The Role of Surveillance Imaging in Patients with Advanced Laryngeal Cancer

Abstract

Background: While almost one-third of patients treated for laryngeal cancer will experience disease recurrence, the current National Comprehensive Cancer Network guidelines do not recommend routine post-treatment imaging follow-up. We aimed to examine the yield of post-treatment imaging surveillance among patients with primary advanced laryngeal cancer. Methods: Patients treated for advanced-stage laryngeal carcinoma between 2000 and 2020 in a tertiary care medical center were retrospectively reviewed. Data collected included demographics, clinical and pathological features, treatment modalities, tumor recurrence data including the diagnostic modality (patient’s symptoms, physical examination, or imaging), and outcome. Results: The cohort included 123 patients with advanced-stage laryngeal cancer. Thirty-five (28.7%) patients experienced disease recurrence with fourteen recurrences (40%) diagnosed by imaging. Patients diagnosed by imaging had a shorter time to recurrence diagnosis (23.8 vs. 45.9 months, p-value = 0.016), with similar 5-year overall and disease-specific survival (20.6% vs. 26.6%, log-rank p-value = 0.53 and 62.1% vs. 59.7%, log-rank p-value = 0.87, respectively). Conclusions: Performance of routine post-treatment imaging follow-up in patients with advanced laryngeal cancer was associated with a shorter time to diagnosis of recurrence and similar survival rates. Imaging follow-up should be considered in cases where clinical follow-up is limited and according to the judgment of the treating physician.

1. Introduction

Laryngeal cancer is the second most common malignancy of the upper aerodigestive tract [1]. Up to 30% of patients treated for laryngeal squamous cell carcinoma (SCC) are subsequently diagnosed with recurrence [2]. Among recurrent head and neck SCC, patients with laryngeal cancer are considered to have the best prognosis, with salvage rates ranging around 50%, including a relative favorable functional outcome [3,4]. Around 90% of recurrences in head and neck SCC occur during the first two years after treatment [3,5]. Hence, a close follow-up of laryngeal SCC survivors is crucial, especially during the first two years, in order to provide timely diagnosis in the case of recurrent disease and enable the best chances for salvage.

Clinical surveillance by physical examination of patients treated for laryngeal SCC, either surgical or by radiotherapy, can be challenging due to post-treatment tissue-related alterations such as edema, scarring, fibrosis, and neovascularization [6]. While the National Comprehensive Cancer Network (NCCN) guidelines recommend a specific frequency for clinical examination after treatment completion (1–3 months during the first year, 2–6 months during the second year, 4–8 months during years 3–5, and every 12 months after the fifth year) [7], they do not give specific recommendations regarding serial imaging follow-up in these patients.

Several studies have attempted to explore the yield of imaging follow-up after definitive treatment for head and neck SCC [5,8,9]. While imaging was able to detect clinically occult persistent or recurrent disease, no improvement in either disease-specific or overall survival was reported. These studies, however, covered all head and neck SCC subsites, and did not distinguish patients with laryngeal SCC from other patients.

Patients with advanced-stage laryngeal SCC undergo baseline imaging before treatment initiation with either computerized tomography (CT) with intravenous contrast or positron emission tomography CT (PET-CT). After treatment, a baseline PET-CT is usually performed after 3 months, but no guidelines exist for further imaging surveillance in these patients.

In this study, we aimed to examine the yield of imaging performed in the post-treatment follow-up of patients treated for advanced-stage laryngeal SCC, regarding detection of recurrent disease and survival.

2. Materials and Methods

2.1. Patients

This was a retrospective cohort reviewing all patients diagnosed with advanced-stage laryngeal SCC at a university-affiliated tertiary care center between 2000 and 2020. Data were collected from patients’ medical charts and included demographics, risk factors, clinical and pathological features, staging, treatment modalities, and outcome. Patients with insufficient data or follow-up period of less than 2 years were excluded from the study. Tumor staging was performed according to the 8th edition of the American Joint Committee on Cancer (AJCC) laryngeal cancer staging system. Patients with advanced disease included all patients with disease stage 3 or 4—either T stage 3 or 4, N stage of 1,2, or 3, or M stage 1. Clinical follow-up, including medical history and complete head and neck physical examination, was performed by our multidisciplinary team, based on intervals dictated by the contemporary NCCN guidelines.

2.2. Treatment Modalities

Advanced-stage laryngeal cancer was treated with either surgery or chemo-radiotherapy depending on the stage and function of the larynx, with surgery considered the treatment modality of choice for T4a disease. Surgery included total laryngectomy with elective bilateral neck dissection of levels 2–4, or therapeutic-modified radical neck dissection when indicated.

Definitive treatment with chemo-radiotherapy included radiation to the primary tumor with 70 Gray (Gy) divided into 35 fractions of 2 Gy each, with radiation of elective neck levels II-IV with 54–63 Gy. Treatment was given daily for 5 days a week, over 7 weeks. Chemotherapy included Cisplatin, given as a bolus in a 100 mg/m² dose at weeks 1, 4, and 7, or at a weekly dose of 40 mg/m² for seven weeks.

2.3. Imaging Follow-Up

Our routine imaging policy among patients treated for advanced-stage disease included positron emission tomography CT (PET-CT) performed at 3 months after the completion of treatment. This baseline imaging was not included in our analysis of imaging follow-up as it was a part of the post-treatment routine used to detect post-treatment persistent disease. Patients whose PET-CT was positive 3 months after treatment were excluded from the analysis and not considered as having recurrent disease. Subsequent imaging (usually PET-CT and in some cases CT or magnetic resonance imaging) was performed every 6 months in the first two years after treatment. Further imaging after the first two years was performed on a case-by-case basis.

2.4. Recurrence Diagnosis

Recurrent disease is defined as evidence of disease by a positive biopsy result for SCC. Patients who experienced recurrent disease were further analyzed regarding the time interval from treatment to evidence of recurrence, the location of recurrence (local, regional, and/or distant), and if there were any patient symptoms, findings on physical examination, or radiological findings at recurrence. In cases with more than one of these modalities present, we determined, by careful review of the medical records, which of the three factors was the most dominant in identifying the recurrence. This review was performed independently by two of the authors (I.A. and M.T.). In cases of disagreement, a third author (E.Y.) reviewed the case in order to decide which modality was the most dominant. Cases in which the most dominant modality of recurrence diagnosis could not be decided based on the medical record data were excluded from further analyses.

2.5. Statistical Analysis

Differences in the means of continuous variables between groups were analyzed using either the Mann–Whitney or Student’s t-test and differences in categorical variables were analyzed using Fisher’s exact test. Overall survival (OS) was calculated from the date of diagnosis of recurrence to the date of death or last follow-up, using Kaplan–Meier survival curves and log-rank test. Analyses were conducted using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA).

2.6. Ethical Considerations

The study was approved by the Rabin Medical Center ethics board (IRB approval number RMC-2020-0254) and informed consent was waived.

3. Results

3.1. Patients

A total of 289 patients were treated for laryngeal SCC during the study period. Of them, 123 had advanced-stage disease (stage 3 or 4) and were included in the initial study cohort. Ninety-four patients were male (76.4%). The mean age at diagnosis was 63.1 years. A total of 93 patients were active smokers at diagnosis (75.6%), five were past-smokers (ceased smoking for at least three months) (4.1%), and 25 never smoked (20.3%). The mean follow-up time after initial diagnosis was 64.5 months (range: 2.8–221 months). Figure 1 describes the inclusion process for patients in the study.

Forty-two patients (34.2%) were treated surgically; out of them, 35 (83.3%) received adjuvant radiotherapy and 27 (64.3%) also received adjuvant chemotherapy. Eighty patients (65%) received radiotherapy as their primary treatment; out of them, 68 (85%) were also treated with chemotherapy. One patient (0.8%) died before receiving any treatment and was excluded from further analyses. A total of 35 patients (28.7%) experienced disease recurrence after their initial therapy. Demographic, clinical, and pathological features are presented in

Table 1. Data of the total 289 patients and the 123 patients with advanced-stage tumor treated in our institution with laryngeal cancer between 2000 and 2020.

Variable	Number of Patients—All Stages (N = 289) (%)	Number of Patients—Advanced Stage (N = 123) (%)
Gender
Male	239 (82.7)	94 (76.4)
Female	50 (17.3)	29 (23.6)
Age at diagnosis, years	65.2 ± 11	63.1 ± 11
Smoking
Current	192 (66.1)	93 (75.6)
Past	31 (10.7)	5 (4.1)
Never	67 (23.2)	25 (20.3)
Alcohol
Yes	15 (5.2)	3 (8.6)
Mean follow-up time, months (range)	68.2 (2.8–221)	64.5 (2.8–221)
Origin Site
Glottis	224 (77.5)	68 (55.3)
Supraglottis	64 (22.2)	54 (43.9)
Subglottis	1 (0.3)	1 (0.8)
T stage
In situ	9 (3.1)	0
1a	78 (27)	1 (0.8)
1b	20 (6.9)	0
2	65 (22.5)	5 (4.1)
3	78 (27)	78 (63.4)
4	39 (13.5)	39 (31.7)
N stage
0	242 (84)	76 (61.8)
1	14 (4.8)	14 (11.4)
2a	10 (3.5)	10 (8.1)
2b	10 (3.5)	10 (8.1)
2c	12 (4.2)	12 (9.8)
3	1 (0.4)	1 (0.8)
M stage
0	287 (99.3)	121 (98.4)
1	2 (0.7)	2 (1.6)
Treatment modality
Surgery	122 (42.2)	42 (34.2)
Adjuvant radiotherapy	76 (62.3)	35 (83.3)
Adjuvant chemotherapy	45 (36.8)	27 (64.3)
Radiotherapy	165 (57.1)	80 (65)
Chemo-radiotherapy	70 (42.4)	68 (85)
No treatment	2 (0.7)	1 (0.8)
Recurrence	76 (26.3)	35 (28.7)

.

3.2. Patients with Disease Recurrence

Out of the 35 patients who experienced disease recurrence following a first negative PET-CT, 22 had local recurrence (62.9%), 13 had regional recurrence (37.1%), and nine experienced distant recurrence (25.7%). The mean time interval from initial diagnosis to recurrence was 37.1 months (range: 7.3–135). Seven cases (20%) were diagnosed during the first 12 months, 18 (51.4%) during the first two years, and 29 (82.9%) during the first five years [Figure 2].

In 21 cases (60%), recurrence was accompanied by the patients’ subjective symptoms. In 26 cases (74.3%), physical examination yielded findings. Imaging follow-up was performed in all cases. Other features of recurrent cases are described in

Table 2. Data of 35 patients with advanced laryngeal cancer diagnosed with recurrence in our institution between 2000 and 2020.

Variable	Number of Patients (%)
Gender
Male	29 (82.9)
Female	6 (17.1)
Age at diagnosis of recurrence, years	63.4 ± 10.6
Smoking
Yes	25 (71.4)
Past	4 (11.4)
No	6 (17.1)
Alcohol
Yes	3 (8.6)
Mean time from primary diagnosis to recurrence, months (range)	37.1 (7.3–135)
Mean follow-up time after recurrence, months (range)	27 (0.3–104.3)
Origin Site
Glottis	19 (54.3)
Supraglottis	16 (45.7)
Subglottis	0 (0)
TNM stage of primary tumor
3	16 (45.7)
4	19 (54.3)
Recurrence location
Local	22 (62.9)
Regional	13 (37.1)
Distant	9 (25.7)
Diagnostic modality of recurrence
Medical history	14 (40)
Physical examination	7 (20)
Imaging	14 (40)
Treatment modality
Surgery	18 (51.4)
Radiotherapy + chemotherapy	6 (17.1)
Palliative treatment	6 (17.1)
Unknown	5 (14.3)

.

Regarding salvage treatment for recurrent disease, 18 patients (51.4%) were treated by surgery, six patients (17.1%) received definitive radiotherapy with or without chemotherapy for the recurrent disease, and six patients (17.1%) were treated with palliative intention. No data regarding treatment modality for recurrence was available for the five remaining patients (14.3%).

Out of all of the recurrent cases, seven had no evidence of disease at last follow-up (20%), 10 had died of the disease recurrence (28.6%), two died of other causes (5.7%), 13 died of unknown causes (37.1%), and three were alive with disease (8.6%).

3.3. Modality of Recurrence Identification

The modality for the identification of the recurrence was patients’ symptoms in 14 cases (40%), findings on physical examination in seven cases (20%), and findings on imaging for 14 cases (40%).

The 14 cases identified by imaging included PET-CT in 11 cases (78.6%) and CT in three cases (21.4%).

The mean time interval for the diagnosis of recurrence was significantly shorter among patients whose recurrence was identified by imaging compared with those diagnosed by other means (23.8 vs. 45.9 months, p-value = 0.016). This difference, however, did not translate into a significant difference in 5-year overall and disease-specific survival rate (20.6% vs. 26.6%, log-rank p-value = 0.53, 62.1% vs. 59.7%, log-rank p-value = 0.87) [Figure 3A,B].

We performed sub-group analysis of patients who were treated with radiotherapy prior to recurrence (N = 31). Diagnosis of recurrence with imaging among these patients was associated with significantly shorter mean time to diagnosis compared with other modalities (23.8 vs. 38.8 months, p = 0.037). This diagnostic benefit did not translate into better DSS of OS among these patients (log-rank p-value = 0.8, log-rank p-value = 0.84, respectively).

We aimed to assess whether imaging was associated with earlier diagnosis and better prognosis among patients with distant recurrence. The mean time to recurrence diagnosis was 45.2 months among the patients whose distant recurrence was diagnosed by imaging (N = 4) compared with 67.8 months among those diagnosed by other modalities (N = 5). This difference did not reach statistical significance (p = 0.56). When comparing one-year OS, no difference was demonstrated between the imaging-diagnosed patients and other modalities (33.3% vs. 0%, log-rank p-value = 0.27) [Figure 4].

Regarding treatment for recurrence, we found no difference in the treatment between the different diagnostic modalities, as the rate of patients treated by either surgery, definitive radiotherapy with or without chemotherapy, and with palliative intent was similar between the different diagnostic modalities sub-groups (p-value = 0.83).

4. Discussion

In this study, we wished to examine whether follow-up imaging after treatment for laryngeal SCC may be associated with the detection of clinically occult recurrence at an early stage and improved prognosis. This retrospective cohort of 123 patients with advanced-stage laryngeal SCC demonstrated that serial imaging follow-up is associated with earlier diagnosis of recurrent disease. However, patients with recurrent disease identified earlier by imaging were not able to demonstrate improved OS or DSS compared with patients diagnosed by their symptoms or physical examination findings.

As most recurrences of head and neck SCC occur during the first two years after treatment, the NCCN guidelines dictate close clinical follow-up recommendations: every 1–3 months in the first year, 2–6 months in the second year, 4–8 months during years 3–5, and every 12 months afterwards [7]. Nevertheless, even with close clinical follow-up and physical examination, tumor recurrence can at times be obscured by edema, granulation tissue, or fibrosis.

While the NCCN guidelines provide clear recommendations regarding patient clinical follow-up after completion of treatment for head and neck SCC, they do not specify whether serial imaging follow-up is advised in head and neck SCC in general or in laryngeal SCC specifically. However, the routine use of PET-CT imaging performed 3 months after treatment completion has been shown to be beneficial in detecting cases of disease persistence and to distinguish them from post-operative inflammatory changes [10,11]. Furthermore, the United States Preventive Services Task Force does recommend serial low-dose chest CT follow-up in patients aged 50 to 80 years with a 20-pack-year smoking history who currently smoke or have quit within the last 15 years [12], as randomized controlled trials have demonstrated that screening by low-dose CT can improve survival among these high-risk patients [13,14].

Several studies have attempted to describe the yield of imaging surveillance after treatment for head and neck SCC. Abgral et al. [15] evaluated the diagnostic value of PET-CT in 91 patients with head and neck SCC, out of whom 27 (29.7%) had laryngeal SCC. They performed PET-CT 12 months after the initial treatment when no clinical evidence of disease was demonstrated and showed a 100% sensitivity, 85% specificity, and a negative predictive value of 100% for diagnosis of recurrent disease. This study did not attempt to evaluate the prognostic effect of PET-CT surveillance.

A different study by Ho et al. [8] evaluated the role of PET-CT performed at 12 and 24 months after treatment for detection of recurrences in head and neck SCC. Imaging performed after one year was able to diagnose clinically occult disease in 9% of cases (15 of 175), and imaging performed after 2 years diagnosed clinically occult recurrent disease in 4% of cases (3 out of 77). No difference regarding disease-free or overall survival was demonstrated between clinically and radiologically diagnosed recurrences in this cohort. This study included 284 patients with head and neck SCC whose initial imaging (either PET-CT or MRI) performed 3 months after treatment was negative. However, within the 284 cases, only 10 cases of laryngeal SCC were included (3.5%), making it difficult to extrapolate these results to laryngeal cancer cases specifically.

Our results are in agreement with the findings by Ho et al. regarding the lack of improvement in prognosis for patients with head and neck cancer and diagnosed with recurrent disease by imaging. Our results, however, focus on laryngeal SCC cases only, unlike the study by Ho et al., which included very few laryngeal cancer cases. Furthermore, as recurrences after treatment for early-stage laryngeal SCC can be diagnosed in the clinic in most cases, we excluded these patients from our cohort and decided to focus on the yield of imaging follow-up for advanced-stage disease alone.

We attempted to evaluate whether patients who were treated with radiotherapy for the primary tumor—either as definitive or adjuvant treatment—and experienced recurrence may benefit from surveillance with imaging. Similar to the general cohort, the patients treated with radiotherapy and diagnosed with imaging had shorter time to recurrence diagnosis, with similar survival rates. As radiotherapy for laryngeal tumors may induce edema, fibrosis, and necrosis, the clinical detection of recurrent disease among these patients based on physical examination may be challenging. Patients’ complaints may also be misleading sometimes, since hoarseness, stridor, and dysphagia may be signs of recurrent disease, but may also be a result of the treatment itself [16]. The role of PET-CT in detecting recurrence among patients with laryngeal SCC treated with radiotherapy was described in previous publications with a high sensitivity rate [5,17,18]. While no survival difference was demonstrated in our study, we did show that imaging was associated with an earlier diagnosis of recurrence in patients with advanced laryngeal cancer. Diagnosis of recurrence at an earlier stage can certainly provide the patient with better treatment options, possibly including laryngeal preserving surgery in some cases, and thereby improve the patient’s quality of life, even if no survival benefit is gained [19,20]. We believe that with a larger cohort, a survival difference could also be demonstrated among patients whose follow-up include routine post-treatment imaging.

Ng et al. [5] evaluated the role of imaging in follow-up after radiotherapy treatment for head and neck SCC. They compared 71 cases of recurrences diagnosed by imaging with 119 recurrences diagnosed clinically and found that imaging allows for an earlier diagnosis of recurrent disease compared with clinical diagnosis (median time of 11 months vs. 16 months, p-value < 0.0001). No difference in overall survival was demonstrated. As the majority of imaging-diagnosed recurrences in their cohort were during the first two years, their recommendation is to consider routine surveillance with imaging during the first two years and to focus on clinical follow-up afterwards, except for specific cases. Additionally, they found that imaging was more likely to diagnose distant recurrence compared with recurrences diagnosed by other modalities. As the number of distant recurrences in our cohort was relatively small (N = 9), we were unable to demonstrate significant differences between patients with distant recurrences who were diagnosed by imaging compared with other modalities. The study by Ng et al. also found no difference in survival of patients with distant recurrence diagnosed by imaging compared with clinical diagnosis. Importantly, most cases described in Ng et al.‘s cohort were of oropharynx origin (82.2%), with only 4.1% of cases of laryngeal cancer.

A recent study by Anzai et al. [21] investigated the association between surveillance imaging and mortality in patients with head and neck cancer using a population-based study design. They demonstrated that in a cohort of 1004 patients, surveillance imaging using PET/PET-CT was associated with lower mortality among patients with SCC for regionalized and distant cancer stages, with a protective association that was observed up to 2 years after completion of treatment.

To our knowledge, no previous study has focused on the yield of imaging follow-up for laryngeal SCC specifically. Most studies published on this issue describe the role of imaging in head and neck cancer in general or in patients treated only by radiotherapy. According to our results, we believe that patients with laryngeal SCC should be followed-up clinically, according to the NCCN guidelines. Imaging follow-up can possibly result in earlier diagnosis of recurrent disease and should be considered in cases where the ability to perform clinical follow-up is limited by either granulation, fibrosis, or edema, as in general it does not promote better prognosis for the patient.

The limitations of our study include its retrospective nature and the fact that it included a single-institute cohort. Our main challenge was to decide how each case of recurrence was diagnosed, as in many cases more than one modality raised suspicious findings during the follow-up. We classified cases of recurrent disease as diagnosed by imaging only when it was the definite modality for the diagnosis of recurrence. As the number of recurrent cases in our study is limited, further studies regarding these patients with larger and possibly prospective cohorts are needed. Even so, our study focuses mainly on recurrences of patients with laryngeal cancer, thereby enabling us to describe the role of post-treatment imaging among these patients and to shed a light on this rather vague subject.

5. Conclusions

While imaging surveillance after treatment for advanced laryngeal SCC may promote earlier detection of recurrent disease in cases of advanced tumors, it does not seem to improve patients’ overall survival. Hence, we believe that clinical follow-up according to the NCCN guidelines should be the mainstay of post-treatment surveillance and imaging should be reserved for specific cases, according to the clinical judgement of the treating physician. Since close clinical follow-up in these patients has a significant role, any suspicion raised by patient’s symptoms or findings on physical examination should be augmented by imaging, tissue sampling for biopsy, or both. Further prospective studies are certainly needed to define the role of post-treatment imaging follow-up among patients with laryngeal cancer.