Keywords
anterolateral craniofacial resection - orbital exenteration - quality of life - skull
base malignant tumor - early psychiatric intervention - hospital anxiety and depression
scale - medical outcomes study 8-items short form health survey
Introduction
Craniofacial resection allows a skull base tumor to be resected en bloc with negative
margins and is considered the gold standard treatment for malignant tumors at this
site. After the first report by Ketcham et al in 1963, craniofacial resection was
initially considered a challenging operation that occasionally had severe complications.[1] However, craniofacial resection has become safe and feasible because of improvements
in diagnostic modalities (computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose-positron
emission tomography) and surgical techniques, for example, free flap reconstruction
and navigation.[2]
[3]
[4]
[5] Moreover, recent advances in technology, such as preoperative surgical simulation
with three-dimensional virtual imaging, have enhanced surgeons' understanding of the
operative anatomy of individual patients in three-dimensions, thereby contributing
to training for surgeons.[6] At our hospital, we have performed craniofacial resection and reported favorable
prognoses and acceptable complication rates in patients with locally advanced malignant
skull base tumors.[5]
[6]
[7]
[8]
[9]
The management of orbital invasion of malignant tumors, such as sinonasal carcinoma
or skin cancer, remains controversial because of the considerable psychological impact
on patients. It is well known that intraperiosteal orbital involvement is an important
prognostic factor for malignant skull base tumors.[10]
[11] The prognosis is negatively affected in patients with malignant maxillary sinus
tumors when there is tumor invasion beyond the orbital periosteum. A clear decrease
in 5-year overall survival (OS) from 49% in patients with invasion of the bony orbital
wall and involvement of the orbital periosteum to 17% in those with involvement of
the orbital soft tissues has been reported.[12] Most authorities agree that, if possible, wide en bloc surgical resection of the
tumor with negative margins is the most important goal. Several reports have shown
that a positive surgical margin is also a risk factor for poor survival in patients
with malignant skull base tumors.[13]
[14] Surgical resection with negative margins is essential when these tumors show widespread
orbital invasion, respond poorly to radiotherapy and chemotherapy, or recur after
radiotherapy.[15] However, the choice of extended surgical resection with orbital exenteration (OE)
is often difficult for patients because of the negative cosmetic impact. Extended
surgery with OE has a marked effect on physical appearance and function, and tends
to cause anxiety, depression, and deterioration in quality of life (QoL).[16]
[17] The indirect negative effect of psychiatric disorders, such as depression, on the
outcomes of cancer treatment is also well known.[18]
[19] A recent prospective clinical cohort study in patients with head and neck cancer
showed an association between depression and mortality and that decreasing psychological
distress was important with regard to the outcome of treatment and improving QoL.[20]
Anterolateral craniofacial resection (AL-CFR) with OE is an effective treatment for
patients with locally advanced malignant skull base tumors, particularly locally advanced
sinonasal carcinoma. However, AL-CFR with OE is a highly invasive surgery, so it is
important to manage psychological distress in patients undergoing this procedure.
To the best of our knowledge, there has been no research on anxiety, depression, and
health-related QoL in patients who undergo AL-CFR with OE. The aim of this study was
to assess the effect of AL-CFR with OE on health-related QoL in patients with malignant
skull base tumors and to investigate the effects of early psychiatric intervention.
Materials and Methods
Study Design
Twenty-six consecutive patients with anterior to middle malignant skull base tumors
who were treated at our hospital between 2005 and 2015 were enrolled in this prospective
observational study. All patients underwent AL-CFR with OE. Patients with a cognitive
disorder, schizophrenia, or another psychotic disorder were excluded. [Fig. 1] shows the psychiatric assessment and intervention protocol for patients who undergo
AL-CFR with OE at our hospital. Health-related QoL is assessed using the Hospital
Anxiety and Depression Scale (HADS) and medical outcomes study 8-items Short Form
health survey (SF-8). These brief self-reported questionnaires are completed by each
patient preoperatively and 3, 6, 12, and 24 months after surgery.
Fig. 1 Psychiatric assessment and intervention for patients who have undergone anterolateral
craniofacial resection with orbital exenteration at our hospital. HADS, hospital anxiety
and depression scale; SF-8, medical outcomes study 8-items Short Form health survey.
The study was approved under the guidelines for epidemiological studies by the Ethics
Review Committee of Nagoya University Graduate School of Medicine and Nagoya University
Hospital (approval no. 2007–0543). Informed consent was obtained from each patient
by the attending psychiatrist before enrolment in the study.
Treatment Strategy
The surgical procedure used at our institution has already been described in detail.[6]
[8] In brief, using a Weber–Fergusson incision, we remove the tumor en bloc with the
surrounding tissues, including the orbit, hard palate, oral mucosa, and affected mucosa
of the nasal septum. A frontotemporal craniotomy is performed, and the anterior and
middle cranial bases are exposed epidurally. After en bloc resection of the tumor,
the defect in the cranial base is covered using a myocutaneous rectus abdominis free
flap and occasionally a temporoparietal-galeal flap. The upper and lower eyelids are
preserved unless the tumor has directly invaded the eyelids. Orbital bony reconstruction
with a free flap and orbital floor reconstruction with titanium mesh are not performed.
The tumor margins are evaluated in all cases, and it is recommended that postoperative
radiotherapy (50–60 Gy in 2-Gy fractions at five fractions per week to the tumor bed)
be administered within 8 weeks of tumor resection. We recommend cisplatin-based chemoradiotherapy
as adjuvant treatment for patients with positive margins or extranodal spread. After
these treatments, the patients are followed up routinely at 3-month intervals in the
outpatient clinic.
Psychiatric Assessment and Intervention
In this study, all patients underwent psychiatric intervention organized by the consultation
liaison psychiatric team preoperatively and postoperatively, as described previously
by Adachi et al.[21] Psychiatrists assessed the mental condition of each patient preoperatively and arranged
active intervention by the psychiatric liaison team for patients with treated psychiatric
disorders. All psychiatric diagnoses were made by psychiatrists based on the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).[22] Baseline demographic and medical data were obtained by interview or from the medical
records. During periods when patients were at high risk for delirium, for example,
stay in the intensive care unit or the first postoperative week, haloperidol 2.5 to
5.0 mg was infused intravenously because of swallowing difficulties. Thereafter, depending
on the patient's postoperative mental state, psychopharmacological agents, for example,
risperidone 0.5 to 1.0 mg for delirium, mirtazapine 15 to 30 mg for depression, and
brotizolam 0.25 mg for insomnia, were more likely to be administered orally.
Hospital Anxiety and Depression Scale Questionnaire
The Japanese version of the HADS questionnaire was used to assess the severity of
depression in our patients.[23] This instrument is often used in cancer studies and consists of two subscales, that
is, anxiety and depression, with seven items each and rated on a four-point (0–3)
Likert's scale. The scores for each subscale range from 0 to 21, with higher scores
reflecting more severe symptoms. A threshold value of 8 is recommended to identify
all potential cases of anxiety and depression.[24]
Short Form-8 Questionnaire
The SF-8 was used to assess health-related QoL in our patients. The SF-8 is a generic
questionnaire that is derived from the longer 36-item Short Form health survey (SF-36).[25] The original instrument was developed in English and was subsequently translated
into Japanese. Importantly, results obtained from the SF-8 demonstrate a high correlation
with the SF-36, and the reliability and validity of this instrument has been confirmed
in the general population of Japan.[26] Administration of the SF-8 generates a health profile of eight domains, including
general health, physical function, role physical, bodily pain, vitality, social functioning,
mental health, and role emotional. The SF-8 also provides two higher order summary
scores, that is, the physical component summary (PCS) and the mental component summary
(MCS). Scores for each summary ranges from 0 to 100. A higher score represents better
health-related QoL. The QoL scores are assessed using the norm-based scoring method
outlined in the manual of the original version of the SF-8.[24] This norm-based scoring method can be used to compare the results of the SF-8 and
SF-36.
Statistical Methods
Descriptive statistics and figures were obtained using GraphPad Prism (Version 6.0c,
GraphPad Software Inc., La Jolla, California, United States). The Kaplan–Meier method
was used to estimate survival, defined as the interval between surgery and a target
event or last contact. The target events included survival (overall [OS]) and (disease-free
[DFS]). Adverse events that occurred within 30 days postoperatively were considered
to be surgical complications. Cerebrospinal fluid (CSF) leak was classified as major
if it lasted for more than 1 week or required operative intervention. Loss of all
or part of the flap used in the reconstruction and the need for surgical treatment
were considered to be major wound complications.
The mean scores on the SF-8 subscales and two SF-8 composite scores before and 3,
6, 12, and 24 months after surgery were compared with 1,000 published sample scores
for the general Japanese population. We performed a homogeneity test with all the
data and applied the Student's t-test when equal variance was assumed and Welch's t-test when equal variance was not assumed. Further analysis of both of the HADS scores
and SF-8 scores was performed for the patients who were alive and disease-free at
the end of the study (survivors) and for the patients who had died (nonsurvivors).
Differences in scores between survivors and nonsurvivors were analyzed using the Mann–Whitney
U-test. A p-value < 0.05 was considered statistically significant.
Results
Patient Characteristics
[Table 1] shows the characteristics and histological diagnoses for the 26 patients (21 men,
5 women; median age at the time of surgery 61.5 years [range, 36–76 years]). Nine
patients (34.6%) were younger than 60 years of age and 17 (65.4%) were aged 60 years
or older. Sixteen patients (61.5%) had T4a disease and 10 (38.5%) had T4b disease.
The tumor was located in the maxillary sinus in 19 patients (73.1%), ethmoid sinus
in four (15.4%), frontal sinus in one (3.8%), and facial skin in two (7.7%). The histological
diagnosis was squamous cell carcinoma in 21 patients (80.8%), adenoid cystic carcinoma
in two (7.7%), anaplastic carcinoma in one (3.8%), adenocarcinoma in one (3.8%), and
myoepithelial carcinoma in one (3.8%). Twelve patients (46.2%) developed surgical
complications after craniofacial resection comprising minor CSF leak in two cases
(7.7%), major CSF leak in four (15.4%), a minor wound in five (19.2%), a major wound
in three (11.5%), and cerebral infarction in one (3.8%). Twelve (46.2%) of the 26
patients experienced tumor recurrences with local recurrence in six cases (23.1%),
regional recurrence in seven (26.9%), and distant metastasis in two (7.7%). The questionnaire
response rates for survivors were 95% preoperatively and 69, 54, 52, and 80% at 3,
6, 12, and 24 months, respectively, after surgery.
Table 1
Patient characteristics
|
Variable
|
n (%)
|
|
Sex
|
|
|
Male
|
21 (81)
|
|
Female
|
5 (19)
|
|
Primary location
|
|
|
Maxillary sinus
|
19 (73)
|
|
Ethmoid sinus
|
4 (15)
|
|
Frontal sinus
|
1 (4)
|
|
Facial skin
|
2 (8)
|
|
T classification
|
|
|
T4a
|
16 (62)
|
|
T4b
|
10 (38)
|
|
Complication
|
|
|
No
|
14 (54)
|
|
Yes
|
12 (46)
|
|
CSF leak, minor
|
2 (8)
|
|
CSF leak, major
|
4 (15)
|
|
Wound, minor
|
5 (19)
|
|
Wound, major
|
3 (12)
|
|
Cerebral infarction
|
1 (4)
|
|
Recurrence
|
|
|
No
|
14 (54)
|
|
Yes
|
12 (46)
|
|
Local recurrence
|
6 (23)
|
|
Regional recurrence
|
7 (27)
|
|
Distant metastasis
|
2 (8)
|
|
Final outcome
|
|
|
Alive without disease
|
16 (62)
|
|
Deceased
|
10 (38)
|
Abbreviation: CSF, cerebrospinal fluid.
Survival Outcome
Ten (38.0%) of the patients died and 16 (62.0%) were alive and disease-free at the
end of the study. The Kaplan–Meier curves for OS and DFS in the 26 patients are shown
in [Fig. 2]. The 3-year OS and DFS rates were 64.9% and 53.3%, respectively.
Fig. 2 Kaplan–Meier survival curves for overall survival (OS) and disease-free survival
(DFS) in 26 cases.
Psychiatric Assessment and Intervention
Twenty-one (80.8%) of the 26 patients developed the following psychiatric complications
after surgery: delirium (n = 13), adjustment disorder (n = 7), insomnia (n = 5), and anxiety disorder (n = 1). In total, 80.8% of patients received psychotropic medication, that is, minor
tranquilizers (n = 20), major tranquilizers (n = 13), and antidepressants (n = 1). Supportive psychotherapy was provided concomitantly to all patients by the
psychiatrists and psychologists. The mean duration of psychiatric treatment was 139
days. The remission rate was 61.5, 69.2, 69.2, and 80.8% at 3, 6, 12, and 24 months,
respectively, after surgery. None of our patients attempted suicide during the study
period.
Hospital Anxiety and Depression Scale Scores during Follow-up
The changes in the HADS score during follow-up are shown in [Fig. 3A] and [B]. The mean anxiety score was 5.1 preoperatively, 4.6, 3.8, 4.6, and 3.3 at 3, 6,
12, and 24 months, respectively, after surgery; the respective mean depression scores
were 5.1, 7.4, 5.8, 5.6, and 4.2. The proportions of patients with HADS anxiety and
depression scores ≥ 8 (indicating all potential cases) are shown in [Fig. 3C] and [D]. Preoperatively, 28% of patients were identified as potentially having anxiety and
20% as possibly having depression. The proportion of patients with anxiety at the
follow-up assessments was not higher than that before surgery; however, possible cases
of depression increased to 60% at 3 months after surgery but trended downwards thereafter.
Fig. 3 Changes in the Hospital Anxiety and Depression Scale (HADS) score during follow-up.
Dotted line: HADS anxiety and depression scores of 8 (indicating all potential cases).
Short Form-8 Scores during Follow-Up
[Table 2] shows the mean scores for all eight components of the SF-8 during follow-up and
compares them with those in the general Japanese population. Before surgery, the mean
scores on the SF-8 were 44.4 for physical function, 37.7 for role physical, 46.0 for
bodily pain, 45.3 for general health, 48.4 for vitality, 40.1 for social functioning,
42.6 for role emotional, and 48.4 for mental health. All scores for the SF-8 items,
except for vitality, were significantly lower than those in the general Japanese population.
As time passed, all scores gradually improved through to 24 months postoperatively,
and finally improved to around 50 points which is the national standard value.
Table 2
Comparison of SF-8 scores in patients who underwent anterolateral craniofacial resection
with orbital exenteration and those in the general Japanese population
|
SF-8 item
|
Assessment time points
|
General Japanese
population
|
|
Preoperatively
|
3 mo
|
6 mo
|
12 mo
|
24 mo
|
|
PF
|
44.4[b]
|
43.8[b]
|
45.8
|
45.9[a]
|
47.8[c]
|
50.7
|
|
RP
|
37.7[a]
|
40.6[b]
|
45.2
|
44.7[c]
|
49.2
|
50.9
|
|
BP
|
46.0[b]
|
47.9
|
48.5
|
50.2
|
52.9
|
51.7
|
|
GH
|
45.3[b]
|
49.6
|
50.4
|
50.5
|
52.3
|
51.2
|
|
VT
|
48.4
|
48.0[c]
|
53.6
|
52.2
|
52.7
|
51.7
|
|
SF
|
40.1[a]
|
41.8[a]
|
45.9
|
45.7[c]
|
46.9
|
50.0
|
|
RE
|
42.6[b]
|
41.1[b]
|
47.8
|
46.4[c]
|
51.6
|
50.9
|
|
MH
|
48.4[c]
|
50.0
|
51.4
|
50.1
|
49.2
|
51.0
|
Abbreviations: BP, bodily pain; GH, general health; MH, mental health; PF, physical
function; RE: role emotional; RP, role physical; SF, social functioning; SF-8, medical
outcomes study 8-items Short Form health survey; VT, vitality.
a
p < 0.001.
b
p < 0.01.
c
p < 0.05.
[Fig. 4] shows the time courses for the PCS and MCS scores on the SF-8 and compares them
with those for the general Japanese population. Before surgery, the mean scores were
41.6 for the PCS and 46.1 for the MCS, both of which were significantly lower than
the general Japanese population scores. Although the PCS and MCS scores remained significantly
lower at 3 months after surgery when compared with the scores in the general population,
both scores finally improved to around 50 points and no significant differences were
found at 24 months after surgery.
Fig. 4 Physical component summary (PCS) and mental component summary (MCS) scores during
follow-up: A comparison with Japanese population norms.
Health-Related Quality of Life in Survivors and Nonsurvivors
[Fig. 5] shows further analysis of the HADS anxiety and depression scores and the SF-8 PCS
and MCS scores in 16 survivors and 10 nonsurvivors, which was not performed at 24
months after surgery because of small number of nonsurvivors. No significant differences
in HADS scores and SF-8 scores were found between survivors and nonsurvivors preoperatively,
and at 3 and 6 months after surgery. However, at 12 months, the mean HADS anxiety
score was significantly lower in survivors than in nonsurvivors (3.5 vs. 7.7, p < 0.05; [Fig. 5A]) and the mean SF-8 MCS score was significantly higher in survivors than in nonsurvivors
(50.7 vs. 39.9, p < 0.05; [Fig. 5D]).
Fig. 5 Comparison of hospital anxiety and depression scale (HADS) anxiety and depression
scores and medical outcomes study 8-items Short Form health survey (SF-8), physical
component summary (PCS) and mental component summary (MCS) scores between survivors
and non-survivors during follow-up. * denotes p < 0.05.
In survivors, the HADS anxiety and depression scores indicated a transient increase
at 3 months after surgery that trended downwards, thereafter, until the risk was no
greater than that in the total study population ([Fig. 5A] and [B]). Similarly, in the survivors, the SF-8 PCS and MCS scores indicated a gradual improvement
to around 50 points by 12 months postoperatively ([Fig. 5C] and [D]).
Discussion
The present study is the first prospective investigation of psychiatric conditions
in patients with malignant skull base tumors who undergo AL-CFR with OE. Given that
AL-CFR is a lengthy procedure and involves considerable intraoperative blood loss,
admission to the intensive care unit (ICU), tracheostomy, and insertion of a feeding
tube, there is a high risk of postoperative delirium and depression. In our study,
20 to 30% of patients were suspected to have anxiety and depression, and scores for
7 of the 8 items in the SF-8 were significantly lower than those in the general Japanese
population before surgery. Moreover, 81% of the patients developed psychiatric complications
after surgery and required treatment with psychotropic medication. Recent studies
have indicated that early psychiatric intervention is essential for patients with
cancer and could improve their QoL and prevent subsequent psychological distress.[27]
[28] Considering the high levels of anxiety about AL-CFR and prolonged treatment in patients
with malignant skull base tumors, early psychiatric intervention before surgery is
important.
Persistent, recurrent, and late depression are associated with worse survival in patients
with head and neck cancer, and those with depression postoperatively are at higher
risk of premature death.[20] The psychological impact of OE is considerable and continues for a prolonged period
after discharge from hospital. Rasmussen et al reported that OE had a marked negative
influence on employment, socioeconomic, and marital status.[17] At 1 year after surgery, 30% of the patients in our study had required psychiatric
treatment, and the scores on four of the SF-8 items were significantly lower than
those in the general population. Similarly, Abergel et al evaluated 39 patients who
had undergone anterior skull base surgery and showed that the QoL score deteriorated
in most patients in the 6 months following surgery but had improved by 12 months postoperatively.[29] Therefore, active intervention by a psychiatric liaison team should be continued
for at least 1 year after surgery in patients who undergo AL-CFR with OE. Furthermore,
patients with head and neck cancer have high-suicide rates and a high prevalence of
major depressive disorder because the cancer may affect communication and functioning
and the surgical treatment required may cause severe facial disfigurement.[30] It is noteworthy that none of our patients attempted suicide during the study period.
A multidisciplinary approach with psychiatrists, psychologists, nurses, and skull
base surgeons is important for patients who undergo AL-CFR with OE, and interventions
can be life-saving when suicidal ideation is present.
QoL is a multidimensional concept, and its measurement should ideally encompass physical,
social, psychological, and functional domains. In skull base surgery, measuring QoL
is challenging because of the variety of characteristics of tumors involving the skull
base. Although many tools have been developed for measurement of QoL, there is no
gold standard test for this concept.[31] In this study, we used the HADS to assess anxiety and depression and the SF-8 to
evaluate health-related QoL. The HADS is used worldwide to evaluate anxiety and depression.
We have previously reported that preoperative evaluation of the severity of depression
before surgery using the HADS can identify patients who develop depression after surgery.[21] The SF-8 has often been used to evaluate the multidimensional concept of QoL.[32]
[33] Using a combination of the HADS and the SF-8, we were able to assess health-related
QoL and psychological status accurately over an extended period in patients treated
by AL-CFR with OE.
The surgical strategy used and whether the orbit should be removed or preserved depends
on the degree of orbital involvement. There is a present trend of preserving the orbit
in patients with minimal invasion of the periosteum and limited periorbital involvement.
Recent reports have shown that orbit-sparing surgery in selected cases can have an
acceptable oncological outcome without functional compromise.[34]
[35] However, there is no high-quality evidence that a conservative approach is beneficial
even when there is minimal orbital invasion.[36] Moreover, Safi et al reported that OE was associated with a significantly better
5-year OS rate (66%) than preservation of the orbit plus radiotherapy (14%) in 52
patients with sinonasal malignancies invading the orbit beyond the orbital periosteum.[37] Despite the fact that only patients with advanced (T4a and T4b) head and neck cancer
were included in the present study, we achieved a relatively good result (3-year OS
of 64.9% and DFS of 53.3%) in comparison with that in the international collaborative
study.[2] Our data indicate that craniofacial resection with OE for locally advanced head
and neck cancer is feasible and well tolerated if patients receive early psychiatric
intervention.
Our study has some limitations, particularly the small sample size and relatively
large number of dropouts during the course of the study. Therefore, our present findings
need to be confirmed in a larger patient population, hopefully with a higher questionnaire
response rate.
Conclusions
Craniofacial resection with OE is feasible and well tolerated in patients with malignant
skull base tumors in whom early psychiatric intervention is implemented to lessen
the psychological impact of the procedure.
