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ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 201-206

Long-term outcomes of locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation treated with neoadjuvant chemotherapy


1 Department of Medical Oncology, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India
2 Centre for Cancer Epidemiology, Section of Biostatistics, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India
4 Department of Surgical Oncology, Tata Memorial Centre, HBNI, Mumbai, Maharashtra, India

Date of Submission09-Mar-2020
Date of Decision27-Mar-2020
Date of Acceptance10-Apr-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_78_20

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  Abstract 


Background: Sinonasal tumors are a rare group of neoplasms with limited data available regarding their treatment.
Objectives: To estimate the 5 year outcomes and late adverse events of locally advanced sinonasal tumors treated with neoadjuvant therapy (NACT) followed by local therapy.
Methods: Twenty-five patients with locally advanced esthesioneuroblastoma or sinonasal neuroendocrine tumors treated between August 2010 and August 2014 with NACT followed by local therapy were selected. The 5-year outcome and late adverse events (CTCAE version 4.02) were noted. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. COX regression analysis was used to identify factors impacting PFS and OS.
Results: The median follow-up was 5.15 years. The 5-year PFS in the esthesioneuroblastoma cohort and in the sinonasal neuroendocrine carcinoma (SNEC) cohort was 63.5% (95% confidence interval [CI]: 28.9–84.7) and 34.6% (95% CI: 10.1–61.1), respectively (P = 0.1). The only factor impacting PFS on multivariate analysis was a response to NACT (P = 0.033). The 5-year OS in the esthesioneuroblastoma cohort and in the SNEC cohort was 91.7% (95% CI: 53.9–98.9) and 46.2% (95% CI: 19.2–69.6), respectively (P = 0.024). Any grade late adverse events were seen in 20 patients (80%). Metabolic late adverse events were seen in 19 patients (76%).
Conclusion: NACT in advanced sinonasal cancers is associated with an improvement in 5-year outcomes. However, late side effects, especially metabolic, are seen in these patients and should be evaluated during follow-up.

Keywords: Adverse event, esthesioneuroblastoma, induction, neoadjuvant, sinonasal, sinonasal neuroendocrine carcinoma


How to cite this article:
Patil VM, Noronha V, Joshi A, Talreja V, Dhumal S, Menon N, Abhyankar A, Dsouza H, Singh GK, Bhattacharjee A, Ghosh-Laskar S, Pai P, Chaturvedi P, Nair D, Chaukar D, DCruz A, Shetty P, Moiyadi A, Prabhash K. Long-term outcomes of locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation treated with neoadjuvant chemotherapy. Cancer Res Stat Treat 2020;3:201-6

How to cite this URL:
Patil VM, Noronha V, Joshi A, Talreja V, Dhumal S, Menon N, Abhyankar A, Dsouza H, Singh GK, Bhattacharjee A, Ghosh-Laskar S, Pai P, Chaturvedi P, Nair D, Chaukar D, DCruz A, Shetty P, Moiyadi A, Prabhash K. Long-term outcomes of locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumor with neuroendocrine differentiation treated with neoadjuvant chemotherapy. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Aug 14];3:201-6. Available from: http://www.crstonline.com/text.asp?2020/3/2/201/287268




  Introduction Top


Sinonasal tumors are a rare subgroup of head-and-neck cancer with an incidence of 0.556 cases per 100,000 per year.[1] Esthesioneuroblastoma and sinonasal neuroendocrine carcinoma (SNEC) are the most common cancer subtypes seen in this location.[2] These tumors are commonly seen in locally advanced stages (60%–66.6%).[3],[4],[5],[6] Management of these advanced tumors is difficult due to the location and anatomical proximity to critical structures. In addition, these tumors are aggressive and show a higher propensity for distant metastasis than other head-and-neck cancers.[7],[8] The 5-year disease-free survival in advanced stage was 51.6% versus 100% in the early stage. The failure pattern suggests that in advanced-stage disease, nearly 53.6% of patients have residual disease in Kadish Stage C.[3]

Locally advanced esthesioneuroblastoma and SNEC are treated with a multidisciplinary approach.[9],[10] In our experience, however, combination surgery followed by adjuvant radiation or chemoradiation led to unsatisfactory outcomes.[9] Hence, we devised the approach of administration of neoadjuvant chemotherapy (NACT) before surgery and adjuvant chemoradiation. This approach had the advantage of improved response rate, orbital preservation, and improvement in short-term outcomes.[9],[11] However, it is common in aggressive histologies to have a high response rate but a short duration of response; whether this translates into a sustained clinical benefit is unknown. We report the results of an audit of patients with locally advanced esthesioneuroblastoma and SNEC treated with NACT, followed by definitive local therapy. In addition, we estimated the incidence of late adverse events in these patients.


  Methods Top


Patient details

The case selection details, NACT details, and local treatment details have already been published.[9] To summarize, this was an audit of 25 consecutive adult patients of esthesioneuroblastoma or sinonasal neuroendocrine histology treated between August 2010 and August 2014. All of these patients received NACT consisting of cisplatin (33 mg/m 2 D1–D3) and etoposide (100 mg/m 2 D1–D3) after obtaining written informed consent. Cisplatin was replaced with carboplatin (area under the curve-5 or 6) if the creatinine clearance was <60 ml/min. Post two cycles, patients underwent response assessment in the multidisciplinary clinic and then based on the response, they underwent either surgical resection followed by adjuvant chemoradiation or radical chemoradiation or palliative radiation [Figure 1]. All the patients were planned for adjuvant chemoradiation. Following completion of treatment, these patients were followed up till death. The follow-up schedule was as follows – three monthly follow-up in the 1st year; four monthly in the 2nd year; and six monthly from the 3rd to the 5th years and annually thereafter. The patient's history was obtained at each visit along with a physical examination including blood pressure measurement. Thyroid-stimulating hormone was measured at each visit, and a complete metabolic profile was done once every 6 months. Since this was a routine audit, institutional ethics approval was not obtained. Permission was obtained from the disease management group and the study was conducted in accordance with ethical principles including the Declaration of Helsinki and ICMR guidelines.
Figure 1: Patient flow sheet. NACT: Neoadjuvant chemotherapy, CTRT: Concurrent chemoradiotherapy

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Data collection

The data of these patients were acquired from a prospectively maintained head-and-neck cancer NACT database. A filtered sheet with baseline details, NACT details, local treatment details, and 2-year outcome details was already available. This same sheet was updated for outcomes with additional details for the current analysis. The additional details sought from the database were late adverse events and outcomes. Adverse events which were seen 90 days after completion of radiation were considered as late adverse events. All patients were included in the analysis of outcomes. The data were censored for the analysis on February 14, 2019.

Statistical analysis

RStudio version 3.6.2 (2019-12-12; “Dark and Stormy Night” © 2019; The R Foundation for Statistical Computing Platform; RStudio, Inc., Boston, MA; Available from: http://www.rstudio.com/.) was used for the analysis, and intention to treat analysis was performed both for efficacy and adverse events. Descriptive statistics were performed. Continuous variables were described using median with interquartile range (IQR), while ordinal and nominal variables were expressed in terms of percentage with 95% confidence interval (CI). Adverse events were scored according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.02. Progression-free survival (PFS) was defined as the time in years from the start of NACT until either first progression or death whichever occurred earlier. Overall survival (OS) was defined as the time in years from the start of NACT until death. All calculations were done from the start of the first cycle of NACT. The PFS and OS were estimated using the Kaplan–Meier method.[12] Median with its 95% CI (Brookmeyer and Crowley) was provided. COX regression analysis was used to identify factors affecting PFS and OS.[13],[14] The hazard ratio (HR) with its 95% CI interval was calculated with Efron's method of tie handling. The assumptions of the proportional hazard model were checked and were met.


  Results Top


Baseline and treatment details

The details of demographics, patient and tumor characteristics, treatment offered, and response have been previously published. To summarize, the median age of the whole cohort was 42 years (IQR: 37–47 years). All patients had locally advanced disease (Kadish C stage). The T-grouping was T4 for all patients. In the SNEC cohort, one of the two patients who did not receive local treatment had progressive disease on NACT and was not fit for further treatment, while one patient refused local treatment.

Adjuvant chemoradiation was completed by all patients (n = 11). The median radiation dose was 6000 cGy (IQR: 6000–6000 cGy), while the median number of weekly chemotherapy cycles (cisplatin: 30 mg/m 2) received was 6 (IQR: 6–6).[15] Of the nine patients started on radical chemoradiation, eight completed it (one patient progressed on radiation). The median radiation dose in the radical chemotherapy-radiotherapy cohort was 6000 cGy (IQR: 6000–6000 cGy), while the median number of weekly chemotherapy cycles (cisplatin: 30 mg/m 2) received was 5 (IQR: 4–6). The median overall cumulative dose of cisplatin and etoposide was 380 mg/m 2 (IQR: 300–450) and 200 mg/m 2 (IQR: 200–300), respectively.

Outcomes

The median follow-up was 5.15 years. At the data cutoff, 12 patients had progressed [Figure 1], four in the esthesioneuroblastoma cohort and eight in the SNEC cohort. The site of progression was locoregional in five patients, local with distant in two patients, distant in four patients, and second primary with distant metastasis in one patient. The overall median PFS was 4.63 years (95% CI: 2.10–not assessable [NA]) [Figure 2]. The median PFS in the esthesioneuroblastoma cohort was not reached (95% CI: 2.63–NA), and in the SNEC cohort, it was 2.1 years (95% CI: 0.69–NA). The 5-year PFS in the esthesioneuroblastoma cohort and in the SNEC cohort was 63.5% (95% CI: 28.9–84.7) and 34.6% (95% CI: 10.1–61.1), respectively (P = 0.1). Factors impacting PFS are shown in [Figure 3]. The only factor impacting PFS on multivariate analysis was a response to NACT (P = 0.033).
Figure 2: Overall progression-free survival graph of patients with locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumors with neuroendocrine differentiation treated with neoadjuvant chemotherapy

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Figure 3: Forest plot depicting the factors impacting progression-free survival of patients with locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumors with neuroendocrine differentiation treated with neoadjuvant chemotherapy. Hazard ratio <1 means a decreased hazard of progression. The factors tested were pathology (esthesioneuroblastoma vs. sinonasal neuroendocrine tumor), response (responder to neoadjuvant chemotherapy vs. nonresponder), Stage (Kadish C vs. D), resectability achieved (yes or no), and operability (operated: yes vs. no)

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At the data cutoff, eight patients had died, one in the esthesioneuroblastoma cohort and seven in the SNEC cohort. The cause of death was disease progression in all eight patients. The median OS was not reached (95% CI: 3.10–NA). The median OS in the esthesioneuroblastoma cohort was not reached (95% CI: NA–NA), and in the SNEC cohort, it was 3.31 (95% CI: 0.919–NA) years [Figure 4]. The 5-year OS in the esthesioneuroblastoma cohort and in the SNEC cohort was 91.7% (95% CI: 53.9–98.9) and 46.2% (95% CI: 19.2–69.6), respectively (P = 0.024). Factors impacting OS are shown in [Figure 5]. There was a trend toward better survival in patients with esthesioneuroblastoma histology.
Figure 4: Estimated overall survival graph according to the histopathology of patients with locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumors with neuroendocrine differentiation treated with neoadjuvant chemotherapy

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Figure 5: Forest plot depicting factors impacting overall survival of patients with locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumors with neuroendocrine differentiation treated with neoadjuvant chemotherapy. Hazard ratio <1 means a decreased hazard of death. The factors tested were pathology (esthesioneuroblastoma vs. sinonasal neuroendocrine tumor), response (responder to neoadjuvant chemotherapy vs. nonresponder), Stage (Kadish C vs. D), resectability achieved (yes or no), and operability (operated: yes vs. no)

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Late adverse events

The details of late local and metabolic adverse events are shown in [Table 1]. Any grade late adverse event was seen in 20 patients (80%). Metabolic late adverse events were seen in 19 patients (76%), while Grade 3 or above adverse events were seen in 4 patients (16%).
Table 1: Late adverse events in patients with locally advanced and borderline resectable esthesioneuroblastoma and sinonasal tumors with neuroendocrine differentiation treated with neoadjuvant chemotherapy

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  Discussion Top


The results of our study confirmed that the improvement seen in outcomes at 2 years with the addition of NACT in esthesioneuroblastoma and SNEC is sustained till the 5th year. The median follow-up of surviving patients in the study was 5.15 years, and only 1 patient was censored prior to the 4th year attesting to the fact that these results were obtained without much “left censoring” for OS [Figure 3].

A PubMed search was done with the following terms without any filters to compare our data with world literature on NACT in sinonasal tumors. The search terms used were ([Induction] OR Neoadjuvant) AND Sinonasal carcinoma, ([Induction] OR Neoadjuvant) AND Esthesioneuroblastoma and ([Induction] OR Neoadjuvant) AND SNEC. The role of NACT is still not defined in sinonasal malignancies. Survival in locally advanced sinonasal tumors is dependent on the type of histology, stage, and type of treatment (unimodality versus multimodality). Five-year OS of sinonasal cancers is 30%–60% in late-stage disease (T3–T4 combined).[16] Esthesioneuroblastoma histology, lower T-grouping, and multimodality treatment have a favorable outcome.[4],[17] In our series, we had nearly 50% SNEC and all our patients had T4-grouping. T4-grouping is an independent negative predictor for OS among sinonasal cancers (HR: 2.035; 95% CI: 1.7–2.436).[17] Considering these factors, the outcomes in our series seem promising in comparison to the world literature. In addition to the improved outcomes, NACT also has the advantage of orbital preservation.

In squamous cell cancer of the head-and-neck region, the quantum of benefit provided by systemic therapy decreases over time due to an increase in deaths as a result of non-cancer causes.[18] Cisplatin with radiation is known for inducing metabolic syndrome,[19],[20],[21] causing renal damage,[22] hypothyroidism,[23] and ototoxicity.[24] As we had used cisplatin during both neoadjuvant and concurrent settings with a median cumulative dose of 380 mg/m 2, we were concerned about its late side effects. The incidence of these metabolic late adverse events was 80% in our series. The incidence of renal dysfunction, type 2 diabetes, and hypertension was particularly concerning. The incidence of type 2 diabetes was 68%, as against the national incidence of 7.3%,[25] in a similar age cohort. However, these did not contribute to non-cancer-related mortality till data cutoff. However, late side effects due to cisplatin can develop over decades,[20] and more follow-up will be required to understand the impact of cisplatin-related adverse events in these patients.

The study was not without its limitations. The median follow-up was 5.1 years, and esthesioneuroblastoma is known to have late recurrences. In addition, more follow-up will be required to understand the development of late side effects. The retrospective design of the study also limits the interpretation of adverse events data. The strength of the study is its follow-up. The follow-up protocol of our institute is vigorous which mandates six monthly nasal endoscopies and at least annual imaging.


  Conclusion Top


NACT in advanced sinonasal cancers is associated with an improvement in 5-year outcomes. However, late side effects, especially metabolic, develop in these patients and should be evaluated during follow-up. Further research should include long-term adverse events as key secondary endpoints.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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