Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden

Charbél Talani; Anders Högmo; Göran Laurell; Antti Mäkitie; Lovisa Farnebo

doi:10.1371/journal.pone.0296534

. 2024 Apr 16;19(4):e0296534. doi: 10.1371/journal.pone.0296534

Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden

Charbél Talani ^1,^2,^*, Anders Högmo ³, Göran Laurell ⁴, Antti Mäkitie ^5,^6,⁷, Lovisa Farnebo ^1,²

Editor: Chung-Ta Chang⁸

PMCID: PMC11020944 PMID: 38625920

Abstract

Background

In general, survival outcomes for patients with Head and Neck Cancer (HNC) has improved over recent decades. However, mortality within six months after diagnosis for curative patients remains at approximately 5%. The aim of this study was to identify risk factors for early death among patients with curative treatment, and furthermore, to analyze whether the risk of early death changed over recent years.

Material and method

This real-world, population-based, nationwide study from the Swedish Head and Neck Cancer Register (SweHNCR) included all patients ≥18 years diagnosed with HNC with a curative treatment intent at the multidisciplinary tumor board from 2008 to 2020. A total of 16,786 patients were included.

Results

During the study period a total of 618 (3.7%) patients with curative-intended treatment died within six months of diagnosis. Patients diagnosed between 2008 and 2012 had a six-month mortality rate of 4.7% compared to 2.5% for patients diagnosed between 2017 and 2020, indicating a risk reduction of 53% (p <0.001) for death within six months. The mean time to radiation therapy from diagnosis in the 2008–2012 cohort was 38 days, compared to 22 days for the 2017–2020 cohort, (p <0.001). The mean time to surgery from diagnosis was 22 days in 2008–2012, compared to 15 days for the 2017–2020 cohort, (p <0.001). Females had a 20% lower risk of dying within six months compared to males (p = 0.013). For every year older the patient was at diagnosis, a 4.8% (p <0.001) higher risk of dying within six months was observed. Patients with a WHO score of 1 had approximately 2.4-times greater risk of early death compared to WHO 0 patients (p <0.001). The risk of early death among WHO 4 patients was almost 28 times higher than for WHO 0 patients (p <0.001). Patients with a hypopharyngeal tumor site had a 2.5-fold higher risk of dying within six months from diagnosis compared to oropharyngeal tumor patients (p <0.001).

Conclusions

We found that the risk of early death decreased significantly from 2008 to 2020. During this period, the mean time to the start of treatment was significantly reduced both for surgery and oncological treatment regimes. Among patients with a curative treatment intention, increased risk of early death was associated with male sex, older age, advanced disease, increased WHO score, and a hypopharyngeal tumor site.

Background

Head and neck cancer (HNC) is one of the most common cancers worldwide, and epidemiological assessments have reported a recent global increasing incidence [1–5], in Sweden as well as elsewhere in the recent years [6, 7]. Simultaneously, a reduced mortality has been noted in HNC in recent decades, due to better available treatments, less smoking, a multidisciplinary approach to treatment, and earlier discovery of tumors [8–11].

Numerous studies have dealt with survival in patients with HNC, but population-based studies focusing on early death in curatively treated patients with HNC are scarce [12, 13]. Early death from HNC was previously defined as patients dying within six months of diagnosis in studies from the Swedish Head and Neck Cancer register (SweHNCR) [12, 14]. 4.5% of patients died within six months of diagnosis between 2008 and 2015, even though they received curative-intended treatment [12]. Curative-intended treatment is often aggressive, costly, and comes with considerable side effects [15, 16]. If patients receiving aggressive treatment die within six months, the physicians involved must address whether the indications and decision-making involved in treatment management should be re-evaluated [17]. Both surgery and radiotherapy—the backbones of head and neck cancer treatment [5, 17, 18]—warrant repeated visits to the hospital and frequent hospitalizations. Understanding the variables linked to patients at risk of early death could help clinicians better select suitable treatments, and thus avoid mutilating surgery and aggressive chemoradiotherapy in cases with a considerable risk of early death.

Sweden has a single-payer healthcare system. Major progress in clinical management of patients with HNC has been made in Sweden since 2008. Care has, in general, been influenced by international initiatives aiming to improve quality of care of patients with HNC [5, 7]. The Swedish National Guidelines for HNC were established 2015 and have since then been used at the tertiary referral hospitals in the country [18]. Therefore, to study the efficacy of the new guidelines in an era of Human Papilloma Virus (HPV) and demographic changes, further analysis of patients dying within six months of treatment is warranted. In this large, real-world, nationwide, population-based study containing 18,739 patients with HNC (16,786 curative and 1769 palliative), the primary aim was to identify patients at risk of early death after treatment with curative intent, and to analyze factors that contribute to this increased risk. Furthermore, we wanted to test the hypothesis as to whether six-month mortality has decreased for HNC patients over recent years.

Material and methods

Data source

Data were obtained from the SweHNCR (Ethics Committee approval; number 2020–01972). The SweHNCR is funded by the Swedish government and includes 98.5% of all HNC patients since 2008 when cross referenced with the register of the Department of Health and Welfare in Sweden. The authors did not have access to information that could identify individual participants during or after data collection. Application for data extraction was sent to Regional Cancer Centre Väst 15 October 2021. Decision of disclosure was made 12 November 2021, and the data file was delivered on November 26, 2021 (Number: SV2803, Diary number: HS2021-01178). Data reported to the SweHNCR included: diagnosis, TNM classification (according TNM 7 [19]), stage, sex, age, WHO score at diagnosis, time to treatment, treatment, follow-up, recurrence, and survival.

The total number of consecutively-affected Swedish patients during the period of January 1, 2008–December 31, 2020 in SweHNCR with at least six months of follow-up was 18,739 [5].

Patient population

All consecutive HNC patients, ≥18 years of age who were diagnosed in Sweden were included in the study. Patients with a palliative treatment decision at multidisciplinary tumor board (MDT) (n = 1953, 10.4%) were excluded, leaving 16,786 patients with curative treatment intent for further analysis. Patients with curatively intended treatment were divided into three groups based on year of diagnosis: 2008–2012 (n = 5778), 2013–2016 (n = 5307), and 2017–2020 (n = 5701) (Fig 1). All three groups had a similar duration, and included a comparable number of patients.

Fig 1 — Excluded patients are shown in red boxes.

Ten tumor sites (classified according to ICD-10 codes) were included: lip (C00.0–2, C00.6, C00.8, C00.9); oral cavity (C00.3, C00.4, C02, C03, C04, C05, C06); oropharynx (C01.9, C05.1, C05.2, C05.8, C05.9, C09, C10); nasopharynx (C11); hypopharynx (C12, C13); larynx (C10.1, C32); nose (C30.0) and nasal sinuses (C31); salivary glands (C07, C08); head and neck cancer of unknown primary origin (C77.0); and middle or inner ear (C 30.1). Malignant tumors located in the esophagus, thyroid, or parathyroid glands were not included, since information regarding these diagnoses is not included in the SweHNCR. The Eastern Cooperative Oncology Group score—the WHO score—runs from 0 to 5, with 0 denoting perfect health and 5 death.[20] The WHO score was rated 0–4, indicating the physical performance status of the patient. A higher score indicates worse physical performance.

HNC treatment in Sweden is centralized to seven university hospitals, although a few regional hospitals provide non-surgical oncological treatment. National Healthcare and Social Security systems are offered equally to all Swedish inhabitants. All patients are examined by either an oncologist or a head and neck surgeon after termination of treatment to evaluate treatment outcome every three months for the first two years post-treatment and every sixth months for three years after that [18].

Statistics

Results are presented as the mean, standard deviation, and range for continuous variables, and as numbers and percentages for categorical variables. Incidence rates of HNC for 2008–2020 and incidence rate ratio was calculated comparing 2020 to 2008 with 95% confidence intervals according to a method described by Martin and Austin [6, 21–23]. Data from Statistics Sweden were used for information regarding yearly Swedish population count. SweHNCR was used to identify the number of new HNC cases annually. For comparisons between two groups (divided by: age, days to treatment, and days from diagnosis to death), the independent student’s t-test was used. ANOVA tests (with Bonferroni method as a post hoc test) and chi-square tests were used for categorical variables (stage, site, age group, sex, TNM score, death, time periods, and WHO function class). Exact binomial confidence intervals were estimated for proportions. Logistic regression analysis was used to control for confounding factors. To describe overall crude survival and early death for subgroups, a Kaplan—Meier plot was used, and the difference between subgroups (sex, time periods, age groups, and WHO class) was analyzed with a log-rank test. Cox regression was used for multivariable analyses with death within six months from diagnosis as failure. All significance tests were two-tailed and conducted at a 5% significance level. For all statistical analyses, we used IBM SPSS Statistics for Macintosh, Version 28.0. Armonk, NY: IBM Corp Released 2021.

Results

Epidemiology

The annual number of new patients with HNC steadily increased from 2008 (n = 1211 cases) to 2020 (n = 1673 cases). During the same period, the Swedish population increased by 12%, from 9.2M to 10.4M, indicating that factors other than a growing population were involved in the increase of new HNC cases. We noted an incidence rate ratio of 23.8% (CI 95% 23.5–24.2) between 2008 (13.0 diagnosed with HNC per 100000) and 2020 (16.1 diagnosed with HNC per 100000), corresponding to an annual incidence increase of 0.25 per 100000 (p <0.001) (calculated as described in the statistics section above) (Fig 2). Both oropharyngeal and oral cavity cancer displayed increased occurrence: the number of patients with oropharyngeal cancer rose 86% from 2008 (n = 270) to 2020 (n = 503); oral cancer rose 48% from 2008 (n = 343) to 2020 (n = 509). The incidence rate ratio for oropharyngeal cancer was 66.1% (CI 95% 64.3–68.0) between 2008 (2.92 per 100000) and 2020 (4.85 per 100000), and for oral cavity cancer was 32.3% (CI 95% 32.0–33.6) from 2008 (3.71 per 100000) to 2020 (4.90 per 100000). All other sites had fairly similar occurrence rates over the years 2008–2020 (Fig 2). The number of patients discussed at multidisciplinary tumor boards (MDT) increased from 2008 to 2020 (95% to 99.5%, mean for the total study period of 97%).

Fig 2 — a. Annual number of new cases of head and neck cancer in Sweden per year 2008–2020. b. Incidence of head and neck cancer in Sweden 2008–2020. c. Distribution of tumor sites of head and neck cancer in Sweden 2008–2020.

During the years 2008–2020, 618 (3.7%) of 16,786 patients died within six months of diagnosis, despite being recommended for curatively intended treatment at MDT (Fig 1).

Predictors for six-month mortality

Year of diagnosis

The total cohort was divided into three groups based on the year of diagnosis. The three groups contained a comparable number of patients: 2008–2012 (n = 5778), 2013–2016 (n = 5307), and 2017–2020 (n = 5701) (Tables 1 and 2). Between 2008–2012, six-month mortality was 4.7% compared to 3.9% and 2.5% for the years 2013–2016 and 2017–2020, respectively (p <0.001) (Table 1, Fig 3). Sex, age, and stage were evenly distributed throughout the three groups. The 2008–2012 group had a slightly higher distribution of unknown WHO scores compared to the two latter groups, (p <0.001) (Table 2). The composition of oropharyngeal and oral cavity cancer differed between the 2017–2020 cohort (30.5% and 28.3% of all HNC cancers, respectively) compared to the 2008–2012 cohort (25.3% and 26.3% respectively), (p <0.001).

Table 1. Descriptive data for patients with curative treatment intent, and univariate analysis of death within 6 months of diagnosis.

N = 16786	Prevalence n (%)	Dead within 6 months/N (%)	Hazard Ratio (95% CI)	P-values
Sex
Male	10,712 (63.8)	424/10,712 (4.0)	1.00	-
Female	6074 (36.2)	194/6074 (3.2)	0.80 (0.68–0.95)	0.012
Total	16,786(100)	618/16,786(3.7)	-	-
Age (mean (sd))	66.1 (12.6)
Age group in years
18–39	463 (2.8)	0/463 (0)	-	-
40–49	1139 (6.8)	14/1139 (1.2)	1.00	-
50–59	3043 (18.1)	52/3043 (1.7)	1.40 (0.77–2.52)	0.268
60–69	5378 (32.0)	155/5378 (2.9)	2.37 (1.37–4.10)	0.002
70–79	4368 (26.0)	203/4368 (4.6)	3.86 (2.24–6.62)	<0.001
80+	2395 (14.3)	194/2395 (8.1)	6.88 (4.00–11.8)	<0.001
WHO Score
0	12,078 (72.0)	206/12,078 (1.7)	1.00	-
1	2244 (13.4)	145/2244 (6.5)	3.88 (3.14–4.80)	<0.001
2	890 (5.3)	108/890 (12.1)	7.53 (5.97–9.51)	<0.001
3	321 (1.9)	68/321 (21.2)	14.4 (11.0–19.0)	<0.001
4	36 (0.2)	16/36 (44.4)	37.2 (22.4–62.0)	<0.001
Missing	1217 (7.3)	75/1217 (12.1)	3.72 (2.85–4.84)	<0.001
Year of diagnosis	16,786 (100)	618/16,786 (3.7)	-	-
2008–2012	5778 (34.4)	273/5778 (4.7)	1.00
2013–2016	5307 (31.6)	205/5307 (3.9)	0.82 (0.68–0.98)	0.026
2017–2020	5701 (34.0)	140/5561 (2.5)	0.51 (0.42–0.63)	<0.001

Open in a new tab

Table 2. Descriptive data for patients with curative treatment intent grouped by time of diagnosis and univariate analyses.

Variable	2008–2012	2013–2016	2017–2020	Sig. (p-value)
Total number of patients N (%)	5778 (100)	5397 (100)	5791 (100)	-
Oropharynx n (%)	1461 (25.3)	1499 (28.2)	1738 (30.5)	<0.001
Oral cavity n (%)	1531 (26.5)	1514 (28.5)	1615 (28.3)	<0.001
Other sites n (%)	2786 (48.2)	2294 (43.2)	2348 (41.2)	<0.001
Male n (%)	3713 (64.3)	3416 (64.4)	3583 (62.8)	0.174
Female n (%)	2065 (35.7)	1891 (35.6)	2118 (37.2)	0.173
Age n (%) 18–39	183 (3.2)	138 (2.6)	142 (2.5)	0.337^a
Age n (%) 40–49	410 (7.1)	376 (7.1)	353 (6.2)	-
Age n (%) 50–59	1113 (19.3)	964 (18.2)	966 (16.9)	0.710^a
Age n (%) 60–69	1999 (34.6)	1696 (32.0)	1683 (29.5)	0.600^a
Age n (%) 70–79	1247 (21.6)	1358 (25.6)	1763 (30.9)	<0.001^a
Age n (%) 80+	826 (14.3)	775 (14.6)	794 (13.9)	0.425^a
Stage I n (%)	1722 (31.1)	1538 (30.4)	1688 (31.1)	-
Stage II n (%)	1063 (19.2)	930 (18.4)	854 (15.8)	<0.001^b
Stage III n (%)	784 (14.2)	617 (12.2)	676 (12.5)	0.063^b
Stage IV n (%)	1967 (35.5)	1982 (39.1)	2204 (40.6)	0.007^b
WHO 0 n (%)	4005 (69.3)	3780 (71.2)	4293 (75.3)	-
WHO 1 n (%)	720 (12.5)	763 (14.4)	761 (13.3)	0.040^c
WHO 2 n (%)	289 (5.0)	287 (5.4)	314 (5.5)	0.830^c
WHO 3 n (%)	108 (1.9)	95 (1.8)	118 (2.1)	0.802^c
WHO 4 n (%)	14 (0.2)	12 (0.2)	10 (0.2)	0.603^c
WHO missing n (%)	642 (11.1)	370 (7.0)	205 (3.6)	<0.001^c
No treatment n (%)	39 (0.7)	27 (0.5)	29 (0.5)	0.697^d
Radiotherapy +/- Chemotherapy n (%)	2488 (43.9)	2382 (45.6)	2608 (46.3)	<0.001^d
Single modality surgery n (%)	1703 (30.1)	1664 (31.8)	2011 (35.7)	<0.001^d
Combination of surgery + radiotherapy +/- chemotherapy n (%)	1432 (25.3)	1152 (22)	987 (17.5)	-
Time to surgery, mean days^**	22	19	14	<0.001
Time to radiotherapy, mean days^**	38	30	22	<0.001

Open in a new tab

^a Chi-square between age group 40–49 and other age groups

^b Chi-square between Stage I and other Stages

^c Chi-square between WHO 0 and other WHO scores

^d Chi-square between combined modality treatments and other treatments

**^{Mean duration in days between 2008–2020}

Time to treatment

Time to start of treatment from diagnosis was shorter in the 2017–2020 group compared to the 2008–2012 group. The mean time to radiotherapy/chemoradiation therapy in the 2008–2012 cohort was 38 days, compared to 22 days for the 2017–2020 cohort, p <0.001. The mean time to surgery from diagnosis was 22 days in 2008–2012, compared to 15 days for the 2017–2020 cohort, p <0.001 (Table 2).

Sex

Altogether, 10,712 (63.8%) of patients were male, and 6074 (36.2%) were female (Table 1). A significant difference in mortality between the sexes was found. The six-month mortality rate among male patients was 4.0% compared to 3.2% for females (p = 0.012) (Table 1) (Fig 4). Therefore, female patients had a 20% lower risk of death within six months compared to male patients.

Fig 4 — a. Kaplan–Meier curve of death within six months from diagnosis based on sex, log rank test (p = 0.012). b. Kaplan–Meier curve of death within six months from diagnosis based on age at diagnosis, log rank test (p <0.001). c. Kaplan–Meier curve of death within six months from diagnosis based on WHO function class at diagnosis, log rank test (p <0.001).

Age

The mean age at diagnosis was 66 years (range: 18–102). Males were on average one year younger than the females (65.7 versus 66.7) at diagnosis (p <0.001). No patient below 40 years of age died within six months, compared to 8.1% of all patients older than 80 years (p <0.001). There was a 6.88-fold increased risk of dying within six months for patients >80 years of age compared to patients <50 years of age (Table 1) (Fig 4).

WHO score

12,078 (72%) of all patients had a WHO score of 0. Only 1.7% of all patients with WHO 0 died within six months, compared to 44.4% of those with WHO 4 (p <0.001). In univariate analysis, the risk of death within six months was 37.2 times higher for patients with WHO 4 compared to those with WHO 0 (Table 1). Mean survival time among patients dying within 6 months was 119 days for WHO 0 patients compared to 76 days for WHO 4 patients (p = 0.004) (Fig 4).

Site

The most common tumor site was the oropharynx (28%), followed by the oral cavity (27.8%) and larynx (12.7%) (Table 3). The six-month mortality rate varied between tumor sites. Worst outcomes were seen in patients with hypopharyngeal cancer, with 10.3% dying within six months, despite curative treatment intent. A univariable analysis showed that patients with a hypopharyngeal tumor had an almost 2.5-fold higher relative risk of dying within six months compared to oropharyngeal patients (p <0.001) (Table 3).

Table 3. Descriptive data for patients with curative treatment intent, and univariate analysis of death within 6 months of diagnosis.

N = 16786	Prevalence n (%)	Dead within 6 months/N (%)	Hazard Ratio (95% CI)	P-value
Tumor site
Oropharynx	4698 (28.0)	146/4698 (3.1)	1.00	-
Oral Cavity	4660 (27.8)	201/4660 (4.3)	1.40 (1.12–1.73)	0.002
Larynx	2134 (12.7)	89/2134 (4.2)	1.35 (1.04–1.76)	0.026
Hypopharynx	591 (3.5)	61/591 (10.3)	3.45 (2.56–4.65)	<0.001
Nasopharynx	381 (2.3)	5/381 (1.3)	0.42 (0.17–1.02)	0.056
Sino Nasal	690 (4.1)	26/690 (3.8)	1.22 (0.80–1.85)	0.355
Salivary Gland	1212 (7.2)	35/1212 (2.9)	0.93 (0.64–1.34)	0.683
Lip	1850 (11.0)	35/1850 (1.9)	0.61 (0.42–0.88)	0.008
CUP	559 (3.3)	19/559 (3.4)	1.10 (0.68–1.77)	0.705
Ear canal	11 (0.1)	1/10 (10)	3.46 (0.48–24.7)	0.216
Stage
I	4948 (29.5)	73/4948 (1.5)	1.00	-
II	2847 (17.0)	66/2847 (2.3)	1.58 (1.13–2.20)	0.007
III	2077 (12.4)	87/2077 (4.2)	2.88 (2.11–3.93)	<0.001
IV A	5507 (32.8)	293/5507 (5.3)	3.68 (2.85–4.75)	<0.001
IV B	553 (3.3)	56/553 (10.1)	7.12 (5.03–10.1)	<0.001
IV C	93 (0.6)	14/93 (15.1)	11.0 (6.23–19.6)	<0.001
Missing	761 (4.5)	-	-	-
T
T1-2	11,649 (69.4)	229/11,649 (2.0)	1.00	-
T3-4	4968 (29.6)	383/4968 (7.7)	4.04 (3.43–4.76)	<0.001
Missing	169 (1.0)	-	-	-
N
N-	10,263 (61.2)	300/10,263 (2.9)	1.00	-
N+	6520 (38.8)	318/6520 (4.9)	1.68 (1.44–1.97)	<0.001
M
M0	16,511(98.4)	596/16,511 (3.6)	1.00
M1	102 (0.6)	15/102 (14.7)	4.36 (2.61–7.28)	<0.001
Missing	173 (1.0)	-	-	-

Open in a new tab

Stage

An association between tumor stage and six-month mortality was found. Among all patients in the total cohort, 54% were diagnosed with stage III or stage IV cancer (Table 3), although 55% of all women were diagnosed in stage I–II compared to 45% of all males (p <0.001). Of the 618 patients who died within 6 months, 76% had stage III or IV disease compared to 12% of patients with stage I. Significant differences in six-month mortality were also noted in stage IV. For stage I patients, six-month mortality was 1.5%, compared to 5.3%, 10.1%, and 15.1% for stages IV A, IV B, and IV C, respectively (p <0.001). In total, a patient with stage IV C disease had a 10-times higher risk of dying within six months compared to stage I patients (Table 3).

TNM class

Higher T class correlated with worse prognosis. Seventy percent of all patients had a T1-2 tumor at diagnosis (Table 3). Only 2% of the patients with a T1-2 tumor died within six months compared to 7.7% of T3-4 patients. We found that a patient with T3-4 tumor had a 3 times higher risk of death within six months compared to T1-2 patients (p <0.001) (Table 3).

A total of 11,649 (61%) of all patients had no neck metastasis (N–) at diagnosis, whereas 6520 (39%) had one or more metastases in the neck at diagnosis (N+). The six-month mortality for N—patients was 2.9%, compared to 4.9% for N+ patients (p <0.001). In total, an N+ patient had a 1.68-fold higher risk of dying within six months compared to a N—patient (Table 3).

A total of 102 (0.6%) patients had distant metastasis (M1) and were still considered (at the MDT) to benefit from curative treatment. However, 3.6% of patients with M0 disease died within six months, compared to 14.7% of patients with a M1 disease (p <0.001). We found that M1 patients had a 4.36-times higher risk of dying within six months compared to M0 patients (Table 3).

Independent factors for death within six months after diagnosis

A multivariable Cox regression was carried out with death within six months as the dependent variable (Table 4). Patients diagnosed between the years 2008–2012 had a six-month mortality rate of 4.7% compared to 2.5% for patients diagnosed between 2017–2020, indicating a risk reduction of 53% (p <0.001) for death within six months (Table 4). Females had a 20% lower risk of dying within six months compared to males (p = 0.013). For every year older the patient was at diagnosis, a 4.8% (p <0.001) higher risk of dying within six months was observed.

Table 4. Multivariable Cox regression with death within six months of diagnosis as target variable for HNC patients undergoing curative-intended treatment.

Factor	Hazard Ratio (95% CI)	Significance
Year of diagnosis
2008–2012	-	-
2013–2016	0.83 (0.69–1.00)	0.052
2017–2020	0.47 (0.40–0.61)	<0.001^*
TNM Score
T1-2 vs 3–4	2.90 (2.43–3.51)	<0.001^*
N+/0	1.60 (1.36–1.99)	<0.001^*
M+/0	2.30 (1.36–3.85)	0.002^*
Sex
Male	-	-
Female	.800 (0.67–0.95)	0.013^*
Age Continuously	1.05 (1.04–1.06)	< .001^*
WHO Function
WHO 0	-	-
WHO 1	2.38 (1.90–2.97)	<0.001^*
WHO 2	3.84 (2.99–4.91)	<0.001^*
WHO 3	7.87 (5.90–10.5)	<0.001^*
WHO 4	27.6 (16.5–46.2)	<0.001^*
WHO Missing	2.90 (2.21–3.81)	<0.001^*
Tumor Site
Oropharynx	-	-
Oral cavity	1.21 (0.95–1.53)	0.121
Larynx	1.13 (0.85–1.51)	0.397
Hypopharynx	1.58 (1.16–2.14)	0.003^*
Nasopharynx	0.510 (0.21–1.24)	0.137
Sino nasal	0.984 (0.63–1.53)	0.943
Salivary Gland	0.890 (0.61–1.31)	0.555
Lip	0.629 (0.41–0.95)	0.029^*
CUP	1.58 (0.95–2.64)	0.077
Ear	4.84 (0.67–34.9)	0.118

Open in a new tab

*^{significant differences in multivariable analysis}

Patients with a WHO score of 1 had approximately 2.4-times greater risk of early death compared to WHO 0 patients (p <0.001). The risk of early death among WHO 4 patients was almost 28 times higher than for WHO 0 patients (p <0.001).

A patient with a tumor localized in the hypopharynx had a 1.58-times higher risk of dying within six months compared to a patient with a tumor in the oropharynx (p = 0.003). Patients with a T3/4 tumor had a 2.9-times higher risk of dying within six months compared to T1/2 patients (p <0.001). It was found that patients with neck metastasis at diagnosis had a 1.6-times higher risk of dying within six months compared to patients without nodal involvement (p <0.001). Distant metastasis at diagnosis gave a 2.3-times higher risk of dying within six months (p = 0.002) (Table 4).

These results form a risk profile where year of diagnosis, higher age, male sex, hypopharyngeal tumor, advanced TNM class, and higher WHO score constitute risk factors for early death.

Discussion

This real-world, population-based, Swedish nationwide study, including 16,786 patients with HNC and curative treatment intent demonstrated that year of diagnosis, higher age, higher TNM class, male sex, higher WHO class, and a tumor in the hypopharynx were independent risk factors for death within six months of diagnosis. This study is a unique contribution to the knowledge of early death in patients with HNC, highlighting the significant reduction of 6-month mortality of 53% from 2008 to 2020. The effects of standardized protocols to ensure that all patients receive adequate treatment without unnecessary delays might have contributed to this reduction.

Throughout the study period, patients with curative treatment intent (n = 16,786) had 3.7% six-month mortality overall. Jensen et al. reported a 7.1% six-month mortality rate in a Danish nationwide study including 11,419 HNC patients between 2000 and 2017 treated with curatively intended radio- or chemoradiotherapy. The same author studied a series of 2209 HNC patients between 2010 and 2017 from multiple centers and found a non—cancer-specific six-month mortality of 4.4% following treatment with radiotherapy [24, 25]. Nieminen et al. reported a six-month mortality of 11.4% in a subgroup of 317 HNC patients undergoing microvascular reconstruction [26]. As patients with HNC comprise a heterogenous population, the early mortality rate differs if subpopulations of patients are analyzed. Studies looking merely at treatment with radiotherapy, or at microvascular reconstruction contain pre-selected patient cohorts likely affecting the rate of early death. Our study includes all surgical and oncological treatment options for patients with curative treatment intent and all T classes. Patients undergoing treatment with a free flap and microvascular reconstruction typically have at least a T2 tumor [17], indicating a disease with a higher risk of early death.

In the present study, men had a higher risk of early death, in accordance with the findings by Kouka et al. in their series of 8288 German HNC patients [27]. Other studies have not shown a sex-dependent rate of early death in HNC patients [12, 24]. In this study there is an uneven distribution between sexes regarding tumor stage and site; for example, only 23.5% of hypopharyngeal cancer patients were female, which can partly explain the better prognostic outcome for females.

Other studies have suggested that estrogen could have a beneficial impact on survival after HNC [28–31], however that correlation was not analyzed here. In consistency with other studies [8, 12, 24, 26, 27, 32, 33], we saw that higher age and performance status correlated with an increased rate of early death. Furthermore, a hypopharyngeal tumor location, higher stage, and advanced T class were confirmed as significant independent risk factors for six-month mortality, in accordance with previous findings [12, 32, 34, 35].

Our study has revealed that the six-month mortality decreased throughout the 2008–2020 period. The reasons are most likely multifactorial. Sweden implemented standardized diagnostic work ups in 2015, which led to faster diagnoses and shortened waiting times before treatment for HNC patients. The same year, national guidelines for HNC treatment were published, leading to a national standardized consensus regarding diagnostic work-up and treatment [18]. Furthermore, oropharyngeal cancer derived from HPV is increasing [2, 7, 36–38], and has a better prognosis compared to HPV-negative tumors [39, 40]. The substantial increase in HPV-positive cancers and the decreased prevalence of daily smokers in Sweden (12% in 2008 to 8% in 2020), contributing to less HPV-negative HNC cases can be part of the explanation as to why six-month mortality is decreasing for HNC patients [41–43].

It is reasonable to speculate that a number of variables not registered in SweHNCR have improved the diagnostic work-up, treatment, and care of patients with HNC. Neck dissection was implemented 2015 in Sweden as the standard treatment for oral cavity cancer patients with a depth of invasion of the primary tumor exceeding 3 millimeters and N0 status [18]. This change is likely contributing to more active treatment of occult metastasis, and therefore to improved survival rates. It is also likely that novel innovative therapy has had an impact on early mortality. Since 2008, there have been several improvements in oncological treatments such as a change in external radiotherapy from using 3D conformal radiotherapy to intensity-modulated radiotherapy and volumetric modulated arc radiotherapy, shifts from neoadjuvant high-dose cisplatin regimens to concomitant cisplatin. Concomitant cetuximab treatment was proven to be less effective than concomitant cisplatin, and was excluded from routine treatment [44]. The rise of checkpoint inhibitors in the treatment of cancer have altered the prognosis for many different types of cancers [45]. However, it should be pointed out that cancer immunotherapy is only used in patients receiving palliative treatment for HNC [17]. New diagnostic tools have been increasingly available for accurate HNC diagnosis. The implementation of sentinel node biopsies in Sweden could also have contributed to identifying more contra- or bilateral metastases [46]. Moreover, the use of Positron Emission Tomography with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with Computed Tomography, FDG-PET/CT has improved the detection of regional and distant metastases [47, 48]. Altogether, this study suggests that standardized and rapid diagnostic work-up and treatment, together with other factors, contributes to fewer HNC patients dying within six months of diagnosis.

The limitations of the study includes its retrospective setting [49], the fact that important parameters influencing overall survival, such as comorbidities, alcohol consumption, HPV status, and smoking habits were not recorded in the early years of SweHNCR. Actual cause of death was not reported in the register, nor were data on occupational exposures, socioeconomic factors, oral hygiene, complications to treatments, and gene mutations; all factors which could influence early mortality [1, 33, 50, 51].

Compensating for several of the study’s limitations is the large population of 16,786 consecutive HNC patients with curative treatment intent, and the homogeneity of healthcare provided to all Swedes. The results in this study can be used to identify patients at high risk of early death, and thus to improve therapeutical decision making and more personalized HNC management.

Conclusion

This first European population-based analysis of trends in six-month mortality among HNC patients with curative treatment intent is based on registry data comprising 16,786 patients. The study provides generalizable epidemiological data on early mortality and survival of curative HNC patients, in a single-payer funded healthcare setting. The mean time to treatment was significantly decreased between the years 2008 and 2012 compared to 2017–2020. Encouragingly, the present results show that early mortality has decreased from 4.7% (2008–2012) to 2.5% (2017–2020) in Sweden. Female patients had a 20% lower risk of death within six months compared to male patients.

Increased age at diagnosis, male sex, higher WHO function class, advanced TNM class, and tumor in the hypopharynx were independent risk factors for death within six months.

Acknowledgments

We would like to thank Mats Fredriksson, statistician at Linköping University, for excellent statistical guidance.

Data Availability

All data are owned by a third party organization. The Swedish Head and Neck cancer Registry (SweHNCR) and Regional Cancer Center Väst owns the data. The SweHNCR contains data on almost 99% of all Head and Neck cancer patients in Sweden. The registry started in 2008. The Registry contains data on sex, age, TNM score, WHO score, smoking habits, date of diagnosis, date of death, stage, tumor site, treatment given, treatment intent, date of treatment, time from diagnosis to treatment. The authors did not receive any special privileges accessing the data that other researchers would not have. To access the data please file a formal application via this link. https://cancercentrum.se/samverkan/vara-uppdrag/kunskapsstyrning/kvalitetsregister/datauttag/ Questions regarding the Registry and access to data can be e-mailed to: arvid.widenlou.nordmark@regionvasterbotten.se.

Funding Statement

This study was supported in the form of funding by Region Östergötland (Grant No. SC-2018-00231-53) awarded to CT, Region Östergötland (Grant No. SC-2018-00231-46) awarded to LF, Cancerfonden (Grant No. 2018/502) awarded to GL, and Finska Läkaresällskapet (Grant No. AM2023) awarded to AM.

References

1.Cohen N, Fedewa S, Chen AY. Epidemiology and Demographics of the Head and Neck Cancer Population. Oral Maxillofac Surg Clin North Am. 2018;30(4):381–95. Epub 20180803. doi: 10.1016/j.coms.2018.06.001 . [DOI] [PubMed] [Google Scholar]
2.Roman BR, Aragones A. Epidemiology and incidence of HPV-related cancers of the head and neck. J Surg Oncol. 2021;124(6):920–2. Epub 20210923. doi: 10.1002/jso.26687 . [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Rettig EM, D’Souza G. Epidemiology of head and neck cancer. Surg Oncol Clin N Am. 2015;24(3):379–96. Epub 2015/05/17. doi: 10.1016/j.soc.2015.03.001 . [DOI] [PubMed] [Google Scholar]
4.Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022;233(9):780–6. Epub 20221111. doi: 10.1038/s41415-022-5166-x . [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Cancercentrum R. Swedish Head and Neck Cancer Register (SweHNCR) http://www.Cancercentrum.se: RCC, 2018.
6.Cancercentrum R. Årsrapport Nationellt Kvalitetsregister 2020. Cancercentrum.se: 2020.
7.samverkan RCi. Arsrapport nationellt kvalitetsregister, 2022. Cancercentrum: RCC; 2021.
8.Guo K, Xiao W, Chen X, Zhao Z, Lin Y, Chen G. Epidemiological Trends of Head and Neck Cancer: A Population-Based Study. Biomed Res Int. 2021;2021:1738932. Epub 20210714. doi: 10.1155/2021/1738932 . [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Gronhoj C, Hjalgrim L, Jakobsen KK, Charabi B, Mirian C, Laier GH, et al. Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014. Pediatr Blood Cancer. 2018;65(7):e27037. Epub 2018/04/01. doi: 10.1002/pbc.27037 . [DOI] [PubMed] [Google Scholar]
10.Gatta G, Botta L, Sanchez MJ, Anderson LA, Pierannunzio D, Licitra L, et al. Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study. Eur J Cancer. 2015;51(15):2130–43. Epub 20150926. doi: 10.1016/j.ejca.2015.07.043 . [DOI] [PubMed] [Google Scholar]
11.Mroueh R, Haapaniemi A, Grenman R, Laranne J, Pukkila M, Almangush A, et al. Improved outcomes with oral tongue squamous cell carcinoma in Finland. Head Neck. 2017;39(7):1306–12. Epub 20170508. doi: 10.1002/hed.24744 . [DOI] [PubMed] [Google Scholar]
12.Talani C, Makitie A, Beran M, Holmberg E, Laurell G, Farnebo L. Early mortality after diagnosis of cancer of the head and neck—A population-based nationwide study. PLoS One. 2019;14(10):e0223154. Epub 2019/10/03. doi: 10.1371/journal.pone.0223154 . [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Mayland CR, Ingarfield K, Rogers SN, Dey P, Thomas S, Waylen A, et al. Disease trajectories, place and mode of death in people with head and neck cancer: Findings from the ’Head and Neck 5000’ population-based prospective clinical cohort study. Palliat Med. 2020;34(5):639–50. Epub 20200227. doi: 10.1177/0269216320904313 . [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Farnebo L, Malila N, Makitie A, Laurell G. Early death among head and neck cancer patients. Curr Opin Otolaryngol Head Neck Surg. 2016;24(2):115–20. doi: 10.1097/MOO.0000000000000236 . [DOI] [PubMed] [Google Scholar]
15.Granström B, Tiblom Ehrsson Y, Holmberg E, Hammerlid E, Beran M, Tano K, et al. Return to work after oropharyngeal cancer treatment-Highlighting a growing working-age population. Head Neck. 2020;42(8):1893–901. Epub 20200224. doi: 10.1002/hed.26123 . [DOI] [PubMed] [Google Scholar]
16.Adnan A, Högmo A, Sjödin H, Gebre-Medhin M, Laurell G, Reizenstein J, et al. Health-related quality of life among tonsillar carcinoma patients in Sweden in relation to treatment and comparison with quality of life among the population. Head Neck. 2020;42(5):860–72. Epub 20200210. doi: 10.1002/hed.26064 . [DOI] [PubMed] [Google Scholar]
17.Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1462–75. Epub 20201023. doi: 10.1016/j.annonc.2020.07.011 . [DOI] [PubMed] [Google Scholar]
18.Cancercentrum. Nationellt vårdprogram huvud- och halscancer [Internet]: Regionala Cancercentrum i samverkan; 2015 [updated 15-08-25; cited 2017 december 4]. https://www.cancercentrum.se/samverkan/cancerdiagnoser/huvud-och-hals/vardprogram/gallande-vardprogram/.
19.Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th 2009. ed. Chichester, West Sussex, UK;: Wiley-Blackwell; 2010. [Google Scholar]
20.Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55. Epub 1982/12/01. . [PubMed] [Google Scholar]
21.Befolkningsdatabas [Internet]. Statistics Sweden. 2022. https://www.statistikdatabasen.scb.se/pxweb/sv/ssd/START__BE__BE0101__BE0101A/BefolkningR1860N/table/tableViewLayout1/.
22.Statistical Database [Internet]. 2022.
23.Martin DO, Austin H. Exact estimates for a rate ratio. Epidemiology. 1996;7(1):29–33. doi: 10.1097/00001648-199601000-00006 . [DOI] [PubMed] [Google Scholar]
24.Jensen KH, Vogelius I, Kristensen CA, Andersen E, Overgaard J, Eriksen JG, et al. Early Mortality after Radical Radiotherapy in Head and Neck Cancer—A Nationwide Analysis from the Danish Head and Neck Cancer Group (DAHANCA) Database. Clin Oncol (R Coll Radiol). 2021;33(1):57–63. Epub 20200719. doi: 10.1016/j.clon.2020.07.004 . [DOI] [PubMed] [Google Scholar]
25.Jensen KH, Vogelius IR, Bernsdorf M, Gothelf A, Kristensen CA, Maare C, et al. Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma. Radiother Oncol. 2022;171:1–6. Epub 20220405. doi: 10.1016/j.radonc.2022.03.020 . [DOI] [PubMed] [Google Scholar]
26.Nieminen T, Tolvi M, Lassus P, Wilkman T, Lehtonen L, Makitie A. Risk factors for evaluating early mortality after microvascular reconstruction of head and neck cancers. Scand J Surg. 2022:14574969221117010. Epub 20220824. doi: 10.1177/14574969221117010 . [DOI] [PubMed] [Google Scholar]
27.Kouka M, Buentzel J, Kaftan H, Boeger D, Mueller AH, Wittig A, et al. Early Mortality among Patients with Head and Neck Cancer Diagnosed in Thuringia, Germany, between 1996 and 2016-A Population-Based Study. Cancers (Basel). 2022;14(13). Epub 20220624. doi: 10.3390/cancers14133099 . [DOI] [PMC free article] [PubMed] [Google Scholar]
28.DEON CP, Brito HO, DAC RMG, Brito LMO. Is There a Role for Sex Hormone Receptors in Head-and-neck Cancer? Links with HPV Infection and Prognosis. Anticancer Res. 2021;41(8):3707–16. doi: 10.21873/anticanres.15162 . [DOI] [PubMed] [Google Scholar]
29.Grunow J, Rong C, Hischmann J, Zaoui K, Flechtenmacher C, Weber KJ, et al. Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells. J Exp Clin Cancer Res. 2017;36(1):25. Epub 20170206. doi: 10.1186/s13046-017-0496-2 . [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Verma A, Schwartz N, Cohen DJ, Patel V, Nageris B, Bachar G, et al. Loss of Estrogen Receptors is Associated with Increased Tumor Aggression in Laryngeal Squamous Cell Carcinoma. Sci Rep. 2020;10(1):4227. Epub 20200306. doi: 10.1038/s41598-020-60675-2 . [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Verma A, Schwartz N, Cohen DJ, Boyan BD, Schwartz Z. Estrogen signaling and estrogen receptors as prognostic indicators in laryngeal cancer. Steroids. 2019;152:108498. doi: 10.1016/j.steroids.2019.108498 [DOI] [PubMed] [Google Scholar]
32.Hamilton SN, Tran E, Berthelet E, Wu J, Olson R. Early (90-day) mortality after radical radiotherapy for head and neck squamous cell carcinoma: A population-based analysis. Head Neck. 2018;40(11):2432–40. Epub 20181008. doi: 10.1002/hed.25352 . [DOI] [PubMed] [Google Scholar]
33.Datema FR, Ferrier MB, van der Schroeff MP, Baatenburg de Jong RJ. Impact of comorbidity on short-term mortality and overall survival of head and neck cancer patients. Head Neck. 2010;32(6):728–36. doi: 10.1002/hed.21245 . [DOI] [PubMed] [Google Scholar]
34.Jakobsen KK, Gronhoj C, Jensen DH, Karnov KKS, Agander TK, Specht L, et al. Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014. Acta Oncol. 2018;57(9):1143–51. Epub 20180215. doi: 10.1080/0284186X.2018.1438657 . [DOI] [PubMed] [Google Scholar]
35.Massa ST, Osazuwa-Peters N, Christopher KM, Arnold LD, Schootman M, Walker RJ, et al. Competing causes of death in the head and neck cancer population. Oral Oncol. 2017;65:8–15. doi: 10.1016/j.oraloncology.2016.12.006 . [DOI] [PubMed] [Google Scholar]
36.Maxwell JH, Grandis JR, Ferris RL. HPV-Associated Head and Neck Cancer: Unique Features of Epidemiology and Clinical Management. Annu Rev Med. 2016;67:91–101. Epub 2015/09/04. doi: 10.1146/annurev-med-051914-021907 . [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Lechner M, Liu J, Masterson L, Fenton TR. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol. 2022;19(5):306–27. Epub 20220201. doi: 10.1038/s41571-022-00603-7 . [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Lorenzoni V, Chaturvedi AK, Vignat J, Laversanne M, Bray F, Vaccarella S. The Current Burden of Oropharyngeal Cancer: A Global Assessment Based on GLOBOCAN 2020. Cancer Epidemiol Biomarkers Prev. 2022;31(11):2054–62. doi: 10.1158/1055-9965.EPI-22-0642 . [DOI] [PubMed] [Google Scholar]
39.Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747–55. Epub 20120120. doi: 10.1002/hed.22015 . [DOI] [PubMed] [Google Scholar]
40.Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37. Epub 20170127. doi: 10.3322/caac.21389 . [DOI] [PubMed] [Google Scholar]
41.Ramström L, Borland R, Wikmans T. Patterns of Smoking and Snus Use in Sweden: Implications for Public Health. Int J Environ Res Public Health. 2016;13(11). Epub 20161109. doi: 10.3390/ijerph13111110 . [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Folkhälsomyndigheten. Vuxnas bruk av tobaks- och nikotinprodukter www.folkhalsomyndigheten.se: Folkhälsomyndigheten; 2022 [cited 2023 230216]. https://www.folkhalsomyndigheten.se/livsvillkor-levnadsvanor/andts/utveckling-inom-andts-anvandning-och-ohalsa/anvandning/anvandning-av-tobaks-och-nikotinprodukter/vuxnas-bruk-av-tobaks-och-nikotinprodukter.
43.Folkhälsomyndigheten. Tobaksrökning, daglig [Internet] Stockholm: Folkhälsomyndigheten; 2022 [cited 2023 230305]. https://www.folkhalsomyndigheten.se/folkhalsorapportering-statistik/tolkad-rapportering/folkhalsans-utveckling/resultat/levnadsvanor/tobaksrokning-daglig/.
44.Gebre-Medhin M, Brun E, Engström P, Cange HH, Hammarstedt-Nordenvall L, Reizenstein J, et al. ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer. Journal of Clinical Oncology. 2021;39(1):38–47. doi: 10.1200/JCO.20.02072 . [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Ling SP, Ming LC, Dhaliwal JS, Gupta M, Ardianto C, Goh KW, et al. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers (Basel). 2022;14(21). Epub 20221024. doi: 10.3390/cancers14215205 . [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Bark R, Kolev A, Elliot A, Piersiala K, Näsman A, Grybäck P, et al. Sentinel node-assisted neck dissection in advanced oral squamous cell carcinoma-A new protocol for staging and treatment. Cancer Med. 2023;12(11):12524–34. Epub 20230421. doi: 10.1002/cam4.5966 . [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Kim SA, Roh JL, Kim JS, Lee JH, Lee SH, Choi SH, et al. 18F-FDG PET/CT surveillance for the detection of recurrence in patients with head and neck cancer. Eur J Cancer. 2017;72:62–70. doi: 10.1016/j.ejca.2016.11.009 . [DOI] [PubMed] [Google Scholar]
48.Marcus C, Sheikhbahaei S, Shivamurthy VKN, Avey G, Subramaniam RM. PET Imaging for Head and Neck Cancers. Radiol Clin North Am. 2021;59(5):773–88. doi: 10.1016/j.rcl.2021.05.005 . [DOI] [PubMed] [Google Scholar]
49.Talari K, Goyal M. Retrospective studies—utility and caveats. Journal of the Royal College of Physicians of Edinburgh. 2020;50(4):398–402. doi: 10.4997/JRCPE.2020.409 [DOI] [PubMed] [Google Scholar]
50.Gaubatz ME, Bukatko AR, Simpson MC, Polednik KM, Adjei Boakye E, Varvares MA, et al. Racial and socioeconomic disparities associated with 90-day mortality among patients with head and neck cancer in the United States. Oral Oncol. 2019;89:95–101. Epub 20181229. doi: 10.1016/j.oraloncology.2018.12.023 . [DOI] [PubMed] [Google Scholar]
51.Rieke K, Schmid KK, Lydiatt W, Houfek J, Boilesen E, Watanabe-Galloway S. Depression and survival in head and neck cancer patients. Oral Oncol. 2017;65:76–82. doi: 10.1016/j.oraloncology.2016.12.014 . [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0296534.r001

Decision Letter 0

Chung-Ta Chang

15 Jan 2024

PONE-D-23-41780Six-month mortality has decreased for patients with curative treatment for head and neck cancer in SwedenPLOS ONE

Dear Dr. Talani,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 29 2024 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.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Chung-Ta Chang

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure:"The Östergötland Regional Research Council, SC-2018-00231-53, SC-2018-00231-46"

Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

4. We note that your Data Availability Statement is currently as follows: "All relevant data are within the manuscript and its Supporting Information files."

Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

For example, authors should submit the following data:

- The values behind the means, standard deviations and other measures reported;

- The values used to build graphs;

- The points extracted from images for analysis.

Authors do not need to submit their entire data set if only a portion of the data was used in the reported study.

If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories.

If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

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: This retrospective cohort study of patients in Sweden with HNC analyzed the incidence of different HNC cancers and the trends in early death during the time period of 2008-2020. The study results are important and deserve to be published after major revision of the article.

The statistical and analytic methods appear appropriate but are not well presented in the Methods, Tables, Results, or Figures. This hinders both the ability to review the methods and any future efforts to replicate the findings. For example, there should be baseline characteristics tables for each cohort (at least in the Supplemental), separate from the analytic results tables, so that the populations can be fully understood. The distribution of treatments received over time across cohorts should be reported. All Kaplan-Meier charts should contain risk tables underneath them per best reporting standards.

In general, there is low precision in the writing that needs to be improved, including missing citations and use of vague language. I noted numerous factual statements lacking a citation and insufficient explanations of statements for a general, not explicitly clinical audience of this journal. The Methods section in both the abstract and the main article are missing essential details, including a clear statement of the outcomes assessed, the comparisons performed, and the explicit inclusion/exclusion criteria. All outcomes and comparisons need to be fully described in the Methods. The separation of the cohorts by the years chosen needs to be rationalized.

Clarity and organization overall need improvement and the article would benefit from English language editing for grammar and flow. The authors are encouraged to include subheadings in the Results that improve the ease of reading, beginning with 'Patient Characteristics' and then one for each outcome assessed. All tables and figures should include appropriate captions describing the comparison displayed, defining abbreviations, notes, etc.

Previous literature on the topic of early death in HNC should be mentioned in the Introduction with better precision in terms of years, outcomes, regional populations, trends over defined periods, etc. The current treatment guidelines for HNC in Sweden should be briefly mentioned in the Introduction, as well as the gap in knowledge leading to the rationale for this study. The Discussion needs to highlight the unique contributions of this study in comparison with prior findings, which is currently not clear.

Throughout, it should be clarified that this is a study in a population of Swedish patients (vs. European or HNC patients generally). This is important as Sweden has a single-payer healthcare system and likely different available treatments for HNC compared to other nations. The impact of the advent of targeted or immunotherapy for HNC in Sweden should be discussed in the context of improved survival. The generalizability of the study findings to other regions and HNC population as a whole should be addressed in the Discussion. The limitations section should be more comprehensive and include the general limitations of retrospective cohort studies.

Reviewer #2: The authors aimed to identify risk factors for early death among patients with curative treatment, and to analyze whether the risk of early death changed over the years. In general, this is a well-written article. However, there are still some points need to be addressed.

1. In the Statistics section, the authors mentioned “… and Fisher’s exact test was used for tables with dichotomous variables (Sex, TNM score, and death).” Why these three variables were tested by Fisher’s exact test but not chi-square test?

2. In the Statistics section, the authors mentioned “Exact binomial confidence intervals were estimated forproportions. …..” Please correct “forproportions” to “for proportions.”

3. In Table 1, the authors had shown “Age continuous (mean(sd)) was 66.1 (12.6). Please delete the redundant word of ” continuous”.

4. In Table 2, the “Total patients” column is redundant and the numbers are wrong. Please correct or delete this column. Moreover, the authors should also show the “Stage” as variable to see if any difference in these three groups.

5. In the “Independent factors for death within six months after diagnosis” section, the authors mentioned “A 67-year-old patient had a 4.8% higher risk of dying within six months than a patient who was 66 years old.” Please revised this sentence to correct sentence.

6. In Table 4, the authors should mention that it is calculated by male vs female or female vs male in factor “Sex”. Moreover, the authors should also include “Stage” as factor in multivariable Cox regression analysis since this factor is also significantly different in univariate analysis.

7. In Figure 3 and 4, the authors should also mark the p values in these figures.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PONE-D-23-41780_reviewer_comments.pdf

pone.0296534.s001.pdf^{(1.8MB, pdf)}

PLoS One. 2024 Apr 16;19(4):e0296534. doi: 10.1371/journal.pone.0296534.r002

Author response to Decision Letter 0

20 Feb 2024

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

The manuscript meets PLOS ONE´s style requirements.

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Thank you for highlighting this, the Funding Information section has now been revised and a financial disclosure section has been added as requested.

3. Thank you for stating the following financial disclosure:"The Östergötland Regional Research Council, SC-2018-00231-53, SC-2018-00231-46"

If this statement is not correct you must amend it as needed.

Thank you for this input. It has been added in the new file named ‘Financial disclosure’ and uploaded in the revised submission.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

The following statement has been added to the cover letter:

“The authors received funding for the work with this article but funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

4. We note that your Data Availability Statement is currently as follows: "All relevant data are within the manuscript and its Supporting Information files."

For example, authors should submit the following data:

- The values behind the means, standard deviations and other measures reported;

- The values used to build graphs;

- The points extracted from images for analysis.

Authors do not need to submit their entire data set if only a portion of the data was used in the reported study.

Data is owned by a third party, the Regional Cancer Center Väst, in Sweden, and the data set even though de-identified can therefore not be shared. Data can be accessed through a formal application to the third-party organization via the following link: https://cancercentrum.se/samverkan/vara-uppdrag/kunskapsstyrning/kvalitetsregister/datauttag/

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: No

We wish to thank the Reviewers for reviewing our work so thoroughly. Revisions have been made throughout the manuscript and appear highlighted in the revised paper.

Thank you for highlighting the issue of raw data. Data are owned by a third party, the Regional Cancer Center Väst and can be accessed through a formal application to them via the following link: https://cancercentrum.se/samverkan/vara-uppdrag/kunskapsstyrning/kvalitetsregister/datauttag/

Reviewer #2: Yes

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

Reviewer #1: No

Revisions have been made as requested and can be visualized in the document with tracked chances.

We would like to point out that a language revision has been carried out twice, first by CBG consult before submission in November 2023 and also after after our revisions in February 2024.

Reviewer #2: Yes

5. Review Comments to the Author

Strengths include the large database contributing substantial N for analyses and, I assume, the amount of clinical detail available on the patients. The ethical statements are sufficient. I found the decline in 6-month mortality interesting and encouraging. However, it is important to note that although there was a statistically significant decline in 6-month mortality post-diagnosis, overall, it remained low for curative approach treatment for HNC across all periods. The statistical and analytic methods appear appropriate but are not well presented in the Methods, Tables, Results, or Figures. This hinders both the ability to review the methods and any future efforts to replicate the findings.

For example, there should be baseline characteristics tables for each cohort (at least in the Supplemental), separate from the analytic results tables, so that the populations can be fully understood.

Thank you for the excellent remarks.

Table 2 has been extended to now contain age group distribution between the three different cohorts, highlighted in Table 2.

The distribution of treatments received over time across cohorts should be reported.

Table 2 has been expanded to include the distribution of treatment in the three cohorts.

All Kaplan-Meier charts should contain risk tables underneath them per best reporting standards.

Thank you for this clarifying remark. Risk tables have now been added to the Kaplan-Meier charts in Fig 3 and 4a-c.

Thank you for pointing this out. These issues have been addressed throughout the manuscript and changes are marked in yellow. References have been added as requested by the Reviewer 1 and language improvements have been made for clarification accordingly.

The Methods section in both the abstract and the main article are missing essential details, including a clear statement of the outcomes assessed, the comparisons performed, and the explicit inclusion/exclusion criteria.

Thank you for addressing this matter. In our nation-wide study we excluded all patients below the age of 18 years. This exclusion criterion was added to the Abstract and the main article. All patients above the age of 18 with a head and neck cancer diagnosis were included. Merely data for 1,5% of the patients were missing. Unfortunately, it is not known why these patients were missing or who they were, but it can be speculated that they were patients having for example T1 lip cancer, and thus having been surgically treated by another specialist than an ENT-doctor/Head and Neck surgeon. Other specialists are not as well informed about the registration of head and neck cancers in the SweHNCR and can thereby miss to register their case. Palliative patients were not included in the statistical analysis since this paper focused on patients with curative treatment intent, as shown in Fig 1.

Fig 1 has clarified this by adding colored boxes in the flow chart and addressing the inclusion of patients with curative treatment intent only. This is now also described in the Figure Legends.

All outcomes and comparisons need to be fully described in the Methods. The separation of the cohorts by the years chosen needs to be rationalized.

This has been addressed in Table 2, as described above. A rationale for the separation of the cohort has been added to the methods section. This separation with 5, 4, and 4 years in the groups seems logical since a 24% incidence increase in HNC during the time period was noted.

Clarity and organization overall need improvement and the article would benefit from English language editing for grammar and flow.

As stated above, English language revision was carried out before submission and again before re-submission.

The authors are encouraged to include subheadings in the Results that improve the ease of reading, beginning with 'Patient Characteristics' and then one for each outcome assessed.

For clarity reasons all headings have been reviewed and subheadings were added on page 4 “Data Source”, and page 6 “Epidemiology”. Style and font size of headings were corrected to add clarification to the subsections.

All tables and figures should include appropriate captions describing the comparison displayed, defining abbreviations, notes, etc.

All tables and figures were revised according to the instructions given by Reviewer 1.

Population-based studies on early death are scarce, which is why we wish to address this subject in our large, nationwide population. We wish to thank the Reviewers for revising our work so thoroughly. Revisions have been made throughout the manuscript and the references on early death defined as, death within six months in HNC are added in the second paragraph on page 3.

The current treatment guidelines for HNC in Sweden should be briefly mentioned in the Introduction, as well as the gap in knowledge leading to the rationale for this study.

Thank you for pointing out this important view. The Introduction has been revised according to the Reviewers’ comments, and highlighted in the manuscript on page 3.

The Discussion needs to highlight the unique contributions of this study in comparison with prior findings, which is currently not clear.

The unique contribution of this study is now emphasized in the Discussion subsection on page 15.

Both the Introduction and the Discussion sections have been revised to underscore that the cohort is Swedish.

Targeted therapy/ immunotherapy in Sweden is currently only used in the palliative setting. This study excludes palliative patients, emphasized in the Methods, and Discussions sections.

The generalizability of the study findings to other regions and HNC population as a whole should be addressed in the Discussion.

Thank you – a discussion on the generalizability has been added in the last sentence of the Discussion section, on page 18.

The limitations section should be more comprehensive and include the general limitations of retrospective cohort studies.

We added the limitation of a retrospective study design according to the Reviewers’ request on page 18, including a reference elaborating on the weaknesses of a retrospective setting (Talari et al).

Sex, TNM score, and death were analyzed using Chi-square test, and the Statistics section was revised according to the Reviewers’ suggestion.

2. In the Statistics section, the authors mentioned “Exact binomial confidence intervals were estimated for proportions. …..” Please correct “forproportions” to “for proportions.”

This has been corrected, thank you for pointing it out.

3. In Table 1, the authors had shown “Age continuous (mean(sd)) was 66.1 (12.6). Please delete the redundant word of ” continuous”.

This has been corrected, thank you for pointing it out.

Thank you for this valuable comment. The “Total patients” column has been deleted and Table 2 was revised and now contains data on stage, Age, and Treatment.

We agree with the Reviewer 2 that this sentence was redundant and have now removed it from the manuscript.

A 67-year-old patient had a 4.8% higher risk of dying within six months than a patient who was 66 years old

6. In Table 4, the authors should mention that it is calculated by male vs female or female vs male in factor “Sex”.

Thank you for pointing out this mistake.

The calculation is performed as female vs male, and male having hazard ratio set to 1. This has been corrected in Table 4 by adding two new rows including male and female, and is now highlighted in the revised manuscript.

Moreover, the authors should also include “Stage” as factor in multivariable Cox regression analysis since this factor is also significantly different in univariate analysis.

TNM and stage are overlapping factors in a multivariable analysis, since they both describe the severity of the disease. Furthermore, stage is derived from the TNM classification. We chose TNM classification over stage in the multivariable analysis, because TNM gives a more detailed risk stratification in the multivariable analysis. We wanted to keep the possibility of showing that an advanced T-class had a higher hazard ratio for death within 6 months than regional metastasis, something that stage could not discriminate.

7. In Figure 3 and 4, the authors should also mark the p values in these figures.

P-values have been added to the figure legends in Figures 3 and 4a-c.

Figure 2 has also been revised according to Reviewers’ remarks. Axis legend has been enlarged and numerical data were added in Fig 2a.

Attachment

Submitted filename: response to reviewers.docx

pone.0296534.s002.docx^{(29.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0296534.r003

Decision Letter 1

Chung-Ta Chang

26 Feb 2024

Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden

PONE-D-23-41780R1

Dear Dr. Talani,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Chung-Ta Chang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0296534.r004

Acceptance letter

Chung-Ta Chang

2 Apr 2024

PONE-D-23-41780R1

PLOS ONE

Dear Dr. Talani,

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

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Chung-Ta Chang

Academic Editor

PLOS ONE

Associated Data

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

Supplementary Materials

Attachment

Submitted filename: PONE-D-23-41780_reviewer_comments.pdf

pone.0296534.s001.pdf^{(1.8MB, pdf)}

Attachment

Submitted filename: response to reviewers.docx

pone.0296534.s002.docx^{(29.4KB, docx)}

Data Availability Statement

[pone.0296534.ref001] 1.Cohen N, Fedewa S, Chen AY. Epidemiology and Demographics of the Head and Neck Cancer Population. Oral Maxillofac Surg Clin North Am. 2018;30(4):381–95. Epub 20180803. doi: 10.1016/j.coms.2018.06.001 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref002] 2.Roman BR, Aragones A. Epidemiology and incidence of HPV-related cancers of the head and neck. J Surg Oncol. 2021;124(6):920–2. Epub 20210923. doi: 10.1002/jso.26687 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref003] 3.Rettig EM, D’Souza G. Epidemiology of head and neck cancer. Surg Oncol Clin N Am. 2015;24(3):379–96. Epub 2015/05/17. doi: 10.1016/j.soc.2015.03.001 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref004] 4.Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022;233(9):780–6. Epub 20221111. doi: 10.1038/s41415-022-5166-x . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref005] 5.Cancercentrum R. Swedish Head and Neck Cancer Register (SweHNCR) http://www.Cancercentrum.se: RCC, 2018.

[pone.0296534.ref006] 6.Cancercentrum R. Årsrapport Nationellt Kvalitetsregister 2020. Cancercentrum.se: 2020.

[pone.0296534.ref007] 7.samverkan RCi. Arsrapport nationellt kvalitetsregister, 2022. Cancercentrum: RCC; 2021.

[pone.0296534.ref008] 8.Guo K, Xiao W, Chen X, Zhao Z, Lin Y, Chen G. Epidemiological Trends of Head and Neck Cancer: A Population-Based Study. Biomed Res Int. 2021;2021:1738932. Epub 20210714. doi: 10.1155/2021/1738932 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref009] 9.Gronhoj C, Hjalgrim L, Jakobsen KK, Charabi B, Mirian C, Laier GH, et al. Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014. Pediatr Blood Cancer. 2018;65(7):e27037. Epub 2018/04/01. doi: 10.1002/pbc.27037 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref010] 10.Gatta G, Botta L, Sanchez MJ, Anderson LA, Pierannunzio D, Licitra L, et al. Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study. Eur J Cancer. 2015;51(15):2130–43. Epub 20150926. doi: 10.1016/j.ejca.2015.07.043 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref011] 11.Mroueh R, Haapaniemi A, Grenman R, Laranne J, Pukkila M, Almangush A, et al. Improved outcomes with oral tongue squamous cell carcinoma in Finland. Head Neck. 2017;39(7):1306–12. Epub 20170508. doi: 10.1002/hed.24744 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref012] 12.Talani C, Makitie A, Beran M, Holmberg E, Laurell G, Farnebo L. Early mortality after diagnosis of cancer of the head and neck—A population-based nationwide study. PLoS One. 2019;14(10):e0223154. Epub 2019/10/03. doi: 10.1371/journal.pone.0223154 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref013] 13.Mayland CR, Ingarfield K, Rogers SN, Dey P, Thomas S, Waylen A, et al. Disease trajectories, place and mode of death in people with head and neck cancer: Findings from the ’Head and Neck 5000’ population-based prospective clinical cohort study. Palliat Med. 2020;34(5):639–50. Epub 20200227. doi: 10.1177/0269216320904313 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref014] 14.Farnebo L, Malila N, Makitie A, Laurell G. Early death among head and neck cancer patients. Curr Opin Otolaryngol Head Neck Surg. 2016;24(2):115–20. doi: 10.1097/MOO.0000000000000236 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref015] 15.Granström B, Tiblom Ehrsson Y, Holmberg E, Hammerlid E, Beran M, Tano K, et al. Return to work after oropharyngeal cancer treatment-Highlighting a growing working-age population. Head Neck. 2020;42(8):1893–901. Epub 20200224. doi: 10.1002/hed.26123 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref016] 16.Adnan A, Högmo A, Sjödin H, Gebre-Medhin M, Laurell G, Reizenstein J, et al. Health-related quality of life among tonsillar carcinoma patients in Sweden in relation to treatment and comparison with quality of life among the population. Head Neck. 2020;42(5):860–72. Epub 20200210. doi: 10.1002/hed.26064 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref017] 17.Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1462–75. Epub 20201023. doi: 10.1016/j.annonc.2020.07.011 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref018] 18.Cancercentrum. Nationellt vårdprogram huvud- och halscancer [Internet]: Regionala Cancercentrum i samverkan; 2015 [updated 15-08-25; cited 2017 december 4]. https://www.cancercentrum.se/samverkan/cancerdiagnoser/huvud-och-hals/vardprogram/gallande-vardprogram/.

[pone.0296534.ref019] 19.Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th 2009. ed. Chichester, West Sussex, UK;: Wiley-Blackwell; 2010. [Google Scholar]

[pone.0296534.ref020] 20.Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55. Epub 1982/12/01. . [PubMed] [Google Scholar]

[pone.0296534.ref021] 21.Befolkningsdatabas [Internet]. Statistics Sweden. 2022. https://www.statistikdatabasen.scb.se/pxweb/sv/ssd/START__BE__BE0101__BE0101A/BefolkningR1860N/table/tableViewLayout1/.

[pone.0296534.ref022] 22.Statistical Database [Internet]. 2022.

[pone.0296534.ref023] 23.Martin DO, Austin H. Exact estimates for a rate ratio. Epidemiology. 1996;7(1):29–33. doi: 10.1097/00001648-199601000-00006 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref024] 24.Jensen KH, Vogelius I, Kristensen CA, Andersen E, Overgaard J, Eriksen JG, et al. Early Mortality after Radical Radiotherapy in Head and Neck Cancer—A Nationwide Analysis from the Danish Head and Neck Cancer Group (DAHANCA) Database. Clin Oncol (R Coll Radiol). 2021;33(1):57–63. Epub 20200719. doi: 10.1016/j.clon.2020.07.004 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref025] 25.Jensen KH, Vogelius IR, Bernsdorf M, Gothelf A, Kristensen CA, Maare C, et al. Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma. Radiother Oncol. 2022;171:1–6. Epub 20220405. doi: 10.1016/j.radonc.2022.03.020 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref026] 26.Nieminen T, Tolvi M, Lassus P, Wilkman T, Lehtonen L, Makitie A. Risk factors for evaluating early mortality after microvascular reconstruction of head and neck cancers. Scand J Surg. 2022:14574969221117010. Epub 20220824. doi: 10.1177/14574969221117010 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref027] 27.Kouka M, Buentzel J, Kaftan H, Boeger D, Mueller AH, Wittig A, et al. Early Mortality among Patients with Head and Neck Cancer Diagnosed in Thuringia, Germany, between 1996 and 2016-A Population-Based Study. Cancers (Basel). 2022;14(13). Epub 20220624. doi: 10.3390/cancers14133099 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref028] 28.DEON CP, Brito HO, DAC RMG, Brito LMO. Is There a Role for Sex Hormone Receptors in Head-and-neck Cancer? Links with HPV Infection and Prognosis. Anticancer Res. 2021;41(8):3707–16. doi: 10.21873/anticanres.15162 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref029] 29.Grunow J, Rong C, Hischmann J, Zaoui K, Flechtenmacher C, Weber KJ, et al. Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells. J Exp Clin Cancer Res. 2017;36(1):25. Epub 20170206. doi: 10.1186/s13046-017-0496-2 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref030] 30.Verma A, Schwartz N, Cohen DJ, Patel V, Nageris B, Bachar G, et al. Loss of Estrogen Receptors is Associated with Increased Tumor Aggression in Laryngeal Squamous Cell Carcinoma. Sci Rep. 2020;10(1):4227. Epub 20200306. doi: 10.1038/s41598-020-60675-2 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref031] 31.Verma A, Schwartz N, Cohen DJ, Boyan BD, Schwartz Z. Estrogen signaling and estrogen receptors as prognostic indicators in laryngeal cancer. Steroids. 2019;152:108498. doi: 10.1016/j.steroids.2019.108498 [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref032] 32.Hamilton SN, Tran E, Berthelet E, Wu J, Olson R. Early (90-day) mortality after radical radiotherapy for head and neck squamous cell carcinoma: A population-based analysis. Head Neck. 2018;40(11):2432–40. Epub 20181008. doi: 10.1002/hed.25352 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref033] 33.Datema FR, Ferrier MB, van der Schroeff MP, Baatenburg de Jong RJ. Impact of comorbidity on short-term mortality and overall survival of head and neck cancer patients. Head Neck. 2010;32(6):728–36. doi: 10.1002/hed.21245 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref034] 34.Jakobsen KK, Gronhoj C, Jensen DH, Karnov KKS, Agander TK, Specht L, et al. Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014. Acta Oncol. 2018;57(9):1143–51. Epub 20180215. doi: 10.1080/0284186X.2018.1438657 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref035] 35.Massa ST, Osazuwa-Peters N, Christopher KM, Arnold LD, Schootman M, Walker RJ, et al. Competing causes of death in the head and neck cancer population. Oral Oncol. 2017;65:8–15. doi: 10.1016/j.oraloncology.2016.12.006 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref036] 36.Maxwell JH, Grandis JR, Ferris RL. HPV-Associated Head and Neck Cancer: Unique Features of Epidemiology and Clinical Management. Annu Rev Med. 2016;67:91–101. Epub 2015/09/04. doi: 10.1146/annurev-med-051914-021907 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref037] 37.Lechner M, Liu J, Masterson L, Fenton TR. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol. 2022;19(5):306–27. Epub 20220201. doi: 10.1038/s41571-022-00603-7 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref038] 38.Lorenzoni V, Chaturvedi AK, Vignat J, Laversanne M, Bray F, Vaccarella S. The Current Burden of Oropharyngeal Cancer: A Global Assessment Based on GLOBOCAN 2020. Cancer Epidemiol Biomarkers Prev. 2022;31(11):2054–62. doi: 10.1158/1055-9965.EPI-22-0642 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref039] 39.Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747–55. Epub 20120120. doi: 10.1002/hed.22015 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref040] 40.Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122–37. Epub 20170127. doi: 10.3322/caac.21389 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref041] 41.Ramström L, Borland R, Wikmans T. Patterns of Smoking and Snus Use in Sweden: Implications for Public Health. Int J Environ Res Public Health. 2016;13(11). Epub 20161109. doi: 10.3390/ijerph13111110 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref042] 42.Folkhälsomyndigheten. Vuxnas bruk av tobaks- och nikotinprodukter www.folkhalsomyndigheten.se: Folkhälsomyndigheten; 2022 [cited 2023 230216]. https://www.folkhalsomyndigheten.se/livsvillkor-levnadsvanor/andts/utveckling-inom-andts-anvandning-och-ohalsa/anvandning/anvandning-av-tobaks-och-nikotinprodukter/vuxnas-bruk-av-tobaks-och-nikotinprodukter.

[pone.0296534.ref043] 43.Folkhälsomyndigheten. Tobaksrökning, daglig [Internet] Stockholm: Folkhälsomyndigheten; 2022 [cited 2023 230305]. https://www.folkhalsomyndigheten.se/folkhalsorapportering-statistik/tolkad-rapportering/folkhalsans-utveckling/resultat/levnadsvanor/tobaksrokning-daglig/.

[pone.0296534.ref044] 44.Gebre-Medhin M, Brun E, Engström P, Cange HH, Hammarstedt-Nordenvall L, Reizenstein J, et al. ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer. Journal of Clinical Oncology. 2021;39(1):38–47. doi: 10.1200/JCO.20.02072 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref045] 45.Ling SP, Ming LC, Dhaliwal JS, Gupta M, Ardianto C, Goh KW, et al. Role of Immunotherapy in the Treatment of Cancer: A Systematic Review. Cancers (Basel). 2022;14(21). Epub 20221024. doi: 10.3390/cancers14215205 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref046] 46.Bark R, Kolev A, Elliot A, Piersiala K, Näsman A, Grybäck P, et al. Sentinel node-assisted neck dissection in advanced oral squamous cell carcinoma-A new protocol for staging and treatment. Cancer Med. 2023;12(11):12524–34. Epub 20230421. doi: 10.1002/cam4.5966 . [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0296534.ref047] 47.Kim SA, Roh JL, Kim JS, Lee JH, Lee SH, Choi SH, et al. 18F-FDG PET/CT surveillance for the detection of recurrence in patients with head and neck cancer. Eur J Cancer. 2017;72:62–70. doi: 10.1016/j.ejca.2016.11.009 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref048] 48.Marcus C, Sheikhbahaei S, Shivamurthy VKN, Avey G, Subramaniam RM. PET Imaging for Head and Neck Cancers. Radiol Clin North Am. 2021;59(5):773–88. doi: 10.1016/j.rcl.2021.05.005 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref049] 49.Talari K, Goyal M. Retrospective studies—utility and caveats. Journal of the Royal College of Physicians of Edinburgh. 2020;50(4):398–402. doi: 10.4997/JRCPE.2020.409 [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref050] 50.Gaubatz ME, Bukatko AR, Simpson MC, Polednik KM, Adjei Boakye E, Varvares MA, et al. Racial and socioeconomic disparities associated with 90-day mortality among patients with head and neck cancer in the United States. Oral Oncol. 2019;89:95–101. Epub 20181229. doi: 10.1016/j.oraloncology.2018.12.023 . [DOI] [PubMed] [Google Scholar]

[pone.0296534.ref051] 51.Rieke K, Schmid KK, Lydiatt W, Houfek J, Boilesen E, Watanabe-Galloway S. Depression and survival in head and neck cancer patients. Oral Oncol. 2017;65:76–82. doi: 10.1016/j.oraloncology.2016.12.014 . [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden

Charbél Talani

Anders Högmo

Göran Laurell

Antti Mäkitie

Lovisa Farnebo

Roles

Abstract

Background

Material and method

Results

Conclusions

Background

Material and methods

Data source

Patient population

Fig 1. Flow chart describing treatment intent, year of diagnosis, and early death for included patients in green boxes.

Statistics

Results

Epidemiology

Fig 2.

Predictors for six-month mortality

Year of diagnosis

Table 1. Descriptive data for patients with curative treatment intent, and univariate analysis of death within 6 months of diagnosis.

Table 2. Descriptive data for patients with curative treatment intent grouped by time of diagnosis and univariate analyses.

Fig 3. Kaplan–Meier curve of death within six months from diagnosis based on year of diagnosis, log rank test (p <0.001).

Time to treatment

Sex

Fig 4.

Age

WHO score

Site

Table 3. Descriptive data for patients with curative treatment intent, and univariate analysis of death within 6 months of diagnosis.

Stage

TNM class

Independent factors for death within six months after diagnosis

Table 4. Multivariable Cox regression with death within six months of diagnosis as target variable for HNC patients undergoing curative-intended treatment.

Discussion

Conclusion

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Chung-Ta Chang

Roles

Author response to Decision Letter 0

Decision Letter 1

Chung-Ta Chang

Roles

Acceptance letter

Chung-Ta Chang

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases