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Neck management in patients with olfactory neuroblastoma
Oral Oncology 101 (2020) 104505
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Neck management in patients with olfactory neuroblastoma Xinmao Song
a,1
, Chuang Huang
b,1
a,⁎
a
c
d,⁎
T
, Shengzi Wang , Li Yan , Jie Wang , Yi Li
a
Department of Radiation Oncology, Eye, Ear, Nose and Throat Hospital of Fudan University, 83 Fenyang Road, Shanghai 200031, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, 181 Hanyu Road, Chongqing 400030, China c Department of E.N.T., Eye, Ear, Nose and Throat Hospital of Fudan University, 83 Fenyang Road, Shanghai 200031, China d Department of Oncology, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Kunming 650032, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Olfactory neuroblastoma Cervical lymph node metastasis Elective neck irradiation Management strategy
Objective: Optimal neck management in patients with olfactory neuroblastoma (ONB), a rare malignancy, remains uncertain. This study aimed to analyse patterns of cervical lymph node metastases and corresponding clinical outcomes and to investigate the value of elective neck irradiation (ENI) in this population. Methods and materials: This study retrospectively reviewed clinical records, imaging findings, nodal metastasis features and treatment data of 217 patients with ONB treated at our hospital during 1991–2019. Univariate and multivariate analyses were used to assess the influence of cervical lymph node involvement on treatment outcomes. Survival and regional failure rates were compared between patients with or without ENI. Results: Thirty-two patients (14.7%) presented initially with cervical lymph node metastases, most frequently at levels II (10.6%, 23/217) and VIIa (5.5%, 12/217). Patients with and without cervical node metastasis differed significantly in overall (OS) (41.9% vs. 86.1%, p < 0.001), progression-free (PFS) (41.9% vs. 84.8%, p < 0.001), regional failure-free (45.9% vs. 89%, p < 0.001) and distant metastasis-free survival (41.5% vs. 86.1%, p < 0.001). Cervical lymph involvement was an independent factor affecting poor OS (hazard ratio, 0.184, 95% confidence interval, 0.078–0.436, p < 0.001) and PFS (hazard ratio, 0.198, 95% confidence interval, 0.088–0.445, p < 0.001). Moreover, 43.8% patients (95/217) underwent ENI, which significantly reduced the incidence of regional recurrence from 10.7% to 3.2% (χ2 = 4.396, p = 0.036) but did not significantly affect other survival outcomes. Regional failures could be resolved using salvage treatment. Conclusions: Our findings indicate the importance of systematic therapy for patients with initial cervical lymph node metastases. ENI is not recommended for N0 disease.
Introduction Olfactory neuroblastoma (ONB) is a rare solid malignancy that arises from the olfactory epithelium in the nasal cavity. According to retrospective studies, primary ONB is mainly treated via surgical resection and subsequent radiotherapy [1]. However, regional failure after treatment remains an issue associated with significant patient mortality [2]. To the best of our knowledge, no consensus has been reached regarding the optimal neck management for patients with ONB. Currently, some investigators initially apply selective neck dissection for the treatment of cervical lymph node metastasis, followed by radiotherapy or chemoradiotherapy [3]. Although the combination of surgery and radiotherapy for the primary tumor has been the standard treatment, the value of neck irradiation for those N0 neck is still no
clear. This issue is complicated by the lack of consensus regarding the indication and delivery of elective neck irradiation (ENI) for patients with clinically negative lymph nodes in the neck [4,5]. A better neck management strategy for patients with ONB would require clarification of the cervical lymph node metastasis incidence and pattern. Although cervical lymph node involvement has been described in 10–30% of patients at the time of diagnosis and was proven to be an independent poor prognostic factor, few reports have described the characteristics of cervical lymph node metastases in ONB in detail. Therefore, this retrospective, descriptive study aimed to analyse the basic patterns of cervical lymph node metastases in newly diagnosed patients with ONB and to assess the influence of the cervical lymph node status on neck management and long-term survival outcomes and the value of ENI in this population.
⁎
Corresponding authors. E-mail addresses: [email protected] (S. Wang), [email protected] (Y. Li). 1 These authors have contributed equally to this work and co-first authors https://doi.org/10.1016/j.oraloncology.2019.104505 Received 23 July 2019; Received in revised form 5 October 2019; Accepted 26 November 2019 1368-8375/ © 2019 Elsevier Ltd. All rights reserved.
Oral Oncology 101 (2020) 104505
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Fig. 1. A 60-year-old male patient with olfactory neuroblastoma. (A) Axial T2-weighted magnetic resonance (MR) imaging reveals an iso-intense mass in the nasal cavity and ethmoidal sinus (arrow). (B) Axial and (C) coronal post-contrast T1-weighted MR images demonstrate heterogeneous enhancement of the mass (arrow), which extends into the right nasal cavity, ethmoidal sinus and sphenoid sinus. (D) The mass exhibits restricted diffusion on diffusion-weighted images, and the intensity depends on the apparent diffusion coefficients (arrow). (E) Axial and (F) coronal post-contrast T1-weighted MR images indicate cervical lymph node enhancement (arrow).
Methods and materials
conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). IMRT and 3D-CRT were delivered using 6-MV photons, while Co-60 was used for two-dimensional radiotherapy. ENI covered the bilateral partial upper neck (levels Ib, II and VIIa) to the middle neck (levels Ib, II, VIIa, III and IV) or the whole neck (levels Ib, II, VIIa, III, IV and V). Surgical resections of primary nasal or sinus tumours were classified generally as endoscopic surgery, partially open surgery or a combination of both approaches. Selective neck dissection was performed in some cases with lymph node metastases. Patients received induction, concurrent or adjuvant chemotherapy with various regimens. Neoadjuvant and adjuvant regimens included platinum-based drugs with vincristine, epirubicin and pirarubicin, whereas concurrent regimens mainly included only platinum-based agents.
Patients This retrospective study included 217 patients who were newly diagnosed with ONB, staged according to the modified Kadish stage classification system and treated at the radiation oncology department of the Eye, Ear, Nose and Throat Hospital of Fudan University from July 1991 to April 2019. The study was approved by the ethics committee of the Eye, Ear, Nose and Throat Hospital of Fudan University, which waived the requirement for written informed consent due to the retrospective study design. The medical charts of included patients were reviewed to obtain initial head and neck computed tomography (CT) and magnetic resonance (MR) imaging findings and radiation therapy data. A retropharyngeal lymph node (RPN) diameter > 5 mm on CT or MR images was considered positive. The following characteristics were used to define positive cervical lymph nodes: shortest diameter of the largest axis > 10 mm, necrosis or extracapsular extension [6].
Outcomes This study assessed the primary outcomes of overall survival (OS), progression-free survival (PFS), regional-failure free survival (RFS) and distant metastasis-free survival (DMFS), as well as the incidence and location of lymph node metastasis as secondary outcomes. OS was defined as the time from the initial treatment date to the date of death. PFS was defined as the time from the date of therapy initiation to the date of disease progression. RFS was defined as the time interval wherein the patient remained free from cervical lymph nodal involvement after treatment completion. DMFS was defined as the time from the initial treatment to the development of distant metastasis.
Treatment The initial therapeutic strategy for ONB comprised surgical resection, radiotherapy and chemotherapy. All patients underwent radiotherapy as a monotherapy or preoperative or postoperative treatment via two-dimensional conventional radiotherapy, three-dimensional 2
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Statistical analysis
Table 1 Baseline characteristics of 217 patients.
Continuous data were compared using Student's t test, and categorical variables were compared using the Pearson chi-square test or Fisher’s exact test. All survival estimates were calculated using the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to conduct a multivariate analysis on prognostic factors for OS and PFS. All tests were two-sided, and a Pvalue < 0.05 was considered statistically significant. SPSS v20.0 statistical software (IBM Corp., Armonk, NY, USA) was used to perform all statistical analyses.
Results Patient characteristics and treatment Of the 217 enrolled patients with a mean age of 48.2 years (range: 7–86 years), 56 (25.8%) were female and 161 (74.2%) were male. The most common presenting symptoms were epistaxis (60.4%, 131/217) and nasal obstruction (56.2%, 122/217), followed by other symptoms including headache (15.7%, 34/217), olfactory dysfunction (13.4%, 29/217) and ophthalmological abnormalities (13.4%, 29/217). Thirtytwo patients (14.7%, 32/217) exhibited evidence of cervical lymph node metastases according to MR/CT imaging findings, physical examinations and biopsy at the initial diagnosis. Notably, MR imaging was superior to CT in terms of defining tumour boundaries and cervical lymph nodes (Fig. 1). Lymph node levels II, VIIa, Ib, III and IV were involved in 23 (10.6%), 12 (5.5%), 7 (3.2%), 3 (1.4%) and 1 patient (0.5%), respectively (Fig. 2). The majority of patients with neck involvement had ipsilateral disease, and only 10 patients (31.3%, 10/32) had bilateral cervical lymph node metastases. Sixty-seven patients (30.9%) underwent initial preoperative chemoradiotherapy for the primary tumour, while 118 (54.4%) received postoperative chemoradiotherapy. Thirty-two patients (14.7%) received only non-surgical treatment, including 21 and 11 who respectively underwent chemoradiotherapy or radiotherapy alone. The baseline characteristics of the patients are shown in Table 1. At diagnosis, 11 patients (5.1%) were classified as Kadish stage A, and none were managed with neck irradiation. However, the majority of patients (80.2%, 174/217) were classified as stage B or C; of them, 51 were managed with partial neck irradiation therapy, 13 underwent whole neck irradiation therapy and 110 patients did not receive ENI. Of the 32 patients classified as Kadish stage D, all presented with cervical lymph node metastases and all but a paediatric patient (age <
Variables
No. of patients (%) n = 217
Age (y) < 60 ≥60
164(75.6) 53(24.4)
Gender Male Female
161(74.2) 56(25.8)
Lymph node Negative Positive
185(85.3) 32(14.7)
Levels of LN Level Ib Level II Level III Level IV Level VIIa
7(3.2) 23(10.6) 3(1.4) 1(0.5) 12(5.5)
Kadish stage A B C D
11(5.1) 63(29.0) 111(51.2) 32(14.7)
Irradiation regions Original site Original site + partial neck 58(26.7) Original site + whole neck 37(17.1)
122(56.2)
Table 2 Characteristics of patients with negative neck. ENI − N (%)
ENI + N (%)
χ2
p
Age < 60 > 60
86(46.5) 35(18.9)
50(27.0) 14(7.6)
1.069
0.301
Gender Male Female
86(46.5) 35(18.9)
52(28,1) 12(6.5)
2.287
0.130
IR technique 2D RT 3D-CRT IMRT
15(8.1) 75(40.5) 31(16.8)
1(0.5) 31(16.8) 32(17.3)
14.328
0.001
Treatment modality IR + S S + IR IR alone
39(21.1) 70(37.8) 12(6.5)
15(8.1) 37(20.0) 12(6.5)
3.626
0.163
Chemotherapy No Yes
60(32.4) 61(33.0)
12(6.5) 52(28.1)
16.744
0.000
12 years) underwent ENI. Of the 31 ENI patients with stage D disease, 8 were managed with upper to middle neck radiation and 24 underwent whole neck radiation. In this group, 26 and 3 patients also underwent chemotherapy and selective neck dissection, respectively. Table 2 presents the basic characteristics and treatment modalities of patients with or without ENI. Regarding radiotherapy, 19 patients (8.8%) underwent two-dimensional radiotherapy, 123 (56.7%) underwent 3D-CRT and 75 (34.5%) underwent IMRT. The prescribed median dose to the gross tumour volume was 6400 cGy (range: 4000–7600 cGy), while the median dose of ENI was 5580 cGy (range: 4500–6300 cGy). Neoadjuvant and concurrent chemotherapy were administered to 113 (51.1%) and 75 patients (34.6%), respectively, while 31 patients (14.3%) also received adjuvant chemotherapy. Chemotherapy was administered to 81.3% of patients (78/96) managed with ENI but only 50.4% of patients (61/121) without ENI, and this difference was
Fig. 2. Distributions of cervical lymph node involvement over different levels at the time of initial diagnosis. 3
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Fig. 3. Log-rank comparison of the Kaplan–Meier curves of 5-year overall survival (A), progression-free survival (B), regional failure-free survival (C) and distant metastasis-free survival (D) between patients with or without cervical lymph node metastasis after treatment completion.
significant (χ2 = 22.108, p < 0.001).
(χ2 = 0.069, p = 1.000) or the initial tumour stage (χ2 = 0.001, p = 0.975). Patients who did and did not undergo ENI had regional recurrence rates of 3.2% (3/95) and 10.7% (13/122), respectively, and this difference was significant (χ2 = 4.396, p = 0.036). Of the 32 patients with initial lymph node metastases, 2 (6.3%, 2/32) developed regional failures; one patient each had undergone partial or whole neck radiation. In N0 cases, ENI appeared to prevent cervical node relapse effectively, as only 1 of the 64 patients (1.6%) managed with ENI developed regional failure, compared to 13 of 121 patients (10.7%) who did not undergo ENI, a significant difference (χ2 = 5.017, p = 0.037). In this study, all patients who developed a regional failure were managed by salvage treatment, which included radiotherapy alone or after selective neck dissection. Among all the patients received salvage treatment, only 1 patient presented regional failure again and distant metastasis 8 months after the completion of salvage treatment.
Clinical outcomes All patients were followed for a median of 58.9 months (range: 1.6–231.4 months). The overall 5-year OS, PFS, LRFS and DMFS rates were 80.0%, 79.0%, 79.3% and 80%, respectively. A log-rank comparison of patients with and without cervical lymph node metastasis at the time of diagnosis revealed significant differences in OS (41.9% vs. 86.1%, p < 0.001), PFS (41.9% vs. 84.8%, p < 0.001), RFS (45.9% vs. 89%, p < 0.001) and DMFS (41.5% vs. 86.1%, p < 0.001) (Fig. 3). A multivariate analysis identified cervical lymph node metastasis as an independent prognostic factor for a poor OS (hazard ratio [HR] = 0.184, 95% confidence interval, [CI] = 0.078–0.436, p < 0.001) and PFS (HR = 0.198, 95% CI = 0.088–0.445, p < 0.001). We next compared the long-term survival outcomes of the 185 patients without cervical lymph node metastasis at the initial diagnosis who did and did not receive ENI. Notably, no significant differences in OS (79.9% vs 88%, P = 0.639), PFS (79.9% vs 87.1%, P = 0.986), RFS (79.9% vs 92.3%, P = 0.402) or DMFS (79.9% vs 88%, P = 0.898) were observed between these groups, suggesting that ENI did not enhance survival (Fig. 4).
Discussion The ideal neck management strategy for patients with ONB remains controversial due to a lack of clinical data from large samples. In this retrospective study of a large sample of patients with ONB at a single institution, our good survival outcomes with surgical resection followed by local radiotherapy were comparable to those of other series [7–9]. We note that locoregional failure was the predominant pattern of treatment failure in our study, suggesting that locoregional control remains an oncological challenge. In this study, we separately evaluated neck treatment strategies in the context of N0 and N positive cases, as the cervical lymph nodal involvement pattern its effects on long-term outcomes are essential factors in decisions regarding neck treatment. First, we analysed the cervical lymph node metastasis incidence and patterns in patients newly diagnosed with ONB. Our observation that nearly 15% of patients initially presented with evidence of cervical lymph node metastasis was consistent with previous studies reporting rates of < 10% to > 30% [10–12]. Our observation that level II was the most common site of cervical lymph node metastasis was consistent with the fact that
Patterns of failure Forty-three patients (19.8%) died of disease-related failure during the follow-up period. The most common failure pattern was locoregional relapse, which occurred in 26 of 217 (12.0%) patients at a median of 18.1 months (range: 3.2–136.5 months). Twenty-two patients (10.1%) developed distant metastases in the bone (n = 8), abdominal organs (liver and pancreas; n = 6), lungs and chest (n = 4), brain (n = 3) and multiple sites (n = 3). Sixteen of 217 patients (7.4%) exhibited evidence of regional failure after treatment completion: 2 had initial cervical lymph node metastases before treatment, while 14 had an initially negative neck status. The risk of regional failure did not correlate with either the initial pre-treatment lymph node status 4
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Fig. 4. Log-rank comparison of the Kaplan–Meier curves of 5-year overall survival (A), progression-free survival (B), regional failure-free survival (C) and distant metastasis-free survival (D) between the patients managed or not with elective neck irradiation.
combined with chemotherapy. In this cohort, 81.3% of patients (26/32) were administered with chemotherapy and were found to be sensitive to chemotherapy. However, the role of chemotherapy in N positive ONB remains uncertain, given the lack of comparison between patients treated or not with this therapeutic modality. Despite aggressive systematic treatment, however, the long-term survival outcomes remain unsatisfactory. This further underscores the challenge associated with improving the treatment outcomes of patients with ONB. Currently, the indications of ENI for patients with N0 disease are not well defined. Some literatures suggest ENI to be beneficial and recommend it as part of the initial treatment for ONB [10,18,19]. However, in a previous study by Yuan [20], 15.2% of patients who had not undergone precautionary neck irradiation experienced a neck relapse, compared to 9.1% after neck irradiation therapy (χ 2 = 0.251, p = 1.0). In other words, ENI did not significantly reduce the rate of cervical lymph recurrence. Furthermore, Yin et al. [11] reported more optimistic 5-year regional failure-free survival and regional failure rates in patients who underwent with ENI. However, although ENI reduced the regional failure rate in our sample from 10.7% to 1.6% (p = 0.037), it did not yield any improvements in the 5-year OS, PFS, RFS and DMFS. Our findings were consistent with other studies wherein ENI significantly reduced the risk of cervical lymph nodal recurrence in ONB patients with clinical N0 disease but did not yield subsequent survival benefits [18,21]. Given the low regional failure rate and lack of significant improvements in long-term survival, we do not recommend ENI for patients with N0 disease because of the associated neck toxicity. Rather, cervical lymph node recurrences should be resolved by salvage surgery and/or locoregional radiation, in accordance with other studies [5,22]. In Mayo Clinic, a study of 52 patients with ONB N0 disease who did not undergo ENI reported a prolonged and modest risk of delayed cervical lymph node metastasis. All 14 cases of regional failure during follow-up were managed via salvage treatments, and only 1 patient presented
these nodes serve as the main sites of drainage from the nasal cavity and paranasal sinuses [13]. Our observation differed somewhat from that of Marinelli, who reported that after level II, levels I and III were most frequently involved, whereas we observed that VIIa and Ib were most frequently affected after level II [14]. Interestingly, we also observed that metastatic lymph nodes tended to be ipsilateral with the primary tumour. Second, we assessed the influence of the cervical lymph node status on long-term survival outcomes and observed significantly shorter 5-year OS, PFS, RFS and DFMS rates in patients with lymph node metastases vs. those without lymph node metastases. Consistent with these observations and previous studies, our univariate and multivariate analyses identified the lymph node metastasis status as an independent prognostic factor for survival [15,16]. The optimal management of lymph nodes at the time of initial treatment is an important factor with respect to survival outcomes. Currently, aggressive treatments such as selective neck dissection and radiotherapy are advocated for clinically or radiologically evident cervical lymph node positive ONB, which is associated with poorer survival [3]. In our cohort, 31 of 32 patients with initial lymph node metastases underwent systematic therapy for the neck, including surgical resection (3 cases) and chemotherapy (26 cases), whereas 2 patients underwent radiation alone. Only 1 paediatric patient with initial lymph node metastases did not undergo ENI. The 31 adult patients treated with ENI include 7 who were managed with upper to middle neck radiation and 24 who received whole neck radiation. More patients in our sample underwent ENI combined with chemotherapy rather than neck dissection, in contrast to a previous study in which selective neck dissection was favoured [3]. During follow-up, 2 patients (6.3%, 2/32) in our study developed regional failures, including 1 patient each from the partial neck and whole neck radiation groups. Currently, most centres advocate the use of neck dissection and postoperative radiation for the treatment of positive neck disease, although the reported 5-year overall survival rates are only approximately 30% [3,17]. As noted, our study differed in that more patients received ENI 5
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References
regional failure again and distant metastasis 8 months after the completion of salvage treatment. So, the salvage treatment can provide a guarantee of good treatment efficacy of for regional failure. As salvage treatments are available, the authors proposed neck observation rather than ENI in these patients. Another study reported the limited role of ENI in the prevention against cervical lymph nodal failure and suggested that this modality could be replaced by a combination of radiotherapy and chemotherapy [23]. Evidence suggests that level II is the most common site of cervical lymph node metastasis from ONB, followed by levels VIIa and Ib, whereas levels III and IV are less likely to be involved. In patients with N0 disease, prophylactic ENI covers levels Ib, II and VIIa, while levels VIIa, Ib, II and III are covered if only level VIIa and/or level Ib are involved. For patients with other cervical lymph node metastases, our irradiation plan specified that ENI would cover the whole neck. For centrally located tumours, we covered the bilateral cervical lymph node levels regardless of the N stage. Although bilateral neck irradiation increased the radiation volume in normal tissues, it could potentially reduce the risk of contralateral recurrence. These prophylactic irradiation regions were consistent with another study of ENI in 50 patients with N0 disease in which 33 underwent bilateral whole neck irradiation and 22 underwent bilateral irradiation of levels Ib, II, VIIa and III [11]. In our sample, we administered bilateral ENI with a median dose of 5580 cGy (range, 4500–6300 cGy), which was higher than the 50-Gy dose reported at the University of Florida [10]. Our study had some limitations of note. For example, the data were collected retrospectively from patients at a single institution with variable follow-up durations. Moreover, the chemotherapy regimens were not uniform which could be recruited for stratified analysis. Therefore, larger multi-centric prospective studies are needed to evaluate further the potential role of ENI in patients with ONB. In summary, approximately 15% of patients with ONB in our sample developed cervical lymph node metastasis, most frequently in levels II and VIIa. We further identified cervical lymph node involvement as an independent prognostic factor indicating a poor survival. For patients with initial cervical lymph node metastases, systematic therapy appeared to be superior to radiotherapy alone. Moreover, the value of ENI for patients with a N0 status remained uncertain. Given the low regional failure rate of N0 disease and the lack of significant improvements in long-term survival and the neck toxicity associated with irradiation, we do not recommend ENI for patients with N0 ONB. In such cases, cervical lymph node recurrences should be treated using salvage surgery and/or locoregional radiotherapy.
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Acknowledgements We thank all the patients and investigators involved in this study. Role of the Funding sources This study was supported by a grant from the Performance Motivation and Guidance Special Project of Chongqing Science and Technology Commission (No. cstc2018jxjl10004), Chongqing City, China. Declaration of Competing Interest None declared
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Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Neck management in patients with olfactory neuroblastoma Xinmao Song
a,1
, Chuang Huang
b,1
a,⁎
a
c
d,⁎
T
, Shengzi Wang , Li Yan , Jie Wang , Yi Li
a
Department of Radiation Oncology, Eye, Ear, Nose and Throat Hospital of Fudan University, 83 Fenyang Road, Shanghai 200031, China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, 181 Hanyu Road, Chongqing 400030, China c Department of E.N.T., Eye, Ear, Nose and Throat Hospital of Fudan University, 83 Fenyang Road, Shanghai 200031, China d Department of Oncology, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Kunming 650032, China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Olfactory neuroblastoma Cervical lymph node metastasis Elective neck irradiation Management strategy
Objective: Optimal neck management in patients with olfactory neuroblastoma (ONB), a rare malignancy, remains uncertain. This study aimed to analyse patterns of cervical lymph node metastases and corresponding clinical outcomes and to investigate the value of elective neck irradiation (ENI) in this population. Methods and materials: This study retrospectively reviewed clinical records, imaging findings, nodal metastasis features and treatment data of 217 patients with ONB treated at our hospital during 1991–2019. Univariate and multivariate analyses were used to assess the influence of cervical lymph node involvement on treatment outcomes. Survival and regional failure rates were compared between patients with or without ENI. Results: Thirty-two patients (14.7%) presented initially with cervical lymph node metastases, most frequently at levels II (10.6%, 23/217) and VIIa (5.5%, 12/217). Patients with and without cervical node metastasis differed significantly in overall (OS) (41.9% vs. 86.1%, p < 0.001), progression-free (PFS) (41.9% vs. 84.8%, p < 0.001), regional failure-free (45.9% vs. 89%, p < 0.001) and distant metastasis-free survival (41.5% vs. 86.1%, p < 0.001). Cervical lymph involvement was an independent factor affecting poor OS (hazard ratio, 0.184, 95% confidence interval, 0.078–0.436, p < 0.001) and PFS (hazard ratio, 0.198, 95% confidence interval, 0.088–0.445, p < 0.001). Moreover, 43.8% patients (95/217) underwent ENI, which significantly reduced the incidence of regional recurrence from 10.7% to 3.2% (χ2 = 4.396, p = 0.036) but did not significantly affect other survival outcomes. Regional failures could be resolved using salvage treatment. Conclusions: Our findings indicate the importance of systematic therapy for patients with initial cervical lymph node metastases. ENI is not recommended for N0 disease.
Introduction Olfactory neuroblastoma (ONB) is a rare solid malignancy that arises from the olfactory epithelium in the nasal cavity. According to retrospective studies, primary ONB is mainly treated via surgical resection and subsequent radiotherapy [1]. However, regional failure after treatment remains an issue associated with significant patient mortality [2]. To the best of our knowledge, no consensus has been reached regarding the optimal neck management for patients with ONB. Currently, some investigators initially apply selective neck dissection for the treatment of cervical lymph node metastasis, followed by radiotherapy or chemoradiotherapy [3]. Although the combination of surgery and radiotherapy for the primary tumor has been the standard treatment, the value of neck irradiation for those N0 neck is still no
clear. This issue is complicated by the lack of consensus regarding the indication and delivery of elective neck irradiation (ENI) for patients with clinically negative lymph nodes in the neck [4,5]. A better neck management strategy for patients with ONB would require clarification of the cervical lymph node metastasis incidence and pattern. Although cervical lymph node involvement has been described in 10–30% of patients at the time of diagnosis and was proven to be an independent poor prognostic factor, few reports have described the characteristics of cervical lymph node metastases in ONB in detail. Therefore, this retrospective, descriptive study aimed to analyse the basic patterns of cervical lymph node metastases in newly diagnosed patients with ONB and to assess the influence of the cervical lymph node status on neck management and long-term survival outcomes and the value of ENI in this population.
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Corresponding authors. E-mail addresses: [email protected] (S. Wang), [email protected] (Y. Li). 1 These authors have contributed equally to this work and co-first authors https://doi.org/10.1016/j.oraloncology.2019.104505 Received 23 July 2019; Received in revised form 5 October 2019; Accepted 26 November 2019 1368-8375/ © 2019 Elsevier Ltd. All rights reserved.
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Fig. 1. A 60-year-old male patient with olfactory neuroblastoma. (A) Axial T2-weighted magnetic resonance (MR) imaging reveals an iso-intense mass in the nasal cavity and ethmoidal sinus (arrow). (B) Axial and (C) coronal post-contrast T1-weighted MR images demonstrate heterogeneous enhancement of the mass (arrow), which extends into the right nasal cavity, ethmoidal sinus and sphenoid sinus. (D) The mass exhibits restricted diffusion on diffusion-weighted images, and the intensity depends on the apparent diffusion coefficients (arrow). (E) Axial and (F) coronal post-contrast T1-weighted MR images indicate cervical lymph node enhancement (arrow).
Methods and materials
conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). IMRT and 3D-CRT were delivered using 6-MV photons, while Co-60 was used for two-dimensional radiotherapy. ENI covered the bilateral partial upper neck (levels Ib, II and VIIa) to the middle neck (levels Ib, II, VIIa, III and IV) or the whole neck (levels Ib, II, VIIa, III, IV and V). Surgical resections of primary nasal or sinus tumours were classified generally as endoscopic surgery, partially open surgery or a combination of both approaches. Selective neck dissection was performed in some cases with lymph node metastases. Patients received induction, concurrent or adjuvant chemotherapy with various regimens. Neoadjuvant and adjuvant regimens included platinum-based drugs with vincristine, epirubicin and pirarubicin, whereas concurrent regimens mainly included only platinum-based agents.
Patients This retrospective study included 217 patients who were newly diagnosed with ONB, staged according to the modified Kadish stage classification system and treated at the radiation oncology department of the Eye, Ear, Nose and Throat Hospital of Fudan University from July 1991 to April 2019. The study was approved by the ethics committee of the Eye, Ear, Nose and Throat Hospital of Fudan University, which waived the requirement for written informed consent due to the retrospective study design. The medical charts of included patients were reviewed to obtain initial head and neck computed tomography (CT) and magnetic resonance (MR) imaging findings and radiation therapy data. A retropharyngeal lymph node (RPN) diameter > 5 mm on CT or MR images was considered positive. The following characteristics were used to define positive cervical lymph nodes: shortest diameter of the largest axis > 10 mm, necrosis or extracapsular extension [6].
Outcomes This study assessed the primary outcomes of overall survival (OS), progression-free survival (PFS), regional-failure free survival (RFS) and distant metastasis-free survival (DMFS), as well as the incidence and location of lymph node metastasis as secondary outcomes. OS was defined as the time from the initial treatment date to the date of death. PFS was defined as the time from the date of therapy initiation to the date of disease progression. RFS was defined as the time interval wherein the patient remained free from cervical lymph nodal involvement after treatment completion. DMFS was defined as the time from the initial treatment to the development of distant metastasis.
Treatment The initial therapeutic strategy for ONB comprised surgical resection, radiotherapy and chemotherapy. All patients underwent radiotherapy as a monotherapy or preoperative or postoperative treatment via two-dimensional conventional radiotherapy, three-dimensional 2
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Statistical analysis
Table 1 Baseline characteristics of 217 patients.
Continuous data were compared using Student's t test, and categorical variables were compared using the Pearson chi-square test or Fisher’s exact test. All survival estimates were calculated using the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to conduct a multivariate analysis on prognostic factors for OS and PFS. All tests were two-sided, and a Pvalue < 0.05 was considered statistically significant. SPSS v20.0 statistical software (IBM Corp., Armonk, NY, USA) was used to perform all statistical analyses.
Results Patient characteristics and treatment Of the 217 enrolled patients with a mean age of 48.2 years (range: 7–86 years), 56 (25.8%) were female and 161 (74.2%) were male. The most common presenting symptoms were epistaxis (60.4%, 131/217) and nasal obstruction (56.2%, 122/217), followed by other symptoms including headache (15.7%, 34/217), olfactory dysfunction (13.4%, 29/217) and ophthalmological abnormalities (13.4%, 29/217). Thirtytwo patients (14.7%, 32/217) exhibited evidence of cervical lymph node metastases according to MR/CT imaging findings, physical examinations and biopsy at the initial diagnosis. Notably, MR imaging was superior to CT in terms of defining tumour boundaries and cervical lymph nodes (Fig. 1). Lymph node levels II, VIIa, Ib, III and IV were involved in 23 (10.6%), 12 (5.5%), 7 (3.2%), 3 (1.4%) and 1 patient (0.5%), respectively (Fig. 2). The majority of patients with neck involvement had ipsilateral disease, and only 10 patients (31.3%, 10/32) had bilateral cervical lymph node metastases. Sixty-seven patients (30.9%) underwent initial preoperative chemoradiotherapy for the primary tumour, while 118 (54.4%) received postoperative chemoradiotherapy. Thirty-two patients (14.7%) received only non-surgical treatment, including 21 and 11 who respectively underwent chemoradiotherapy or radiotherapy alone. The baseline characteristics of the patients are shown in Table 1. At diagnosis, 11 patients (5.1%) were classified as Kadish stage A, and none were managed with neck irradiation. However, the majority of patients (80.2%, 174/217) were classified as stage B or C; of them, 51 were managed with partial neck irradiation therapy, 13 underwent whole neck irradiation therapy and 110 patients did not receive ENI. Of the 32 patients classified as Kadish stage D, all presented with cervical lymph node metastases and all but a paediatric patient (age <
Variables
No. of patients (%) n = 217
Age (y) < 60 ≥60
164(75.6) 53(24.4)
Gender Male Female
161(74.2) 56(25.8)
Lymph node Negative Positive
185(85.3) 32(14.7)
Levels of LN Level Ib Level II Level III Level IV Level VIIa
7(3.2) 23(10.6) 3(1.4) 1(0.5) 12(5.5)
Kadish stage A B C D
11(5.1) 63(29.0) 111(51.2) 32(14.7)
Irradiation regions Original site Original site + partial neck 58(26.7) Original site + whole neck 37(17.1)
122(56.2)
Table 2 Characteristics of patients with negative neck. ENI − N (%)
ENI + N (%)
χ2
p
Age < 60 > 60
86(46.5) 35(18.9)
50(27.0) 14(7.6)
1.069
0.301
Gender Male Female
86(46.5) 35(18.9)
52(28,1) 12(6.5)
2.287
0.130
IR technique 2D RT 3D-CRT IMRT
15(8.1) 75(40.5) 31(16.8)
1(0.5) 31(16.8) 32(17.3)
14.328
0.001
Treatment modality IR + S S + IR IR alone
39(21.1) 70(37.8) 12(6.5)
15(8.1) 37(20.0) 12(6.5)
3.626
0.163
Chemotherapy No Yes
60(32.4) 61(33.0)
12(6.5) 52(28.1)
16.744
0.000
12 years) underwent ENI. Of the 31 ENI patients with stage D disease, 8 were managed with upper to middle neck radiation and 24 underwent whole neck radiation. In this group, 26 and 3 patients also underwent chemotherapy and selective neck dissection, respectively. Table 2 presents the basic characteristics and treatment modalities of patients with or without ENI. Regarding radiotherapy, 19 patients (8.8%) underwent two-dimensional radiotherapy, 123 (56.7%) underwent 3D-CRT and 75 (34.5%) underwent IMRT. The prescribed median dose to the gross tumour volume was 6400 cGy (range: 4000–7600 cGy), while the median dose of ENI was 5580 cGy (range: 4500–6300 cGy). Neoadjuvant and concurrent chemotherapy were administered to 113 (51.1%) and 75 patients (34.6%), respectively, while 31 patients (14.3%) also received adjuvant chemotherapy. Chemotherapy was administered to 81.3% of patients (78/96) managed with ENI but only 50.4% of patients (61/121) without ENI, and this difference was
Fig. 2. Distributions of cervical lymph node involvement over different levels at the time of initial diagnosis. 3
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Fig. 3. Log-rank comparison of the Kaplan–Meier curves of 5-year overall survival (A), progression-free survival (B), regional failure-free survival (C) and distant metastasis-free survival (D) between patients with or without cervical lymph node metastasis after treatment completion.
significant (χ2 = 22.108, p < 0.001).
(χ2 = 0.069, p = 1.000) or the initial tumour stage (χ2 = 0.001, p = 0.975). Patients who did and did not undergo ENI had regional recurrence rates of 3.2% (3/95) and 10.7% (13/122), respectively, and this difference was significant (χ2 = 4.396, p = 0.036). Of the 32 patients with initial lymph node metastases, 2 (6.3%, 2/32) developed regional failures; one patient each had undergone partial or whole neck radiation. In N0 cases, ENI appeared to prevent cervical node relapse effectively, as only 1 of the 64 patients (1.6%) managed with ENI developed regional failure, compared to 13 of 121 patients (10.7%) who did not undergo ENI, a significant difference (χ2 = 5.017, p = 0.037). In this study, all patients who developed a regional failure were managed by salvage treatment, which included radiotherapy alone or after selective neck dissection. Among all the patients received salvage treatment, only 1 patient presented regional failure again and distant metastasis 8 months after the completion of salvage treatment.
Clinical outcomes All patients were followed for a median of 58.9 months (range: 1.6–231.4 months). The overall 5-year OS, PFS, LRFS and DMFS rates were 80.0%, 79.0%, 79.3% and 80%, respectively. A log-rank comparison of patients with and without cervical lymph node metastasis at the time of diagnosis revealed significant differences in OS (41.9% vs. 86.1%, p < 0.001), PFS (41.9% vs. 84.8%, p < 0.001), RFS (45.9% vs. 89%, p < 0.001) and DMFS (41.5% vs. 86.1%, p < 0.001) (Fig. 3). A multivariate analysis identified cervical lymph node metastasis as an independent prognostic factor for a poor OS (hazard ratio [HR] = 0.184, 95% confidence interval, [CI] = 0.078–0.436, p < 0.001) and PFS (HR = 0.198, 95% CI = 0.088–0.445, p < 0.001). We next compared the long-term survival outcomes of the 185 patients without cervical lymph node metastasis at the initial diagnosis who did and did not receive ENI. Notably, no significant differences in OS (79.9% vs 88%, P = 0.639), PFS (79.9% vs 87.1%, P = 0.986), RFS (79.9% vs 92.3%, P = 0.402) or DMFS (79.9% vs 88%, P = 0.898) were observed between these groups, suggesting that ENI did not enhance survival (Fig. 4).
Discussion The ideal neck management strategy for patients with ONB remains controversial due to a lack of clinical data from large samples. In this retrospective study of a large sample of patients with ONB at a single institution, our good survival outcomes with surgical resection followed by local radiotherapy were comparable to those of other series [7–9]. We note that locoregional failure was the predominant pattern of treatment failure in our study, suggesting that locoregional control remains an oncological challenge. In this study, we separately evaluated neck treatment strategies in the context of N0 and N positive cases, as the cervical lymph nodal involvement pattern its effects on long-term outcomes are essential factors in decisions regarding neck treatment. First, we analysed the cervical lymph node metastasis incidence and patterns in patients newly diagnosed with ONB. Our observation that nearly 15% of patients initially presented with evidence of cervical lymph node metastasis was consistent with previous studies reporting rates of < 10% to > 30% [10–12]. Our observation that level II was the most common site of cervical lymph node metastasis was consistent with the fact that
Patterns of failure Forty-three patients (19.8%) died of disease-related failure during the follow-up period. The most common failure pattern was locoregional relapse, which occurred in 26 of 217 (12.0%) patients at a median of 18.1 months (range: 3.2–136.5 months). Twenty-two patients (10.1%) developed distant metastases in the bone (n = 8), abdominal organs (liver and pancreas; n = 6), lungs and chest (n = 4), brain (n = 3) and multiple sites (n = 3). Sixteen of 217 patients (7.4%) exhibited evidence of regional failure after treatment completion: 2 had initial cervical lymph node metastases before treatment, while 14 had an initially negative neck status. The risk of regional failure did not correlate with either the initial pre-treatment lymph node status 4
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Fig. 4. Log-rank comparison of the Kaplan–Meier curves of 5-year overall survival (A), progression-free survival (B), regional failure-free survival (C) and distant metastasis-free survival (D) between the patients managed or not with elective neck irradiation.
combined with chemotherapy. In this cohort, 81.3% of patients (26/32) were administered with chemotherapy and were found to be sensitive to chemotherapy. However, the role of chemotherapy in N positive ONB remains uncertain, given the lack of comparison between patients treated or not with this therapeutic modality. Despite aggressive systematic treatment, however, the long-term survival outcomes remain unsatisfactory. This further underscores the challenge associated with improving the treatment outcomes of patients with ONB. Currently, the indications of ENI for patients with N0 disease are not well defined. Some literatures suggest ENI to be beneficial and recommend it as part of the initial treatment for ONB [10,18,19]. However, in a previous study by Yuan [20], 15.2% of patients who had not undergone precautionary neck irradiation experienced a neck relapse, compared to 9.1% after neck irradiation therapy (χ 2 = 0.251, p = 1.0). In other words, ENI did not significantly reduce the rate of cervical lymph recurrence. Furthermore, Yin et al. [11] reported more optimistic 5-year regional failure-free survival and regional failure rates in patients who underwent with ENI. However, although ENI reduced the regional failure rate in our sample from 10.7% to 1.6% (p = 0.037), it did not yield any improvements in the 5-year OS, PFS, RFS and DMFS. Our findings were consistent with other studies wherein ENI significantly reduced the risk of cervical lymph nodal recurrence in ONB patients with clinical N0 disease but did not yield subsequent survival benefits [18,21]. Given the low regional failure rate and lack of significant improvements in long-term survival, we do not recommend ENI for patients with N0 disease because of the associated neck toxicity. Rather, cervical lymph node recurrences should be resolved by salvage surgery and/or locoregional radiation, in accordance with other studies [5,22]. In Mayo Clinic, a study of 52 patients with ONB N0 disease who did not undergo ENI reported a prolonged and modest risk of delayed cervical lymph node metastasis. All 14 cases of regional failure during follow-up were managed via salvage treatments, and only 1 patient presented
these nodes serve as the main sites of drainage from the nasal cavity and paranasal sinuses [13]. Our observation differed somewhat from that of Marinelli, who reported that after level II, levels I and III were most frequently involved, whereas we observed that VIIa and Ib were most frequently affected after level II [14]. Interestingly, we also observed that metastatic lymph nodes tended to be ipsilateral with the primary tumour. Second, we assessed the influence of the cervical lymph node status on long-term survival outcomes and observed significantly shorter 5-year OS, PFS, RFS and DFMS rates in patients with lymph node metastases vs. those without lymph node metastases. Consistent with these observations and previous studies, our univariate and multivariate analyses identified the lymph node metastasis status as an independent prognostic factor for survival [15,16]. The optimal management of lymph nodes at the time of initial treatment is an important factor with respect to survival outcomes. Currently, aggressive treatments such as selective neck dissection and radiotherapy are advocated for clinically or radiologically evident cervical lymph node positive ONB, which is associated with poorer survival [3]. In our cohort, 31 of 32 patients with initial lymph node metastases underwent systematic therapy for the neck, including surgical resection (3 cases) and chemotherapy (26 cases), whereas 2 patients underwent radiation alone. Only 1 paediatric patient with initial lymph node metastases did not undergo ENI. The 31 adult patients treated with ENI include 7 who were managed with upper to middle neck radiation and 24 who received whole neck radiation. More patients in our sample underwent ENI combined with chemotherapy rather than neck dissection, in contrast to a previous study in which selective neck dissection was favoured [3]. During follow-up, 2 patients (6.3%, 2/32) in our study developed regional failures, including 1 patient each from the partial neck and whole neck radiation groups. Currently, most centres advocate the use of neck dissection and postoperative radiation for the treatment of positive neck disease, although the reported 5-year overall survival rates are only approximately 30% [3,17]. As noted, our study differed in that more patients received ENI 5
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References
regional failure again and distant metastasis 8 months after the completion of salvage treatment. So, the salvage treatment can provide a guarantee of good treatment efficacy of for regional failure. As salvage treatments are available, the authors proposed neck observation rather than ENI in these patients. Another study reported the limited role of ENI in the prevention against cervical lymph nodal failure and suggested that this modality could be replaced by a combination of radiotherapy and chemotherapy [23]. Evidence suggests that level II is the most common site of cervical lymph node metastasis from ONB, followed by levels VIIa and Ib, whereas levels III and IV are less likely to be involved. In patients with N0 disease, prophylactic ENI covers levels Ib, II and VIIa, while levels VIIa, Ib, II and III are covered if only level VIIa and/or level Ib are involved. For patients with other cervical lymph node metastases, our irradiation plan specified that ENI would cover the whole neck. For centrally located tumours, we covered the bilateral cervical lymph node levels regardless of the N stage. Although bilateral neck irradiation increased the radiation volume in normal tissues, it could potentially reduce the risk of contralateral recurrence. These prophylactic irradiation regions were consistent with another study of ENI in 50 patients with N0 disease in which 33 underwent bilateral whole neck irradiation and 22 underwent bilateral irradiation of levels Ib, II, VIIa and III [11]. In our sample, we administered bilateral ENI with a median dose of 5580 cGy (range, 4500–6300 cGy), which was higher than the 50-Gy dose reported at the University of Florida [10]. Our study had some limitations of note. For example, the data were collected retrospectively from patients at a single institution with variable follow-up durations. Moreover, the chemotherapy regimens were not uniform which could be recruited for stratified analysis. Therefore, larger multi-centric prospective studies are needed to evaluate further the potential role of ENI in patients with ONB. In summary, approximately 15% of patients with ONB in our sample developed cervical lymph node metastasis, most frequently in levels II and VIIa. We further identified cervical lymph node involvement as an independent prognostic factor indicating a poor survival. For patients with initial cervical lymph node metastases, systematic therapy appeared to be superior to radiotherapy alone. Moreover, the value of ENI for patients with a N0 status remained uncertain. Given the low regional failure rate of N0 disease and the lack of significant improvements in long-term survival and the neck toxicity associated with irradiation, we do not recommend ENI for patients with N0 ONB. In such cases, cervical lymph node recurrences should be treated using salvage surgery and/or locoregional radiotherapy.
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Acknowledgements We thank all the patients and investigators involved in this study. Role of the Funding sources This study was supported by a grant from the Performance Motivation and Guidance Special Project of Chongqing Science and Technology Commission (No. cstc2018jxjl10004), Chongqing City, China. Declaration of Competing Interest None declared
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