was adopted to determine a significant trend. Regression analysis was performed using STATA 14.0 software (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). The annual increment fee was calculated using Microsoft^® Office Excel^® 2018 software.

Compliance with ethical standards

This study is exempt from evaluation by the Research Ethics Committee; informed consent was not needed due to all data being public, from secondary sources, open access and with no identification of subjects [21].

Results

Expenditure on OC healthcare in Brazil, from 2008 to 2016, was I$495.6 million, which was composed of 50.8% outpatient and 49.2% inpatient expenditure. The oropharynx (21.9%), floor of the mouth (17.8%) and base of the tongue (17.2%), which is also part of the oropharyngeal anatomical region, were the sites with the highest expenditure (Table 1).

Table 1. Healthcare expenditure on inpatient and outpatient care for oral cancer in Brazil, 2008–2016.

Malignant neoplasm site	Inpatient					Outpatient		Total costs (inpatient + outpatient)—I$ million (%)	Regression (beta)	Annual incremental ratio			Trend
Malignant neoplasm site	Admission (n)	Professional costs—I$ million (%)	Hospital service costs—I$ million (%)	Intensive care unit costs—I$ million (%)	Total costs—I$ million (%)	Procedures (n)	Total costs—I$ million (%)	Total costs (inpatient + outpatient)—I$ million (%)	Regression (beta)	Ratio (%)	95% CI		Trend
C00 –Lip	27,632	9.2 (50.8)	7.9 (43.7)	1.0 (5.5)	18.1 (79.7)	311,019	4.6 (20.3)	22.7 (4.6)	−0.0053	−1.20	−5.54	3.34	Stationary
LC	27,632	9.2 (50.8)	7.9 (43.7)	1.0 (5.5)	18.1 (79.7)	311,019	4.6 (20.3)	22.7 (4.6)	-	-	-	-	-
C02—Other and unspecified parts of the tongue	32,933	17.8 (47.3)	14.9 (39.6)	4.9 (13.1)	37.6 (46.4)	1,121,205	43.5 (53.6)	81.1 (16.4)	0.0021	0.48	−6.10	7.52	Stationary
C03 –Gum	2,148	1.6 (55.2)	1.1 (37.9)	0.2 (6.9)	2.9 (39.7)	113,519	4.6 (61.3)	7.5 (1.5)	0.0087	2.01	−4.87	9.39	Stationary
C04—Floor of the mouth	19,256	34.2 (52.6)	26.9 (41.3)	4.0 (6.1)	65.1 (73.6)	596,597	23.4 (26.4)	88.5 (17.9)	0.0092	2.14	−6.68	11.80	Stationary
C05 –Palate	7,670	3.0 (51.7)	2.4 (41.4)	0.4 (6.9)	5.8 (21.0)	519,107	21.8 (79.0)	27.6 (5.6)	0.0207	4.89	−2.33	12.64	Stationary
C06—Other and unspecified parts of the mouth	22,825	13.0 (46.9)	9.9 (35.9)	4.8 (17.2)	27.7 (52.9)	649,690	24.7 (47.1)	52.4 (10.6)	0.0037	0.86	−5.50	7.66	Stationary
OCC	84,832	69.6 (50.0)	55.2 (39.7)	14.3 (10.3)	139.1 (54.1)	3,000,118	118.0 (45.9)	257.1 (51.9)	-	-	-	-	-
C01—Base of the tongue	25,690	20.0 (39.9)	15.4 (30.8)	14.7 (29.3)	50.1 (58.8)	662,749	35.1 (41.2)	85.2 (17.2)	0.0237	5.61	−1.90	13.69	Stationary
C09 –Tonsil	4,698	1.8 (51.4)	1.4 (40.0)	0.3 (8.6)	3.5 (15.8)	399,711	18.6 (84.2)	22.1 (4.5)	0.0194	4.56	−2.25	11.84	Stationary
C10 –Oropharynx	34,465	17.3 (52.1)	12.6 (38.0)	3.3 (9.9)	33.2 (30.6)	1,850,639	75.3 (69.4)	108.5 (21.9)	0.0249	5.90	1.38	10.62	Growing
OPC	64,853	39.1 (45.0)	29.4 (33.9)	18.3 (21.1)	86.8 (40.2)	2,913,099	129.0 (59.8)	215.8 (43.5)	-	-	-	-	-
Total	177,317	117.9 (48.3)	92.5 (37.9)	33.6 (13.8)	244.0 (49.2)	6,224,236	251.6 (50.8)	495.6 (100.0)	-	-	-	-	-

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Over the investigated period, the annual incremental rate of expenditure was stationary for all sites (LC, OCC, base of the tongue, and tonsil) except for the oropharynx (C10). For the oropharynx, the increase rate was 5.9% per year (95% CI 1.4–10.6; beta = 0.0249; p < 0.05) (Table 1).

In the period 2008–2016, 177,317 hospital admissions were registered. I$118.0 million was spent on professional services (48.4%), I$92.5 million on hospital services (37.9%) and I$33.5 million on the ICU (13.7%) (Table 1).

The total number of outpatient procedures and services registered was 6,224,236, totalling I$251.7 million spent. Clinical procedures accounted for the largest numbers in quantity 93.7% (n = 5,831,242) and in expense 95.8% (I$241.1 million). Of the clinical procedures, radiotherapy and related procedures (cobalt therapy, radiotherapy and collimation planning, and radiotherapy imaging verification), together with chemotherapy also added up to the largest number of procedures (88.8%) and costs (94.9%) (Table 2).

Table 2. Most common procedures and services and their associated costs adopted during outpatient oral cancer care in Brazil, 2008–2016.

Nature of procedure	Total procedures		Most used procedures	Quantity		Costs		Cost per procedure
Nature of procedure	n	I$ million^*	Most used procedures	n	%^**	I$ million*	%^***	I$ million
Diagnostic	149,400	7.7	Computed tomography	143,471	2.3	4.9	2.0	20.583,0
			Scintigraphy	3,557	0.1	0.5	0.2	510,3
			Magnetic resonance	2,547	0.0	0.5	0.2	365,4
			Biopsy	20,847	0.3	0.4	0.1	2.990,8
			Mammography	9,272	0.1	0.4	0.1	1.330,2
			Immunohistochemistry of malignant neoplasms	4,487	0.1	0.3	0.1	643,7
			Total diagnostic	184,181	3.0	7.0	2.8	740,7
Clinical	5,831,242	241.1	Chemotherapy	177,658	2.9	128.7	51.1	743,9
			Radiotherapy	3,742,209	60.1	73.8	29.3	15.668,7
			Cobalt therapy	1,279,969	20.6	23.2	9.2	5.359,2
			Radiotherapy and collimation planning	209,936	3.4	9.0	3.6	879,0
			Radiotherapy imaging verification	115,309	1.9	4.0	1.6	482,8
			Total clinical	5,525,081	88.8	238.8	94.9	22220,5
Surgery	96,989	1.5	Excision	58,331	0.9	1.1	0.4	38.946,1
			Abscess drainage	29,650	0.5	0.3	0.1	19.796,6
			Grade II dressing	5,126	0.1	0.1	0.0	3.422,5
			Total surgery	93,107	1.5	1.5	0.6	374,5
Orthoses and prostheses	4,800	0.1	Prostheses	3,264	0.1	0.1	0.0	27.420,2
Orthoses and prostheses			Colostomy/urostomy plate and/or pouch	1,420	0.0	0.0	0.0	11.929,1
			Total orthoses and prostheses	4,684	0.1	0.1	0.0	18,8
Complementary actions	141,805	1.2	Allowance for patient/companion food	22,747	0.4	0.3	0.1	18.546,5
Complementary actions			Patient/companion transport/displacement	119,058	1.9	0.9	0.4	97.072,6
			Total complementary actions	141,805	2.3	1.2	0.5	570,3
Total	6,224,236	251.7	Total (most used)	5,948,858	95.6	248.6	98.8	23.924,9

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*Costs are presented in I$ million dollars (currency: 1 I$ = R$2.044) (The World Bank Group, 2018) [18].

**Quantity (%) percentage relative to the total number of procedures reported during outpatient care in the period.

***Cost (%) percentage relative to the total outpatient costs in the period.

Italic markings represent the partial sum for each category, and bold markings represent the total sum.

The highest consumption of procedures, both outpatient and inpatient, and their associated costs were by male patients (75.6% of the cost). The total cost ratio/1,000 inhabitants was I$4,006 among men and I$1,241 among women. For both men (67.9%) and women (73.3%), spending was higher for those with OCC (Table 3).

Table 3. Healthcare procedures, admissions and their associated expenditure (I$ million) for inpatient and outpatient care for oral cancer in Brazil, by site group, sex and age group in Brazil, 2008–2016.

Variable		Outpatient			Inpatient			Total
Variable		Procedures (n)	Cost (I$ million)^*	% Cost	Admissions (n)	Cost (I$ million)^*	% Cost	Cost (I$ million)^*	% Cost
Sex^**
	Male
	LC	153,883	3.0	1.5	15,426	10.5	6.2	13.6	3.6
	OCC	2,228,526	91.9	45.3	60,352	101.0	58.8	192.9	51.6
	OPC	1,852,106	107.7	53.2	50,253	60.0	35.0	167.7	44.8
	Total	4,787,409	202.6	80.8	126,031	171.5	70.0	374.2	75.5
	Female
	LC	157,136	1.6	3.3	12,206	7.4	10.0	9.0	7.4
	OCC	771,592	26.7	55.4	24,480	38.2	52.0	64.9	53.3
	OPC	480,936	19.9	41.3	14,600	27.9	38.0	47.8	39.3
	Total	1,409,664	48.2	19.2	51,286	73.5	30.0	121.7	24.5
Age group (years)^**
	≤ 40	377,067	14.6	5.9	21,744	34.7	14.3	49.2	10.1
	41–50	1,114,455	46.7	19.0	26,278	36.6	15.1	83.3	17.1
	51–60	2,161,502	90.6	36.8	71,867	67.7	27.9	158.3	32.4
	61–70	1,529,599	60.8	24.7	34,174	56.3	23.2	117.0	24.0
	> 70	1,014,450	33.4	13.6	23,254	47.1	19.4	80.5	16.5
Brazilian region^**
	Northern	183,853	6.5	2.6	3,354	3.2	1.5	9.7	2.1
	Northeast	1,330,370	49.1	19.6	48,928	61.4	29.2	110.5	24.0
	Southeast	3,281,996	133.1	53.1	76,705	88.5	42.1	221.6	48.0
	Southern	1,101,947	47.9	19.1	36,478	44.3	21.1	92.2	20.0
	Midwest	298,907	14.2	5.7	11,852	13.0	6.2	27.2	5.9

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LC: Lip cancer; OCC: Oral cavity cancer; OPC: Oropharyngeal cancer.

*Costs are presented in I$ million dollars (currency: 1 I$ = R$2.044) (The World Bank Group, 2018) [18].

** Missing values: 27,163 outpatient procedures.

Most of the costs (72.9%) were spent on individuals over 50 years old. The lowest cost ratio/1,000 inhabitants was among individuals under 40 years old (I$364.4/1,000 inhabitants) and the highest was in the age group 61 to 70 years old (I$11,317/1,000 inhabitants) (Table 3).

The lowest expenditure was in the North region of Brazil (2.1%) and the highest was in the Southeast region of the country (48.1%) (Table 3).

Discussion

The main contribution of this study was to estimate the costs of OC in Brazil (I$495.6 million), which has not been reported before. This finding corresponds to an annual average cost of I$55.1 million (SD ± 5.0 million). Differences in the costing method and in the organisation of health systems are two of the main reasons that makes economic evaluation results comparisons a challenge. Evidence has shown an increase in the number of health economic evaluations (HEEs) of cancer in Brazil [4]. However, although oral cancer is one of the five most common neoplasms among males, only 1.8% of the HEEs found were related to the oral cavity or pharyngeal cancer, from 1998 to 2013 [4] and none of them was a cost-of-illness study. We did not find any specific study on the cost of oral cancer. The only cost-of-illness study found in the head and neck region, with epidemiological (incidence rate) and methodological (same methodology of aggregate cost from the information systems of the Ministry of Health of Brazil, using ICD-10 code, 2008–2015) similarities to ours, it was related to thyroid cancer [22], for which the therapeutic approach is very different, making the costs incomparable.

For OC, the number of procedures was considered high, with an annual average of 691.6 thousand. Even though outpatient procedures presented a higher total value, the cost per procedure was 34 times higher for inpatient (I$1,375) than outpatient procedures (I$40). In Brazil, studies have shown that most patients are diagnosed with oral cancer at an advanced stages (III and IV), and in these cases the treatment includes more procedures and demand more resources [23,24]. Treatment costs for cancer may vary according to the stage of disease. Souza et al. (2009) showed that the cost of illness for skin cancer in Brazil ranges from I$187.3 (R$382.8) in stage 0 to I$15,667 (R$32,024) in stage IV [25]. In the United Kingdom, the average of outpatient and inpatient costs per patient, after one year of treatment, were US$3,343 (I$6,133) for precancerous lesions and US$24,890 (I$45,664) for cases in stage IV [13].

Cancer staging may also influence the length of hospital stay, with those diagnosed with potentially malignant disorders remaining in hospital for 1.9 days on average, while individuals with a late diagnosis (stage IV) remain in hospital for 29.9 days [13]. Although our results do not explicitly state this cost by stage, based on this evidence it is possible assume that, the more advanced the disease, the more inpatient procedures will be necessary, which substantially increases the cost of the illness. Part of these efforts could be better allocated to other diseases if the incidence and severity of OC were reduced.

Some anatomical sites of OCC, such as the tongue and floor of the mouth, are presented in the literature as having the highest incidence of OC [26–28]. This could explain this study’s findings that this group was shown as the costliest for males and females and is also the one with highest demand for hospitalisation hours, attendants, and ICU. Also, this highest incidence regions are anatomically more complex and, considering that most cases of oral cancer that reach treatment are in advanced stages [29], the high cost of cancers in these regions may be related to a greater demand for more complex multimodal and surgical treatments, integrating multi- professional teams (vascular microsurgery, plastic surgery) and requiring professionals specialised in long-term rehabilitation [30].

The high OPC costs may be related to the rising incidence trend in OPC that has been observed in the recent decades, worldwide. The association of the burden of the disease in young patients and with human papillomavirus (HPV) infection [31] has required investments in new diagnostic and treatment approaches, which may also have contributed to the high cost of OPC. The treatment has become longer, and new radiotherapy techniques have been implemented to reduce the side effects of the treatment and the multidisciplinary team needed to learn more about the disease in the oropharynx. Individuals with HPV-positive OPC have responded better to treatment than others. These individuals have shown an average survival of two years (87.5%-95.0%) higher than negative-HPV individuals (62.0%-67.2%) [32]. Different from others head and neck tumours, OPC associated with HPV tends to occur in the young population group (30 to 50 years old), in non-smokers and non-drinking individuals, and in people who are employed and have young families; consequently, this cancer has a considerable social and economic impact [33,34].The inclusion of the diagnosis of HPV [35] as a routine and the need for training of pathologists for this diagnosis, also need to be highlighted as possible contributors to the high cost of OPC.

Tobacco smoking and alcohol drinking are responsible for a large proportion of oral and pharyngeal cancers and account for a higher proportion of head and neck cancers among men than among women. Even though the data collection was not based on individuals, the results reproduce the epidemiological aspects of OC [3,9,10,26,36–39], since the number of procedures and cost of illness were three times higher for men over 50 years of age than for women.

Regarding Brazilian regions, three of them (South, Southeast and Northeast) consumed 92% of the total costs for OC. This distribution coincides with the highest proportion of smokers, which is also concentrated in these three Brazilian regions [40]. The Southeast region received approximately 50% of the total resources. Although the costs of OC by region are proportional to the population distribution in them, these results might be related to better access to technologies, greater service offerings, greater population access to the health system and a more effective systematisation of SUS notifications [41].

In terms of the limitations of this study, we highlight the below aspects, which could be considered in the planning for further studies: the SIA-SUS and SIH-SUS data do not allow for identifying the OC costs by individual; the number of procedures and actual costs tend to be underestimated, since the data used was only from public health services and did not include the private system data. Another important aspect to be considered for further studies is presenting costs in international dollars, as it is recommended by WHO [19], since it would be a trying to equalise the purchasing power of different currencies, by eliminating the differences in price levels between countries.

According to the WHO (2018) [42], a strategy for reducing OC incidence as a noncommunicable disease must include cost-effective interventions and be affordable, feasible and scalable in all settings. Examples of these would be to enact and enforce effective anti-smoking and alcohol-related harm public policies; vaccinate 9 to 13-year-old girls against human papillomavirus and prevent it by screening [42]. In addition, OC organized screening programs in lower middle- and upper middle-income countries can be ineffective in achieving the desired impact or suffer from poor quality of testing and follow up services. An alternative would be generating population awareness about the early detection of OC and training the frontline healthcare professional regarding the early symptoms, as an early detection approach [5,43].

Conclusions

Direct healthcare costs for OC represented an average of I$55.1 million annually. Outpatient procedures were responsible for the highest total cost; however, inpatient procedures had a higher cost per procedure ratio. Men over 50 years old consumed most of the direct healthcare costs and procedures for OC, which is consistent with epidemiological data worldwide. The oropharynx and tongue were the anatomical sites with the highest costs, with the oropharynx presenting an annual growth trend. Further studies are needed to investigate cost per individual, direct non-medical costs and indirect costs for OC.

Acknowledgments

We thank Dr Erika Carvalho Aquino for performing trend analysis of the linear regression.

Data Availability

Data are available from Figshare (DOI: 10.6084/m9.figshare.13641449.v1).

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0246475.r001

Decision Letter 0

Gabriel A Picone

17 Sep 2020

PONE-D-20-19121

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

PLOS ONE

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Reviewer #2: Partly

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Reviewer #1: No

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The study presents estimates of the direct medical expenditure incurred on oral cancer by the Brazilian health system. The study is really useful in defining the magnitude of the disease in terms of economic burden. Further, the estimates from the present study can also be used for assessing the efficiency of the present health system and strategies for reducing the health expenditure. Although, the study achieves its main objective of estimating the direct cost on OC, but I have a few concerns in the methodology followed:

1. The present analysis is actually a type of prevalence based cost of illness study. But, I am not confident (as per details mentioned in the methods section) that it uses the principles of top-down costing methods. The study simply measures the actual quantity of services delivered as the part of management of OC in Brazil (for the reference time period) and then multiply it with the cost of delivering these services. As the top down approach uses some type of aggregate data (morbidity, treatment utilization or total cost on health care delivery) which is then allocated to specific service or diseases. The authors should justify the use of top-down approach in the present study as the details of it in either data collection or data analysis is not clearly mentioned in the methods section.

2. The authors report that the data from Inpatient Information System (SIH-SUS) and the Outpatient Information System (SIA-SUS) was used to record hospitalization and outpatient information. It should be clearly mentioned that what type of information or data was assessed from the above mentioned resources. Whether only the utilization data on the number of hospitalizations, ICU admissions and outpatient procedures corresponding to the specific ICD-10 codes was extracted or the information on the specific resource use for each of the inpatient and outpatient procedure was also available from the data sources (as mentioned on the lines 114 -119 and 121-122). If the segregated information on resource use was not available (lines 119-120), how the inpatient costs were segregated into professional costs and hospital service costs/ICU costs (table 1).

3. Operational definition of professional cost (with regards to inpatient care) is missing (what cost components were included in this). ICU cost also seems to include some component of professional cost (cost of technical teams). Authors should take into consideration that is there is no duplication of costs.

4. The authors mentioned that expenses based on prices represented by the Brazilian Ministry of Health’s reimbursements to all health providers were used for estimating the cost. The manuscript lacks details on what type of information on prices was used from the reimbursement system.

a. Whether, an estimate of average unit cost on outpatient procedures or inpatient stay/ICU stay was extracted from the reimbursement system and simply multiplied with the number of procedures to estimate the total direct cost.

b. OR it is the actual amount reimbursed to the health care provider for each of the outpatient procedure or inpatient stay.

c. OR prices of various resources consumed in the delivery of outpatient and inpatient care were extracted from the reimbursement system and then these were used to calculate the cost the treatment given.

5. Transport cost and cost of companion is usually included in the category of direct non-health care cost. Author can think of adjusting this issue.

6. Is there any other reason for the higher cost in oropharynx/floor of mouth/base of tongue besides the higher incidence of cancer for these specific sites? Or there was more utilization of outpatient procedures and inpatient services for the management of these specific cancer sites as compared to other sites. Similarly, what is the possible reason of ‘growing’ expenditure in the case of oropharynx as compared to stationary rates for other sites? It is important and should be mentioned in the discussion section.

7. Authors have mentioned total number of procedures and total cost of each procedure in table 2. It will be also useful to add cost per procedure in a separate column in the table.

8. It should be mentioned in table 1 that the cost are presented in I$ million dollars.

9. The authors mention that costs for skin cancer in Brazil can vary highly according to the stage of disease. If possible, the authors should provide the segregation of total direct cost on OC as per stage of diagnosis of the disease. This will further strengthen the argument.

10. The line 249-250 i.e., ‘presentation of the SIA-SUS and SIH-SUS values by number of procedures is an impairment to identifying the individual costs of OC”. Please try to rephrase it for better understanding.

11. Overall, the discussion section needs improvement in terms of clarity of the language for better understanding of the readers.

Reviewer #2: The authors presented a paper about direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil. There is a large gap in the scientific literature on studies evaluating the economic impact of cancer treatment, especially in lower-middle- and upper-middle income countries. It is very important to disseminate information about this issues in regions where this information are rare. Particularly for OC, where the late detection enlarge exponentially costs and lives it is very important evaluate its economic impact to built efficient public policies.

I would like to contribute with some questions on intention to clarify some aspects of the paper

Major issues:

Methodology

1. Page 6, lines 133-139. Although the authors has explained the source of databases and how they extract the information, it is unclear the choice of this methodology and a theoretical support. When the authors use to calculate TCR the total cost in numerator, they are introducing an important bias in the results because they are treating procedures as individuals, wich produce an overestimation of the TCR. We know that the we have linked to an only person a set of procedures to the same treatment.

2.Page 7, lines 140-141. The authors should explain why they choose the Prais-Winsten method to perform linear regression and include more details about the model

Results

1. Page 9, lines 157-160 and Table 1. The parameters of the linear regression on table 1 is insufficient to conclude about the model adjustment and about the significance of the β parameters.

Discussion

1. Page 15, lines 194-202. It is difficult to compare both studies at least to reasons: the thyroid study use a methodology that really estimates a cost by patient. The other reason is despite of both topographies had similar incidence rates, the terapeutic approach is very different which made the costs incomparable.

2. Page 15, lines 203-206. The authors should take in mind the OC epidemiology. The incidence in males is about 3,5 times higher than in woman and this issue will be reproduced in the healthcare costs

3. Page 17, lines 236-247. The authors should take in mind that regional distribution follow the population distribution and it is not easy to link with the inequalities in public spending between the different regions

Minor issues:

Introduction:

1. Page 3, lines 50-51: Update the information about Brazilian cancer estimates to 2020-2022, like the authors already done in another part of the manuscript.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 17;16(2):e0246475. doi: 10.1371/journal.pone.0246475.r002

Author response to Decision Letter 0

28 Nov 2020

We carefully revised all the points raised during the manuscript review process, accepted and / or justify the reviewer' suggestions. The answers are described in detail in the rebuttal letter, and bellow (Figures inserted in the rebuttal letter could not be copied to here).

Reviewer 1, comment 1: “The study presents estimates of the direct medical expenditure incurred on oral cancer by the Brazilian health system. The study is really useful in defining the magnitude of the disease in terms of economic burden. Further, the estimates from the present study can also be used for assessing the efficiency of the present health system and strategies for reducing the health expenditure. Although, the study achieves its main objective of estimating the direct cost on OC, but I have a few concerns in the methodology followed:”

Our response: We really appreciate Reviewer’s 1 comments and time spent reviewing our manuscript.

Reviewer 1, comment 2:“1. The present analysis is actually a type of prevalence based cost of illness study. But, I am not confident (as per details mentioned in the methods section) that it uses the principles of top-down costing methods. The study simply measures the actual quantity of services delivered as the part of management of OC in Brazil (for the reference time period) and then multiply it with the cost of delivering these services. As the top down approach uses some type of aggregate data (morbidity, treatment utilization or total cost on health care delivery) which is then allocated to specific service or diseases. The authors should justify the use of top-down approach in the present study as the details of it in either data collection or data analysis is not clearly mentioned in the methods section.”

Our response: Thank you for raising this question and for the opportunity to clarify it. The bottom-up approach relies on individual data, obtained by multiplying the unit costs by quantities [Tarricone 2006]. This information is not publicly available in the information systems in Brazil (namely Inpatient and Outpatient Information Systems – SIH-SUS and SIA-SUS, respectively). In these information systems, the unit of analysis is the procedure instead of the individual. Moreover, patients can use different combinations of services (procedures) on the same inpatient or outpatient bill. Based on that, we cannot claim that our estimates are based on bottom-up approach. On the other hand, we used aggregate data to estimate the oral cancer (OC) costs. Our estimates consist of allocating total national health care expenditures by type of care (inpatient and outpatient) among the oral cancer sites by using the ICD-10 codes for each site of OC. In other terms, we identified the portions of the total health expenditure due to oral cancer sites. Moreover, we have not calculated the costs; we just extracted the aggregate costs from the information systems. We reworded the text in the manuscript to clarify it:

‘We defined prevalence-based as all OC patients were included, regardless of the level of severity or onset of the disease. A top-down approach was used because our estimates consist of allocating total national health care expenditures by type of care (inpatient and outpatient) among the OC sites by using the ICD-10 codes for each site of OC (i.e. we identified the portions of the total health expenditure due to OC sites).’ (Methods, Study design, page 4, line 76-80).

Reference:

Tarricone R. Cost-of-illness analysis. What room in health economics? Health Policy. 2006 Jun;77(1):51-63. doi: 10.1016/j.healthpol.2005.07.016. Epub 2005 Sep 1. PMID: 16139925.

Reviewer 1, comment 3: “The authors report that the data from Inpatient Information System (SIH-SUS) and the Outpatient Information System (SIA-SUS) was used to record hospitalization and outpatient information. It should be clearly mentioned that what type of information or data was assessed from the above mentioned resources. Whether only the utilization data on the number of hospitalizations, ICU admissions and outpatient procedures corresponding to the specific ICD-10 codes was extracted or the information on the specific resource use for each of the inpatient and outpatient procedure was also available from the data sources (as mentioned on the lines 114 -119 and 121-122). If the segregated information on resource use was not available (lines 119-120), how the inpatient costs were segregated into professional costs and hospital service costs/ICU costs (table 1)”.

Our response: The issue raised by the reviewer is closely related to the previous comment. We apologise for not providing a complete picture of the Brazilian health information systems. We hope to clarify it at this stage of the review, as follows:

‘Health facilities (hospitals, urgent care, clinics, pharmacies, etc.) included all procedures delivered to a patient during an outpatient or inpatient after his/her discharge, including health workers services. Each procedure is valued based on a fixed value defined by the Ministry of Health of Brazil. The sum of all procedures as an outpatient or inpatient is sent to the Ministry of Health by means of reimbursement. On this basis, it represents the actual amount reimbursed to the health care providers for each outpatient procedure or inpatient stay. It is worth noting that each patient may have a different combination of procedures depending on disease severity.’ (Methods, Data sources, page 5, line 104-112)

Reviewer 1, comment 4: “Operational definition of professional cost (with regards to inpatient care) is missing (what cost components were included in this). ICU cost also seems to include some component of professional cost (cost of technical teams). Authors should take into consideration that is there is no duplication of costs.

Our response: Thank you for your comment. As we stated by Reviewer 1, comment 2, we have not calculated the costs related to OC (prices multiplied by quantities). We collected the aggregate cost from the information systems of the Ministry of Health of Brazil, using ICD-10 codes for OC. For each procedure, the Ministry of Health defined a reimbursement fee, which has a fixed value. The Ministry of Health is the one that multiplies prices by quantities. On this basis, there is no duplication of cost. Regarding the definition of professional costs, the Ministry of Health of Brazil also defined a reimbursement fee for this purpose, which depends on the complexity of the procedure and the qualification of the professional team (Methods, Data sources, page 5, line 104-112).

Reviewer 1, comment 5: “The authors mentioned that expenses based on prices represented by the Brazilian Ministry of Health’s reimbursements to all health providers were used for estimating the cost. The manuscript lacks details on what type of information on prices was used from the reimbursement system. a. Whether, an estimate of average unit cost on outpatient procedures or inpatient stay/ICU stay was extracted from the reimbursement system and simply multiplied with the number of procedures to estimate the total direct cost. b. OR it is the actual amount reimbursed to the health care provider for each of the outpatient procedure or inpatient stay. c. OR prices of various resources consumed in the delivery of outpatient and inpatient care were extracted from the reimbursement system and then these were used to calculate the cost the treatment given.

Our response: Thank you again for the opportunity to clarify this issue. Option ‘b’ is correct as it is the actual amount reimbursed to the health care provider for each outpatient procedure or inpatient stay. This information was also included in the manuscript, in the Methods, Data sources, page 5, line 104-112, as was mentioned in response to comment 3 above.

Reviewer 1, comment 6:“Transport cost and cost of companion is usually included in the category of direct non-health care cost. Author can think of adjusting this issue.

Our response: Thank you for suggesting this change, with which we totally agree. We have corrected it in the manuscript. (Methods, Data analysis, page 6, line 132; page 7, lines 142-143)

Reviewer 1, comment 7:“Is there any other reason for the higher cost in oropharynx/floor of mouth/base of tongue besides the higher incidence of cancer for these specific sites? Or there was more utilization of outpatient procedures and inpatient services for the management of these specific cancer sites as compared to other

sites. Similarly, what is the possible reason of ‘growing’ expenditure in the case of oropharynx as compared to stationary rates for other sites? It is important and should be mentioned in the discussion section.”

Our response: Thank you for your suggestion. We restructured the discussion session to address the suggested aspects. A paragraph was added in the discussion section, as follows:

‘Considering that most cases of oral cancer that reach treatment are in advanced stages [29] and that the floor of the mouth and the posterior boundary of the oral cavity are anatomically more complex, the high cost of cancers in these regions may be related to a greater demand for more complex multimodal and surgical treatments, integrating multi-professional teams (vascular microsurgery, plastic surgery) and requiring professionals specialised in long-term rehabilitation [30].’ (Discussion, page 18-19, lines 279-284)

Another paragraph was reformulated in the discussion section, as follows:

‘The high OPC costs may be related to the rising incidence trend in OPC that has been observed in recent decades worldwide. The association of the burden of the disease in young patients and with human papillomavirus (HPV) infection [31] has required investments in new diagnostic and treatment approaches, which may also have contributed to the high cost of OPC. The treatment has become longer, and new radiotherapy techniques have been implemented to reduce the side effects of the treatment and the multidisciplinary team needed to learn more about the disease in the oropharynx. Individuals with HPV-positive OPC have responded better to treatment than others. These individuals have shown an average survival of two years (87.5%-95.0%) higher than negative-HPV individuals (62.0%-67.2%) [32]. Different from other head and neck tumours, OPC associated with HPV tends to occur in the young population (30 to 50 years old), in non-smokers and non-drinking individuals, and in people who are employed and have young families; consequently, this cancer has a considerable social and economic impact [33, 34].The inclusion of the diagnosis of HPV [35] as routine and the need for training pathologists for this diagnosis also need to be highlighted as possible contributors to the high cost of OPC.’ (Discussion, pages 19-20, lines 296-312)

Reviewer 1, comment 8:“Authors have mentioned total number of procedures and total cost of each procedure in table 2. It will be also useful to add cost per procedure in a separate column in the table.”

Our response: Thank you for your suggestion. We have included this column in Table 2. (Results, page 11-12, Table 2)

Reviewer 1, comment 9:“It should be mentioned in table 1 that the cost are presented in I$ million dollars.”

Our response: Thank you for identifying this missing information. We have included ‘million’ in Table 1. Just to clarify, we have used international dollars, which take into consideration the Purchase Parity Power. (Results, page 9, Table 1).

Reviewer 1, comment 10:“The authors mention that costs for skin cancer in Brazil can vary highly according to the stage of disease. If possible, the authors should provide the segregation of total direct cost on OC as per stage of diagnosis of the disease. This will further strengthen the argument.”

Our response: We totally agree with the reviewer. However, our databases do not allow us to estimate costs by cancer stages. As we explained in the Methods, the Brazilian health information systems are based on ICD-10 codes, which is not categorised by cancer staging. (Methods, Data sources, page 5, line 104-112).

Reviewer 1, comment 11:“The line 249-250 i.e., ‘presentation of the SIA-SUS and SIH-SUS values by number of procedures is an impairment to identifying the individual costs of OC”. Please try to rephrase it for better understanding.”

Our response: Thank you for the comment and the opportunity to clarify this. For better understanding, we rephrased the statement as follows:

‘the SIA-SUS and SIH-SUS data do not allow to identifying the OC costs by individual;’ (Discussion, page 20, lines 331-332)

Reviewer 1, comment 12:“Overall, the discussion section needs improvement in terms of clarity of the language for better understanding of the readers.”

Our response: Thank you for raising this issue. The discussion section was reorganised and the entire article underwent a new linguistic review.

------------------------------------------------------------------

Reviewer 2, comment 1:“The authors presented a paper about direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil. There is a large gap in the scientific literature on studies evaluating the economic impact of cancer treatment, especially in lower-middle- and upper-middle income countries. It is very important to disseminate information about this issues in regions where this information are rare. Particularly for OC, where the late detection enlarge exponentially costs and lives it is very important evaluate its economic impact to built efficient public policies.

I would like to contribute with some questions on intention to clarify some aspects of the paper”

Our response: We would like to thank you for your consideration and time spent reviewing our manuscript.

Reviewer 2, comment 2: “Major issues:Methodology1. Page 6, lines 133-139. Although the authors has explained the source of databases and how they extract the information, it is unclear the choice of this methodology and a theoretical support. When the authors use to calculate TCR the total cost in numerator, they are introducing an important bias in the results because they are treating procedures as individuals, which produce an overestimation of the TCR. We know that the we have linked to an only person a set of procedures to the same treatment.”

Our response: Thank you for your comment. In fact, we used the general population as the denominator, which is also inappropriate. Unfortunately, we have not identified any study or database that estimates the prevalence of OC stratified by anatomical site in Brazil. Based on that, we decided to exclude these estimates from our study. We excluded column 10 from Table 3 and the text related to this calculation in the Methods section. (Results, page 14-15)

Reviewer 2, comment 3: “Major issues:Methodology2.Page 7, lines 140-141. The authors should explain why they choose the Prais-Winsten method to perform linear regression and include more details about the model”

Our response: Thank you for your comment. We have included in the Methods section an explanation as to why the Prais-Winsten method was chosen to perform linear regression as follows:

‘The trend analysis of OC costs, by anatomical site, was performed using the Prais-Winsten method of linear regression, considering the trend analysis to model the seasonality that is present in the time series data of this study. The Prais-Winsten method is recommended in this type of analysis, especially to deal with the serial autocorrelation present in these cases. The serial autocorrelation can induce misinterpretation resulting from undue significance of minor variations. The smaller the number of points included in the series, the more sensitive this effect will be [20].’ (Methods, Data analysis, page 7, lines 157-162)

Reviewer 2, comment 4: “Major issues:Results1. Page 9, lines 157-160 and Table 1. The parameters of the linear regression on table 1 is insufficient to conclude about the model adjustment and about the significance of the β parameters.”

Our response: Thank you for your comment. The average annual increment rate (AIR) was calculated based on the following equation [Antunes JLF, Cardoso MRA. 2015]:

Annual increment rate= -1+10^b

where b is the slope coefficient obtained in the regression analysis that relates the logarithm of the expenditure with the year of occurrence. The 95% confidence interval of AIR was calculated as [Antunes JLF, Cardoso MRA. 2015]:

IC95%=-1+10^((b±t*EP))

where t is the value at which the Student t distribution showing 16 degrees of freedom at a 95% two-tailed confidence level; EP is the standard error of the estimate of b obtained in regression analysis. The degrees of freedom equal the number of elements in the sample n minus the number of parameters estimated (n-1). In the present study, the number of elements n was equal to the period of 9 years (2008 to 2016) considered in the analysis. Figure 1 presents the results of the Prais-Winsten estimates and the 95% IC for each site of OC considered in our analyses. Different to the others, the C10 – oropharynx coefficient is significant, which shows a tendency in the time series of these costs. It is supposed that this difference is related to the high prevalence of OC at this anatomical site, as commented on by Reviewer 1, comment 6.

Reference:

Antunes JLF, Cardoso MRA. Using time series analysis in epidemiological studies. Epidemiol. Serv. Saúde, Brasília, 2015; 24(3):565-576.

Figure 1 - Prais-Winsten estimators of the total costs by anatomical sites

Reviewer 2, comment 5: “Major issues: Discussion1. Page 15, lines 194-202. It is difficult to compare both studies at least to reasons: the thyroid study use a methodology that really estimates a cost by patient. The other reason is despite of both topographies had similar incidence rates, the terapeutic approach is very different which made the costs incomparable.”

Our response: We appreciate the comment and agree that thyroid cancer is not the best comparator to our findings. However, we did not find any specific study on the cost of oral cancer. Therefore, we choose this study to be discussed in parallel with our findings since, besides the similarity in the incidence rate of thyroid cancer, the authors have used the same methodology of aggregate cost from the information systems of the Ministry of Health of Brazil, using ICD-10 codes, a similar period of time, i.e. 2008-2015, and discussed head and neck cancer with a biological behaviour similar to oral squamous cell carcinoma. However, in light of your comment and following a deep discussion within the research group, we decided to reformulate the text as follows:

‘Differences in the costing method and in the organisation of health systems are two of the main reasons that makes economic evaluation results comparisons a challenge. Evidence has shown an increase in the number of health economic evaluations (HEEs) of cancer in Brazil [4]. However, although oral cancer is one of the five most common neoplasms among males, only 1.8% of the HEEs found were related to the oral cavity or pharyngeal cancer, from 1998 to 2013 [4], and none of them was a cost-of-illness study. We did not find any specific study on the cost of oral cancer. The only cost-of-illness study found in the head and neck region, with epidemiological (incidence rate) and methodological (same methodology of aggregate cost from the information systems of the Ministry of Health of Brazil, using ICD-10 code, 2008-2015) similarities to ours, was related to thyroid cancer [22], for which the therapeutic approach is very different, making the costs incomparable.’ (Discussion, page 16, lines 217-228)

Reviewer 2, comment 6: “Major issues:Discussion2. Page 15, lines 203-206. The authors should take in mind the OC epidemiology. The incidence in males is about 3,5 times higher than in woman and this issue will be reproduced in the healthcare costs”

Our response: Thank you for your comment. We have rephrased the text to better reflect the relationship between the results of the cost of illness in Brazil and the global epidemiological aspects oral cancer, as follows:

‘Even though data collection was not based on individuals, the results reproduce the epidemiological aspects of OC [3,9,10,26, 36-38], since the number of procedures and cost of illness were three times higher for men over 50 years of age than for women’. (Discussion, page 20, lines 313-315)

Reviewer 2, comment 7: “Major issues:Discussion3. Page 17, lines 236-247. The authors should take in mind that regional distribution follow the population distribution and it is not easy to link with the inequalities in public spending between the different regions”

Our response: Thank you for the opportunity to clarify this. The impact of inequalities in public spending between different regions is the subject of important discussions in the Brazilian social economic context. However, we agree that it should not be taken in a generalised context. Thus, this paragraph, which was based on a Brazilian study, was removed from the text.

Reviewer 2, comment 8:Minor issues:Introduction1. Page 3, lines 50-51: Update the information about Brazilian cancer estimates to 2020-2022, like the authors already done in another part of the manuscript.”

Our response: We have updated the estimates in the text as suggested by the reviewer. (Introduction, page 3, lines 50-53)

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PLoS One. doi: 10.1371/journal.pone.0246475.r003

Decision Letter 1

Gabriel A Picone

29 Dec 2020

PONE-D-20-19121R1

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

PLOS ONE

Dear Dr. ROTTA,

Please submit your revised manuscript by Feb 12 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have done a good work in terms of providing better explanation of the procedures/methodology followed and a background on the health information system in the methods section of the manuscript. But, I feel that the discussion can still be improved in terms of better structuring, content and flow. Below are few suggestions:

1. The issue (mentioned on line 278-281) of presentation of results in USD by other studies cannot be stated as a limitation of the present study. Firstly, it is not a limitation (of the methodology followed) of the present study. Secondly, authors can easily adjust the estimates from US$ to I$ based on the latest conversion and inflation rates. So, I think that the authors should try to report the results of the ‘other small number of studies’ (by adjusting the estimates to I$) on OC in the discussion section.

2. The paragraphs are never three lines short. However, the paragraphs on lines 197-199, 259-161 and 262-266 are of just 3-4 lines. They can either be merged with the other paragraphs maintaining the flow of the discussion or can be deleted strategically without breaking the flow.

3. The paragraph from lines 262-266 does not fit in the flow the discussion section. It could either be deleted or merged in the other paragraph on line 282-292. Similarly, the paragraph with lines 229-236, can be reduced (by summarizing the information presented in it) and merged with the subsequent paragraph.

4. Information mentioned in the last 2 paragraphs (of the discussion section) specifically focuses on strategies to reduce the incidence of cancers. This information is quite important, but authors can try to summarize in a better and intelligible fashion in a short informative paragraph.

Reviewer #2: The authors made satisfactory explanations, accepted the revisor suggestions and improve the paper make them better.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 17;16(2):e0246475. doi: 10.1371/journal.pone.0246475.r004

Author response to Decision Letter 1

6 Jan 2021

Dear Editor,

Thank you for considering a revised version of our manuscript PONE-D-20-19121 entitled ‘Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil’. All addressed points raised during the review process were considered and the manuscript changes are presented below. The manuscript line numbers cited on each answer below are in accordance with the file “manuscript_with_track_changes”.

Yours sincerely,

The Authors

Reviewer 2, comment 1: “1.The issue (mentioned on line 278-281) of presentation of results in USD by other studies cannot be stated as a limitation of the present study. Firstly, it is not a limitation (of the methodology followed) of the present study. Secondly, authors can easily adjust the estimates from US$ to I$ based on the latest conversion and inflation rates. So, I think that the authors should try to report the results of the ‘other small number of studies’ (by adjusting the estimates to I$) on OC in the discussion section. ”

Our response: Thank you for raising this question and for the opportunity to clarify and fix it. In fact, in the paragraph from lines 278-281 we intended to highlight limitations of our study but also, other aspects to be considered for further studies, which were not a limitation of our study. However, the text was not clear not only about that, but also regard the “small number of studies”, which were already discussed on the first paragraph of the discussion and their results were reported on the second paragraph of discussion section (lines 213-224) adjusting their estimates to I$. The paragraph from lines 278-281 was rephrased (lines 296-299).

Reviewer 2, comment 2: The paragraphs are never three lines short. However, the paragraphs on lines 197-199, 259-161 and 262-266 are of just 3-4 lines. They can either be merged with the other paragraphs maintaining the flow of the discussion or can be deleted strategically without breaking the flow.

Our response: We agree with the suggestions and changes in the text were done aiming to maintain the flow of the discussion, which can be seen on lines: 199-212; 232-240; 296-299.

Reviewer 2, comment 3: The paragraph from lines 262-266 does not fit in the flow the discussion section. It could either be deleted or merged in the other paragraph on line 282-292. Similarly, the paragraph with lines 229-236, can be reduced (by summarizing the information presented in it) and merged with the subsequent paragraph.

Our response: Changes on paragraph from lines 262-266 can be seen on lines 271-276.The paragraph from lines 229-236 was merged with subsequent paragraph and summarized into the paragraph from lines 232-240.

Reviewer 2, comment 4: Information mentioned in the last 2 paragraphs (of the discussion section) specifically focuses on strategies to reduce the incidence of cancers. This information is quite important, but authors can try to summarize in a better and intelligible fashion in a short informative paragraph.

Our response: The last two paragraphs of discussion were summarized in a shorter paragraph from lines 300-309 and one reference (43*) was added to strength scientific support.

Reference 43*: Brocklehurst P, Kujan O, O'Malley LA, Ogden G, Shepherd S, Glenny AM. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev. 2013;19(11):CD004150. doi: 10.1002/14651858.CD004150.

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PLoS One. doi: 10.1371/journal.pone.0246475.r005

Decision Letter 2

Gabriel A Picone

20 Jan 2021

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

PONE-D-20-19121R2

Dear Dr. ROTTA,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Gabriel A. Picone

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have adequately addressed all the comments raised in the review. The authors have done a good work in terms of providing better explanation of the procedures/methodology followed and improving the discussion section of the manuscript.

**********

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Reviewer #1: No

PLoS One. doi: 10.1371/journal.pone.0246475.r006

Acceptance letter

Gabriel A Picone

2 Feb 2021

PONE-D-20-19121R2

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

Dear Dr. ROTTA:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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This section collects any data citations, data availability statements, or supplementary materials included in this article.

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Data Availability Statement

Data are available from Figshare (DOI: 10.6084/m9.figshare.13641449.v1).

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PERMALINK

Direct healthcare costs of lip, oral cavity and oropharyngeal cancer in Brazil

Vanessa Milani

Ana Laura de Sene Amâncio Zara

Everton Nunes da Silva

Larissa Barbosa Cardoso

Maria Paula Curado

Rejane Faria Ribeiro-Rotta

Roles

Abstract

Introduction

Materials and methods

Study design

Brazilian health system

Data sources

Data analysis

Compliance with ethical standards

Results

Table 1. Healthcare expenditure on inpatient and outpatient care for oral cancer in Brazil, 2008–2016.

Table 2. Most common procedures and services and their associated costs adopted during outpatient oral cancer care in Brazil, 2008–2016.

Table 3. Healthcare procedures, admissions and their associated expenditure (I$ million) for inpatient and outpatient care for oral cancer in Brazil, by site group, sex and age group in Brazil, 2008–2016.

Discussion

Conclusions

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Gabriel A Picone

Roles

Author response to Decision Letter 0

Decision Letter 1

Gabriel A Picone

Roles

Author response to Decision Letter 1

Decision Letter 2

Gabriel A Picone

Roles

Acceptance letter

Gabriel A Picone

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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