The treatment modalities and outcomes of recurrent nasopharyngeal carcinoma: a retrospective cohort study in the modern era

Introduction

Nasopharyngeal carcinoma (NPC) is considered as a rare malignancy in most of the countries (1). But the incidence is much higher in East and Southeast Asia, including Taiwan, which has an average annual incidence of 5.1 per hundred-thousand people during 2010–2015 (2,3). While the role of chemoradiotherapy for treatment-naïve NPC being well established, the optimal treatment choice for locoregionally recurrent NPC (LRrNPC) is still under debate (4-8).

According to published literatures, re-irradiation and surgical resection (SR) have been two major treatment options for residual or recurrent NPC. The 5-year local control rate of LRrNPC receiving re-irradiation and surgical treatment ranged from 15–85.5% and 40–85.5%, respectively (7-11). The high heterogeneity among studied populations in recurrent stage, nodal recurrence, or disease-free interval may be the reasons of quite different results from studies (7,12-17). Severe complication rates up to 65.5% is also challenging in retreating LRrNPC (18-21). Omitting locoregional treatment has also been proposed considering the lack of survival benefit and high complication rate (22). However, with the critical location of nasopharynx, not only treatment-related adverse event but also locoregional disease progression might deteriorate the quality of life of patients.

Among recent literatures reporting comparative outcomes, You et al. reported a superior 5-year survival rate of 77.1% with endoscopic resection comparing to 55.5% with re-irradiation by IMRT in resectable T1-T3 LRrNPCs. Nevertheless, a high treatment-related mortality rate of 34.7% in the re-irradiated early recurrent NPCs might overshadow the potential benefit of re-irradiation (18). In another observational study, Weng et al. suggested an additional survival benefit when combining endoscopic resection with chemoradiotherapy in treating residual or recurrent NPCs (23). Yet, 91.7% of the adjuvant chemoradiotherapies were performed following margin-free resections. In consideration of severe complications and lack of surgical control group, this might limit the extrapolation of the results (23).

With detail review of medical records and long-term follow-up, this study aimed to evaluate outcomes of different treatment modalities in LRrNPC patients.

Methods

Study cohort and endpoint definition

Patients with LRrNPC diagnosed in single medical center who had achieved a complete remission after first treatment course, proven by endoscopic or image study, with disease-free interval greater than 6 months were enrolled. Those who had residual disease, known distal metastasis, and other malignant disease were excluded. Patients’ characteristics including sex, age, recurrent stage, disease free interval, salvage treatment, and survival data were retrospectively collected from medical charts, hospital cancer registry records, and the National Death Registry.

Outcomes were calculated from the date of recurrence diagnosed to the date of sequential events recorded. The primary endpoint was locoregional-progression-free survival (LRPFS), which was defined as no progression recorded on subsequent image or endoscopic examinations. The secondary endpoint was overall survival (OS). For the severe adverse events, fatal acute complications and severe late complications limited to osteoradionecrosis, temporal lobe necrosis, and dysphagia causing frequent aspiration pneumonia or long-term feeding tube dependence were identified during follow-up course.

The study protocol had been registered and verified by the institutional review board (VGHKS18-CT11-11).

Statistical analysis

The software Statistical Package for Social Science, 20^th edition (SPSS 20^th) was used for data analysis. The baseline characteristics between treatment groups were compared using the Pearson’s chi square test. Factors imbalanced among treatment groups would be adjusted in further analysis. For survival outcomes, the Kaplan-Meier method was performed. Cox regression model was used to recognize possible prognostic factors. Logistic regression was performed to evaluate risk factors for severe adverse events. Factors achieving a P value <0.15 in univariate analysis were kept for multivariate test (24). And a P value <0.05 was considered statistically significant.

Results

Patients inclusion and treatment modalities

From 2006–2017, 31 consecutive patients were identified with distal-metastasis-free LRrNPC. Recurrences were diagnosed with pathological proof in 86.2% of the cases. Others were diagnosed by serial image studies including PET/CT or MRI and clinical judgement. PET/CT was performed in 39.3% cases to rule-out distal metastasis and whole body bone scan, chest image, and abdominal sonogram were used as substitute in 60.7% cases. While 2 were excluded for not receiving any treatment, 29 cases were enrolled for the final analysis, including 37.9% rT1-2 and 62.1% rT3-4. 34.5% of the cases had concurrent nodal recurrences and 72.4% had IMRT for the initial NPC treatment.

Twenty-six patients had received locoregional treatments, consisting of 14 re-irradiations (reRT), 6 SRs, and 6 combinations of surgery and re-irradiation (SR + reRT). The baseline characteristics of enrolled cases and their distribution among treatment modalities were shown in Table 1. Cases with early recurrences were inclined to have SR and most of those with advanced recurrences underwent re-irradiation. For SR, endoscopic approach accounted for 83.3% of the operations and a confident free-margin was achieved in 66.7% of rT1-2 and 33.3% of rT3-4 cases. Adjuvant re-irradiations were performed in cases with microscopic or macroscopic residual tumor. Among the 20 re-irradiations, all radiotherapies were performed with intensity-modulated radiotherapy (IMRT) technique, with the median dose of 60 Gy (40–70 Gy) and 60 Gy (50.4–63 Gy) for re-RT and SR + re-RT groups, respectively.

For systemic therapy, 3 cases (10.3%) received target therapy with Erbitux, and 20 cases (70.0%) received chemotherapy, including 8 concurrent with radiotherapy, 5 as adjuvant to either surgery or radiotherapy, and 7 receiving both. LRrNPCs that were diagnosed after the year of 2013 were more likely to receive chemotherapy for salvage treatment.

Overall outcomes and prognostic factors

After median follow-up of 36 months (range, 7–118 months), 12 locoregional progressions, 5 distal metastases, and 15 deaths were recorded. The LRPFS rates were 56.5% (95% CI: 45.6–67.4%) at 3-year and 38.7% (95% CI: 25.8–51.6%) at 5-year. The OS rates were 64.1% (95% CI: 54.9–73.3%) at 3-year and 54.3% (95% CI: 44.2–64.4%) at 5-year.In univariate analysis, salvage treatments with SR, reRT, and SR + reRT all revealed superior LRPFS comparing to systemic treatment alone. Considering possible selection bias of rT stage among treatment groups, rT stage was included in multivariate analysis for adjustment. After adjusted for rT stage, the LRPFS advantage still presented in reRT group and SR + reRT group (reRT, HR: 0.06, P=0.009; SR + reRT, HR: 0.069, P=0.021). However, SR group failed to show a statistically significant LRPFS benefit (HR: 0.084, P=0.130) (Table 2). To exclude the STx group with a limited case number, further analysis was performed comparing LRPFS of SR, reRT, and SR + reRT groups. Nonetheless, no statistically significant difference was found (Table 2). For secondary endpoint, there was no significant difference in OS among treatment groups, chemotherapy use, recurrent stage, nor age groups found in this cohort.

Severe adverse events

Overall, 51.7% of the enrolled cases developed severe adverse events, including ORN in 34.5%, severe dysphagia in 20.7%, and temporal lobe necrosis in 6.9%. The distribution of severe complications among salvage modalities was provided in Table 3. Though there was no significant difference in the risk of severe complications among the 4 salvage treatment groups, cumulative EQD2 ≥130 Gy (RR: 9.0, P=0.013) over nasopharyngeal region was associated with higher risk of severe adverse events.

Grade 5 complications occurred in 2 (6.9%) cases, both underwent re-irradiation for rT2N0 recurrent NPCs. One suffered from nasal bleeding complicated with suffocation 8 months after re-irradiation. The other experienced hypovolemic shock due to nasal bleeding superimposing acquired-hemophilia, which developed 7 months after re-irradiation.

Discussion

In this preliminary analysis of treatment modalities, our study found superior LRPFS in re-irradiation and SR + re-RT subgroups when compared to systemic treatment alone, after adjustment for recurrent T stage (Table 2). Despite having possible negative confounding factors such as advanced rT stage and positive resection margins, the superiorities in LRPFS were still presented in the less favorable cases treated by reRT and SR + reRT (7,14). On the other hand, SR group, having more favorable population with all rT1-2 recurrences, failed to reach a statistically significant benefit over systemic treatment alone (Table 2, multivariate analysis). However, there was no significant difference in LRPFS when focusing on the 3 locoregionally-treated subgroups. Considering the limited case number in the STx group and discrepancy between the analytical results, further evaluation would be needed.

IMRT re-irradiation in LRrNPC

According to our finding, the role of re-irradiation was essential for recurrent NPC. The pooled 5-year local-failure-free survival of 72% was reported with great heterogeneity in a meta-analysis for re-irradiation of recurrent NPC (21). As recurrent T stage being a prognostic factor for local control, Leung et al. reported the 3-year local failure free survival of 66.7%, 66.7%, and 18.4% for rT1, rT2, and rT3 receiving salvage re-irradiation, respectively (25). However, there is limited literatures available for comparative outcomes between re-irradiation and other modalities, especially for advanced recurrent NPC.

In a retrospective propensity score-matched analysis, re-irradiation with IMRT technique revealed an inferior 5-year OS in selective rT1-3 NPC patients, comparing to endoscopic nasopharyngectomy (5-year OS: 55.5% vs. 77.1%, P=0.003) (18). Treatment complication-related deaths occurred in 34.7% of the re-irradiation group having early recurrent NPCs. Grade 5 complications up to 35% was also reported in other re-irradiated cohorts (18,20,21,26). Yet, the enrolled cases of these studies exclusively received 2D conventional radiotherapy for their first NPC treatment courses. With the improvement of technique, complication-related death has declined to 10% for the re-irradiated cases in our study, having IMRT as first radiotherapy in 72.4% of the cohort. Similarly, in another cohort having 60.5% of the first NPC treatment done by IMRT, grade 5 adverse event rate of re-irradiation was only 7.4% (26). With the popularity of IMRT in primary NPC treatment, fatal toxicity would be expected to decrease in salvage re-irradiation.

Despite the improvement in lethal toxicity with IMRT, high risk of ≥ grade 3 adverse events remains a major concern. Re-irradiation doses ranging from 40–70 Gy were still associated with severe complication rate up to 60% to 73.7% (20,21,26). Several dose constraints for critical organs in re-irradiation situations have been proposed (Table 4). While the salvage RT dose >60 Gy was reported to have better disease control (12), cumulative dose of EQD2 >130 Gy over nasopharyngeal region was associated with a 9 times higher risk for severe complications in our study. It seems that even with IMRT technique, adequate dose for oncological control still accompanied with the cost of high risk for developing severe complications and adverse effects on the quality of life (20,26).

Fractionated stereotactic radiotherapy (FSRT) was increasingly reported as an alternative modality for residual and recurrent NPC, having the 2-year local control rate of 55–82% with 10–49 Gy in 2–8 fractions (29). In a cohort study with median follow-up of 20.2 months, Wu et al. reported the late complication rate being 18.9% for 90 patients treated by FSRT (30). Seo et al. reported a 35 cases cohort treated by FSRT that the grade 4–5 complication rate was as low as 14.3% (31). With emerging evidences and longer follow-up, FSRT may become an important treatment option for residual and recurrent NPC in near future. Nevertheless, the optimal dose regimen and long-term result for late adverse event still warrant investigation at present.

Possible role of combining SR and re-irradiation in the modern era

In our study, combination of SR and re-irradiation was also an appropriate treatment option for recurrent NPC. With less destructive procedure and better visualization of surgical field, endoscopic surgery was increasingly used for locally advanced recurrent NPC in recent years (23,32,33). Weng et al. and Liu et al. have reported the complete resection rates of 91.6% and 90.1% in cohorts with 52.8% and 52.7% of rT3-4 NPC, respectively (23,32). When further stratified by rT stage, margin-free resections were achieved in 50–100% of rT3 and 53.8% rT4 recurrent NPC (33-35). No fatal surgical complication was recorded in previous nor this cohort (23,32,33). Regardless of these promising reports, all of the five rT3-4 cases receiving SR in our cohort had either involved margin or gross residual disease and therefore receiving adjuvant radiotherapy.

Comparative outcomes including that of combined modalities had been reported in five retrospective cohort studies as listed in Table 5. While two of them showed similar or worse outcomes, the other three revealed superior survival with combination of radiotherapy and SR. King et al. reported the mean disease-free survival (mDFS) of 55 months for recurrent NPC treated by combined modalities, which was even better than that of SR group achieving free surgical margins, having mDFS of 46.5 months (36). In a retrospective cohort study with 83.3% rT1-2 NPC, Na’ara et al. revealed that SR with additional adjuvant radiotherapy improved the 5-year OS and disease-specific survival (SR vs. SR + reRT, OS: 39% vs. 67%, P=0.05; DSS: 52% vs. 65%, P=0.048) (16). When comparing to salvage chemoradiotherapy, Weng et al. suggested a better survival outcome combining salvage surgery with adjuvant chemoradiotherapy (OS, HR: 0.468, P=0.043; DFS, HR: 0.393, P=0.008) (23). The benefit of combining surgery and chemoradiotherapy persisted in subgroup analysis for locally advanced disease (23). In regard of adverse events, there was no significant additional hazard found for combined modalities in our study nor previous literatures (16,23). Further evaluation of the safety is warrant considering limited case number and possible selection bias in this study.

Strengths and limitations

With median follow-up of 3 years, this study compared local controls among SR, reRT, SR + reRT, and STx alone in LRrNPC. Having 83.3% of tumor resection done by endoscopic approach and IMRT accounted for 72.4% and 100% of the initial and salvage radiotherapy, our cohort could well reflect the clinical practice nowadays. The main limitations of this study included small sample size and retrospective design. The results were at risk of being underpowered to detect possible difference and affected by unadjusted confounders.

Conclusions

For LRrNPCs, locoregional treatments including reRT and SR + reRT may have local control advantage in comparison to systemic therapy alone, especially having the technical improvement with IMRT and endoscopic resection. Grade 5 complication of salvage re-irradiation would be expected to decrease with increasing use of IMRT in primary NPC treatment. Nonetheless, high incidence of severe complications was still a major concern. Larger cohort or prospective clinical trials are warrent to further evaluate the efficacy and safety of treatment modalities.

Acknowledgments

We appreciated the great dedication of the Head and Neck Cancer multidisciplinary team and all colleges from department of radiation oncology for thoughtful patient cares and inspiring discussions.

Funding: None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study protocol had been registered and verified by the institutional review board (VGHKS18-CT11-11). Informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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