Nasopharyngeal carcinoma. A “different” head and neck tumour. Part B: treatment, prognostic factors, and outcomes| ACTA Otorhinolaryngologica Italica

Abstract

Nasopharyngeal carcinoma (NPC) is the most interesting and intriguing malignant tumour located in the nasopharynx, because it is a “peculiar” malignancy, “different” from almost all the other head and neck tumours according to several points of view. Given that radiotherapy (RT) is the treatment of choice for NPC, chemotherapy (CT) has been added to standard RT to improve outcome in high-risk patients, either as an adjuvant, neoadjuvant or concurrent treatment modality with radiation. Surgery plays an important role in rescuing recurrent or persistent disease after primary (CT)RT. This second part of the review provides a critical analysis of various treatment described in the literature, both for primary cancer and for regional and distant metastases. The prognostic factors and the final results of the various treatments will also be analysed.

Treatment

Primary local-regional disease

Both surgery and chemo-radiotherapy (CT-RT) play an important role in the primary treatment of cancers of almost any location in the head and neck. Surgery is preferred to RT in some sites and vice versa in others. For some sites, both surgeons and chemo-radiotherapists claim the right to the primogeniture. On the contrary, there is no discussion about the primary treatment of nasopharyngeal carcinoma (NPC). Apart from the indication for surgery for few rare histologic forms as minor salivary glands tumours, RT is the backbone of treatment for NPC. Due to its radiosensitive behaviour and deep-seated anatomic location, RT has been established as the primary treatment since the 1950s ^1,2. In 1992, Lee et al. ³ analysed as many as 5,037 cases treated with RT in the period 1976-1985, and wrote: “Because of its peculiar predilection for southern Chinese, large series consisting of more than 1,000 patients were all reported from Oriental centres. Prospective randomised studies have rarely been conducted in the East because of resource limitations, and in the West because of insufficient number of patients. Almost all the claims on improvement of treatment results were based on comparison with historical data”. Although the treatment in those years was made with conventional two-dimensional (2D-RT) or three-dimensional RT (3D-RT), Lee et al. underlined that “wide field coverage, high tumour dose, and technical accuracy were emphasized in our radiation therapy for NPC” ³.

Nowadays, intensity-modulated RT (IMRT) has become the gold standard in the management of NPC, providing enhanced outcomes and less severe toxicities compared with previous RT techniques. In a recent study, the authors found 10 publications meeting the criteria for their meta-analysis and including 13,304 patients, of whom 5,212 received IMRT and 8,092 were treated with 2D-RT ⁴. Compared with 2D-RT treatment, the IMRT group was associated with a better 5-year overall survival (OS), local-regional free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). Additionally, the incidence of late toxicities such as xerostomia, trismus and temporal lobe neuropathy for NPC patients in IMRT group was significantly lower than in 2D-RT group. However, the side effects are not negligible even in patients treated with IMRT, mainly in those with advanced tumours treated with high radiation dose. In a series of 80 patients with T4 NPC treated with CT-IMRT (70.4 Gy), Kong et al. ⁵ reported 6 cases of radiation-induced temporal lobe necrosis, 16 cases of hearing loss and 2 cases of cranial nerve palsy. Huang et al. ⁶ conducted an observational, cross-sectional study of quality of life (QOL) and late toxicities in 242 patients with NPC with survival of > 5 years after treatment with IMRT (n = 100) or non-IMRT (n = 142). They found that the IMRT group had both statistically and clinically better outcomes in global QOL, cognitive functioning, social functioning and fatigue than the 2D-RT group. However, they reported that 34.0% of survivors suffered from symptomatic xerostomia and 22.0% from dysphagia after IMRT. In a recent study, Weng et al. found that the late incidence of hypothyroidism in their patients treated with IMRT was 38%, higher than that previously reported in the era of 2D-RT (14%). The authors speculated that “In the pursuit of better local control rates, increasing the dose of radiotherapy to the target area in clinical practice has led to increased radiotherapy complications. Although IMRT can delineate the thyroid gland in patients with lymph node metastases in regions III and IV of the neck, the thyroid gland is inevitably irradiated due to its proximity to the lymph nodes in the neck” ⁷.

Particle therapy (protons and carbon ions) is gaining popularity, mainly when it is added as a boost for locally advanced disease ⁸. The newest form of proton beam therapy is intensity-modulated proton radiation therapy (IMPT), also known as “pencil beam proton therapy”. It is a sophisticated mode of proton therapy that is analogous to IMRT and an active area of investigation in cancer care. Li et al. stated : “It has been found to significantly reduce the complication probability of key surrounding normal tissues, including parotid glands, inner ears, larynx, oral cavity, and esophagus, thereby being considered to be a promising irradiation modality pursuing a better QOL for patients with NPC” ⁹. In a review on the IMPT, Moreno et al. wrote: “Several dosimetric studies have demonstrated the superiority of IMPT over IMRT to improve dose sparing of nearby organs such as the larynx, salivary glands, and esophagus. Evidence of the clinical translation of these dosimetric advantages has been demonstrated with documented toxicity reductions (such as decreased feeding tube dependency) after IMPT for patients with head and neck cancer (HNC)” ¹⁰. However, in the literature there are few clinical studies and small series on the use of IMPT in the treatment of NPC. Taheri-Kadkhoda ¹¹ et al. presented 8 cases, and Lewis et al. ¹² treated with IMPT 10 patients. Both studies concluded that “The practicality of IMPT in NPC deserves further exploration when this technique becomes available on wider clinical scale” ¹¹, and “We observed dosimetric advantages conferred by IMPT compared to IMRT. Further study is needed to determine if these translate into reduced toxicity and/or improved disease control” ¹². One problem with the systematic use of the IMPT in some countries is the availability of operational proton centres and its high cost (about 3.2-4.8 times that of IMRT). For example, Li et al. ⁹ made a theoretical analysis of the cost-effectiveness of IMPT in China. China, despite having the largest global amount of NPC cases (about 44,600 cases, that is 80% of the newly diagnosed NPC cases worldwide), has only one operational proton centre, although the government has authorised 16 new ones. The authors concluded that: “IMPT has potential to be cost-effective for average Chinese NPC patients and should be validated clinically”.

Since the 1970s, CT has been added to standard RT in some centres to improve outcomes in high-risk patients, either as adjuvant (AC) ¹³, neoadjuvant (induction chemotherapy, ICT) ¹⁴, or concurrent treatment with radiation (CRT) ¹⁵. AC was tested also in childhood with contradictory results, either with improvement ¹⁶ or worsening ¹⁷ of the cure rate. A randomised clinical trial demonstrated that CRT was associated with a considerable survival benefit for patients with stage II NPC ¹⁸. In a meta-analysis performed in 2002 to evaluate the impact of integrating CT with RT, Huncharek et al. ¹⁹ identified six randomised controlled trials (RCTs) enrolling more than 1,500 patients and comparing CRT vs RT alone. Pooling all six studies, the meta-analysis demonstrated that concurrent CRT increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment.

Nowadays, the standard treatment for stage I disease is RT alone ²⁰. A systematic review and meta-analysis found 11 comparative studies (2,138 patients) on the treatment of patients with stage II NPC and concluded that CRT was better than 2D-RT alone with significant benefit in LRFS, while IMRT alone was superior to CRT, with equivalent survival outcomes and fewer grade 3-4 acute toxicities ²¹. Stage III and IV without distant metastasis are treated by CRT with cisplatin ²⁰.

Because distant metastases are a major cause of treatment failure and death, intensification of systemic treatment has been tested in several studies. A phase III RCT demonstrated that AC with cisplatin and fluorouracil after CRT was difficult to complete for heavy adverse events and did not significantly improve failure-free survival in loco-regionally advanced NPC ²².

A recent phase III trial compared ICT with gemcitabine and cisplatin plus CRT with CRT alone, and concluded that ICT and CRT significantly improved LRFS and OS, as compared with CRT alone, among patients with loco-regionally advanced NPC ²³.

However, as many ICT regimens have been proposed over the years, Liu et al. ²⁴ have recently performed a network meta-analysis on this topic. The fundamental criterion for the inclusion of studies was that they were RCTs. In the initial database search, they identified as many as 1,789 records, and thereafter excluded 37 duplicates and 976 irrelevant articles. After reviewing the titles and abstracts of the remaining 776 studies, 35 were screened in full-text. They excluded 3 phase II RCTs, 1 phase III RCT with paediatric patients, and 24 articles failing to meet their inclusion criteria. The remaining RCTs, involving 2,496 patients treated with different regimens of ICT, were enrolled in the meta-analysis. The different regimens were: gemcitabine plus cisplatin (GP), paclitaxel plus carboplatin and gemcitabine (GCP), mitomycin, epirubicin, cisplatin, fluorouracil plus leucovorin (MEPFL), cisplatin plus fluorouracil (PF), capecitabine plus cisplatin (PX), and docetaxel plus cisplatin and fluorouracil (TPF). The analysis revealed that the combined IC regimen of GP gained not only the most favourable OS benefit, but also longer DMFS and manageable adverse events (AEs). An even more recent RCT tried to determine whether IC with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs. PF prior to CRT for patients with stage IVA to IVB NPC ²⁵. The authors found that combined ICT regimen with 2 cycles of TPC for patients with stage IVA and IVB NPC improved failure-free survival (FFS) compared with 2 cycles of PF, with no increase in the toxicity profile.

Another controversial issue is the ideal number of ICT cycles. In another network meta-analysis, Li et al. ²⁶ found 10 propensity score-matching studies investigating ICT + CRT, which included 1,431 participants. In almost all of these studies, patients underwent 2-3 cycles of ICT given every 3 weeks. In none of the reported studies was the duration of treatment with ICT specified and any lengthening of the intervals between one cycle and another due to toxicity. However, the authors concluded that “The results showed that therapeutic strategies based on ICT + CRT may be recommended as the most effective treatment to improve OS and DMFS, but not LRFS”.

It should be noted that some studies demonstrated that another advantage of ICT is the possibility to reduce the IMRT target volume without reducing the rates of local control and survival in loco-regionally advanced NPC; the doses received by normal tissues can be decreased, and QoL scores may improve ²⁷.

Hence, it is established that ICT improves prognosis of patients with advanced NPC; but, how can this treatment interfere with the initiation of CT-RT? Two recent studies, made by the same team on patients treated in the same Chinese Medical University Cancer Hospital, are paradigmatic of the pros and cons of a ICT that is too prolonged ^28,29. In the first study, the authors analysed 498 patients with locoregionally advanced NPC (LANPC) treated with 2-3 cycles of ICT plus CRT. All patients underwent nasopharyngeal and neck MRI at initial diagnosis and after two cycles of ICT. Two independent clinicians reviewed the images for evaluation of tumour response; 340 (68.3%) patients were judged to have had a complete (CR) or partial (PR) response to treatment, and 158 (31.7%) patients had stable disease (SD) or progressive disease (PD). The 5-year OS, LRFS, DMFS and PFS rates for SD/PD vs CR/PR were 60.6% vs 84.0% (p < 0.001), 85.1% vs 94.3% (p < 0.001), 67.7% vs 85.0% (p < 0.001) and 49.7% vs 76.4% (p < 0.001). Tumour response was an independent prognostic factor ²⁸. The second study included 648 patients with LANPC treated with ICT followed by CRT and explored the prognostic significance of wait time for radical RT. Authors stated: “Compared with those receiving two cycles of ICT, patients with three cycles tended to have a wait time exceed 75 days (p < 0.001)”, and: “Moreover, we found older patients (≥ 50 years) were generally more associated with prolonged wait time”. A worse 5-year DMFS rate (76.5% vs 83.9%, p = 0.023) was found in patients with a prolonged wait time (≥ 75 days) than those with an acceptable wait time (≤ 75 days) ²⁹. To support this concept, He et al. demonstrated that two and three cycles of ICT are associated with similar survival, while four cycles reduce survival and increase treatment-related toxicity in endemic regions ³⁰.

A recent network meta-analysis (20 trials and 5,144 patients) tried to establish the best timing of the systemic treatment ³¹. The authors identified seven treatments: RT alone, which was used as the reference category; ICT followed by RT (ICT-RT); RT followed by AC (RT-AC); ICT followed by RT followed by AC (IC-RT-AC); CRT; ICT followed by CRT (ICT-CRT); and CRT followed by AC (CRT-AC). The conclusion was that the addition of AC to CRT achieved the highest survival benefit and consistent improvement for OS, PFS and distant control (DC). The addition of ICT to CRT achieved the highest effect on DC. Regarding toxicities, this network meta-analysis confirmed that the treatments with AC (CRT-AC and RT-AC) were the most toxic regimens for mucositis/hearing loss and neutropenia/weight loss, which underlines the potential toxicity of AC, either alone or administered with CRT.

Given the jumble of results, the ESMO-EURACAN Clinical Practice Guidelines stated: “As a prerequisite, ICT added to CRT should not hinder the subsequent delivery of full-dose CRT, and the time between the end of ICT and the start of RT should be kept as short as possible” ⁸.

The NCCN guidelines conclude that the addition of CT to CRT is indicated in patients with loco-regionally advanced NPC, but it is not clear whether before or after CRT ²⁰.

Given the aforementioned high frequency of neck lymph nodes (LN) metastases, radiation oncologists traditionally treated all neck levels comprehensively with definitive-intent or prophylactic RT. In 2009, Tang et al. ³² compared the outcomes of patients with N0 disease who received selective neck RT with the outcomes of those who received comprehensive treatment of all neck levels to provide a reference for the volume to be irradiated. According to the criteria for involved LNs detected by MRI, the incidence of metastases was 85.1% (786 of 924 patients). In patients who had N0 disease, the risks of regional recurrence and distant metastasis did not significantly differ between patients with inferior border of the neck irradiation field either at the cricoid cartilage or below the cricoid cartilage. The authors concluded that, as observed by using MRI, LN metastases spread in an orderly fashion from higher to lower neck levels, and that their results did not support prophylactic irradiation of Level IV and supraclavicular LNs in N0 patients.

As stated above, post-attinic toxicity remains high, despite the notable improvements after the introduction of IMRT. In order to avoid these problems, in 2019 Liu et al. ³³ presented their initial experience with endoscopic nasopharyngectomy (ENPG) alone in stage I NPC, aiming to assess the efficiency and cost-effectiveness of such treatment as an alternative for IMRT in T1N0M0 NPC. The indication criteria for ENPG were: a maximum diameter of the primary tumour ≤ 1.5 cm, distance of the tumour margin to the internal carotid artery ≥ 0.5 cm, an axial diameter at MRI no more than 0.4 cm for retropharyngeal lymph nodes (RLNs) and 0.6 cm for cervical lymph nodes (CLNs). Such small tumours are rare; however, they stated: “With the popularity of health education and the development of early cancer screening in NPC, an increasing number of NPC patients with early stage cancer were screened and diagnosed” ³³. In the study by Liu et al, 10 newly diagnosed stage I NPC patients voluntarily received ENPG alone from June 2007 to September 2017 ³³. Simultaneously, the data of 329 stage I NPC patients treated with IMRT were collected and used as a reference cohort. The survival outcomes, QOL and medical costs between two groups were compared. After a median follow-up of 59 months, no death, locoregional recurrence, or distant metastasis was observed in patients treated with ENPG. In addition, compared with IMRT, ENPG was associated with decreased total medical costs and improved QOL scores including dry mouth and sticky saliva. Correctly, the authors concluded that: “ENPG alone was associated with promising long-term survival outcomes, low medical costs, and satisfactory QOL and might therefore be an alternative strategy for treating newly diagnosed localized stage I NPC patients who refuse radiotherapy. However, the application of ENPG should be prudent, and prospective clinical trials are needed to further verify the results” ³³.

In order to avoid or reduce post-attinic toxicity, a recent study proposed a different strategy: ENPG combined with low-dose radiotherapy (LDRT) in T1-2 NPC. Zhang et al. ³⁴ recruited 37 newly diagnosed T1-2 NPC patients who voluntarily accepted ENPG+LDRT. Meanwhile, the data of 132 T1-2 NPC patients treated with IMRT were collected and used as a control group. In the ENPG+LDRT group, the average RT dose was 58.6 + 0.9 Gy, which was significantly lower than in the IMRT group (70.7 + 1.9 Gy, p < 0.001). There were no significant differences in age, gender, body mass index (BMI), smoking history, Karnofsky performance status score, T and N categories, clinical stage, or chemotherapy between the two groups. The authors found similar survival outcomes, including 5-year OS, DMFS, and LRFS, between patients treated by ENPG+LDRT and those receiving IMRT. Moreover, ENPG+LDRT exhibited better QOL and less late RT related sequelae. These authors concluded that well-designed large randomised clinical trials are needed to confirm their findings.

Personalised medicine and targeted therapy

In a recent review, Bashraheel et al. ³⁵ wrote: “Until recently, patients who have the same type and stage of cancer all receive the same treatment. It has been established, however, that individuals with the same disease respond differently to the same therapy. Further, each tumour undergoes genetic changes that cause cancer to grow and metastasize. The changes that occur in one person’s cancer may not occur in others with the same cancer type. These differences also lead to different responses to treatment. Precision medicine, also known as personalized medicine, is a strategy that allows the selection of a treatment based on the patient’s genetic makeup”. Next generation sequencing (NGS) describes a DNA sequencing technology which has revolutionised genomic research. Using NGS, an entire human genome can be sequenced in a single day. Many molecular targeted therapies approved by the Food and Drug Administration (FDA) have demonstrated remarkable clinical success in the treatment of a myriad of cancer types including breast, leukaemia, colorectal, lung, and ovarian cancers. With regards specifically to the NPC, Kang et al. ³⁶ wrote: “Targeted therapy involves the design of specific drugs that bind specifically to oncogenic targets within tumour cells to inhibit the development of tumours. The genetic and epigenetic alterations of NPC have been unveiled by the constant genome-wide studies, which involve cytogenic, allelotyping, comparative genomic hybridization (CGH), and array-based CGH analysis”. I made a search on PubMed using the key words “nasopharyngeal carcinoma” and “targeted therapy”, and I found as many as 1,555 articles. Despite this huge number of studies, Kang underlined that “at present, clinical trials on targeted therapy for NPC are not abundant, which are mainly targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR)” ³⁶. Moreover, they stated: “most of the clinical trials of targeted therapy against NPC are clinical phase I or II trials, which show that different targeted drugs can delay the process of NPC to different degrees and prolong the life of patients” ³⁶. In addition, there are some problems when studying clinical trials in targeted therapy of NPC. They wrote: “The quantity of patients is small, which may cause the inaccuracy of the results. Almost all the targets that occurred in clinical trials of NPC are VEGFR or EGFR. More phase III clinical trials are needed after the drug has passed phase I and phase II clinical trials” ³⁶.

There has been a great improvement in the effectiveness of the first NPC treatment over the years due to the optimisation of RT techniques and the addition of ICT and/or AC to concomitant CT in high-risk patients. Although the most frequent relapses are distant metastases, a good proportion of patients have recurrence of disease only at a local-regional level. Kong et al., in their series of 370 cases of NPC, found that “18 patients (4.9%) developed clinical or radiographic local-regional recurrences; 78% (14/18) of the patients were locally advanced (staged T3 or T4). In the 18 patients who developed a local-regional recurrences, 7 patients had isolated regional recurrences, other 7 patients had isolated local recurrences, and 4 patients had both local and regional recurrences” ³⁷. In another study of 81 T4 NPC analysed by Kong et al., 12 patients (14.8%) experienced local-regional failure ⁵. In a series of 1,039 patients with NPC receiving IMRT Liu et al. ³⁸ found that 75/1039 patients developed recurrences, and 88% (66/75) were considered as having in-field failures. Among these, 62.7% (40/66) had local recurrence alone, 32.0% (22/66) had regional recurrence alone, and 5.3% (4/66) had both local and regional recurrence. Multivariable analysis revealed that pre-treatment gross tumour volume (≥ 68.8 mL vs < 68.8 mL) and histopathological types (NKDC vs NKUC) were the most significant independent factors for in-field local recurrence. The pre-treatment volume of the involved lymph nodes (≥ 19.9 mL vs < 19.9 mL) and cervical nodal necrosis (CNN) (presence vs absence) were closely associated with in-field regional recurrence.

However, the fact is that for the same stage of T and N, histopathological type, and macroscopic characteristics of the tumour, there are still a non-negligible number of patients suffering from relapse and metastasis. Thus, in addition to the aforementioned features of the primary tumour and lymph node metastases, some authors tried to discover the possible intrinsic causes of the radioresistance of NPCs. Elevated expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) was observed in various human cancers such as breast, colorectal, oesophageal, and hepatocellular carcinoma, and overexpression of PDK1 was associated with poor prognosis of these tumours ³⁹. Zhang et al. examined the expression of PDK1 and the role and potential mechanism of PDK1 in radiation in NPC. They demonstrated that depletion of PDK1 enhanced radiosensitivity in NPC cells both in vitro and in vivo, and a specific inhibitor of PDK1 also had radio-sensitising effects on radioresistant NPC cells ³⁹.

The NCCN guidelines divide cases with local-regional relapses into resectable and unresectable; for the former the therapeutic indication is surgery ± post-operative reirradiation or systemic therapy/RT, and for the latter, the therapeutic indication is reirradiation ± systemic therapy. Recurrences in an untrated neck, should undergo radical, modified, or selective neck dissection ²⁰. The ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up of NPC specify that the main therapeutic options for small local recurrences include nasopharyngectomy, brachytherapy, radiosurgery, stereotactic RT (SRT), IMRT or a combination of surgery and RT, with or without concurrent CT ⁸.

The role of surgery

As mentioned above, the mainstay of treatment for NPC is (CT)RT. Beyond the recent studies on the primary surgical treatment of T1-T2 NPC ^33,34, surgical resection of NPC has traditionally been reserved for histological forms that are not very radiosensitive (adenoid cystic carcinoma, adenocarcinoma, etc). On the contrary, surgical treatment plays an important role in rescuing recurrent or persistent NPC after primary (CT)RT. Surgical salvage can be divided into salvage for locally recurrent cancer and salvage for nodal recurrence; only in exceptional cases can resection of distant metastases be indicated.

The deep position of the nasopharynx makes its surgical approach very difficult, because one must bypass uninvolved structures to reach a narrow operative field. Various surgical approaches have been proposed in the past: trans-palatal, trans-maxillary, midline mandibulotomy, midfacial degloving, and trans-pterygoid. Some other approaches have great historical value, but are very complex and difficult. Median labiomandibular glossotomy was proposed by Trotter in 1920 for tumours of the base of the tongue and in the 1980s it was used to expose the nasopharynx and the clivus ⁴⁰. The infratemporal fossa approach developed by Fisch is even more complex. It requires a mastoidectomy and subtotal petrosectomy with a complete conductive hearing loss ⁴¹. The facial translocation approach involves elective osteotomies with temporary removal of a large portion of the craniofacial skeleton (anterior wall of the maxillary sinus, inferior and lateral walls of the orbit and zygomatic arch) ⁴². After resection of the tumour, these bones are replaced and fixed. However, as these bones are not vascularised, often previously irradiated, and subsequently re-irradiated, the likelihood of possible osteoradionecrosis is very high. In 1991, Wei et al. ⁴³ presented their “maxillary swing approach”. They wrote: “The maxilla, severed from its bony connections, is swung laterally to provide exposure of the nasopharynx. Tumours in the nasopharynx and the paranaso-pharyngeal space can be adequately resected and tubings for after loading brachytherapy can be positioned accurately during surgery. The blood supply of the maxilla is from the attached cheek flap and masseter muscle”. Wei et al. presented 3 cases and wrote: “The wounds in all of them healed primarily with minimal morbidity. The only disadvantage is the development of mild trismus, which responded to conservative treatment”. In reality, things probably did not go so well, because in many subsequent (and often repetitive) articles, the authors modified their technique. First of all, to avoid a possible palatal fistula, the incision over the soft tissue on the hard palate was changed from the midline incision originally described to a curved incision along the lingual border of the teeth on the upper alveolus. Second, and more importantly, Chang et al., from the same staff as Wei, wrote that when they began to operate on patients with extensive local relapses, exposing the internal carotid artery into the parapharyngeal space, “3 patients developed torrential bleeding and died from internal carotid artery blowout 6 weeks after discharge from the hospital while they were receiving postoperative adjuvant radiotherapy” ⁴⁴. For this reason, they began to use free flaps to cover the exposed bone at the clivus and the exposed internal carotid artery. From 1990 to 2012, they performed as many as 338 nasopharyngectomies using the maxillary swing approach for persistent or recurrent NPC after previous chemoradiation ⁴⁴. The maxillary swing was the most widely used approach for open resection of NPC recurrences, with hundreds of cases treated, mainly in Asian countries.

In 1990’s, some surgeons started to perform endoscopic resection of sinonasal malignancies. Endoscopic nasopharyngectomy (ENPG) was a natural extension of application of endoscopic sinus surgery. To my knowledge, the first reported case of ENPG was made by Yoshizaki et al. in 2005 ⁴⁵. Since then, several small series of patients treated with ENPG for local recurrence of NPC have been published. In 2020 Yang et al, performed a meta-analysis on recurrent NPC patients treated with ENPG and found a total of 761 articles ⁴⁶.

Obviously, the role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent NPC who have previously received radiotherapy was (and is) a matter of debate. In order to demonstrate which treatment of local relapses (rNPC) after (CT)RT achieves the best results, Liu et al. ⁴⁷ reported the results of a multicentre, open-label, randomised, controlled, phase III trial that was done in three hospitals in southern China. Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n = 100) or IMRT (n = 100). The authors concluded that “Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy” ⁴⁷.

The attempts to use the Da Vinci robot for endoscopic resection of local NPC recurrences cannot be forgotten. To my knowledge, the first cadaveric experiment on robotic nasopharyngectomy was described by Ozer and Waltonen in 2008 ⁴⁸. In 2015, Tsang et al. published a series of 12 cases of robotic-assisted ENPG; with a 2-year follow-up, the cure rate was 86% ⁴⁹. However, they pointed out two disadvantages of robotic ENPG; first, the Da Vinci surgical robot is not designed for use in the head and neck region and still needs to be adapted for use in the nasopharynx, and second, in order for the robotic arms to reach the nasopharynx via a transoral route, the soft palate needed to be split for access.

More recently, some preclinical anatomic studies have been published on the use of flexible robotic surgical systems using human cadavers. Using a highly articulated endoscope with flexible instrumentation, a complete nasopharyngectomy can be performed without palatal incisions ⁵⁰. In 2016, Tsang et al. published the long-term results of 31 patients treated with robotic-assisted nasopharyngectomy for recurrent nasopharyngeal carcinoma. The median follow-up period for all patients was 38 months. Five-year local control rate, OS, and DFS were 85.1%, 55.7%, and 69.1%, respectively ⁵¹.

Given the modern treatments of NPC (IMRT ± CT), isolated nodal failure is uncommon. Li et al. ⁵³ found that only 6% of patients had isolated nodal failures. Some studies analysed the recurrence-related characteristics with respect to the original treatment, and classified failures as ‘in-field’, ‘marginal’ or ‘out-field’. Li et al. ⁵² found that “6/10 of the nodal failures were in-field, of which five occurred in level II; whereas four had out-field failures, all of which were in the protected parotid gland area”. These authors concluded that “Comprehensive assessment of nodules in or around the parotid gland is therefore a key aspect of treatment planning and follow-up”.

Zhang et al. wrote: “Salvage surgery has an important role in the treatment of recurrent nodal disease, although some centres advocate re-irradiation with external beam or boost radiotherapy, with reported cure rates of 14-28%. This, however, is associated with treatment-related morbidity, secondary to cumulative radiation-induced injury” ⁵³.

The type of neck dissection (ND) to be performed in case of persistent or recurrent nodal disease is controversial. A historical study by Wei et al. in 1992 (in the pre-IMRT era) showed that “70% of the nodal recurrences had extra-capsular spread (ECS). The lymph nodes also had propensity to spread along the spinal accessory chain in the posterior triangle. Tumour tissue in close proximity of the spinal accessory nerve was found in 27.5% of the specimens and 35% of the specimens had isolated clusters of tumour cells in the soft tissues not inside the lymph nodes” ⁵⁴. Moreover, Wei et al. found that metastatic cancers can spread to all five levels of lymph nodes in the neck in patients with extensive nodal metastasis. Hence, they proposed to adopt classical radical neck dissection (RND) to salvage nodal failures in NPC in order to eradicate tumours in soft tissue that extended beyond the capsule of the lymph nodes. Wei’s conclusions were so authoritative that for several years no one questioned them. A small attempt to propose less extensive interventions was made by Yen et al. ⁵⁵. These authors presented 31 patients who underwent a RND, modified radical (MRND), or level I-sparing RND. It is not known which patients were selected for a more limited intervention. In 2011, Zhang et al. ⁵³ analysed a very large series of patients (355 cases) who were diagnosed with neck residue or recurrence of NPC, after radical definitive radiotherapy with or without chemotherapy, and tried to assess the outcomes and identify prognostic factors. The group with recurrent nodal disease consisted of 285 patients (80.3%), while the group with residual nodal disease included 70 patients (19.7%). All patients were pathologically confirmed as having neck metastasis by FNA and underwent RND. The multivariable analysis revealed that stage, EBV encoded RNA (EBERs), lymph node status (residue or recurrence), invasion of the soft tissues or organ outside the lymph node, and completeness of the surgical excision had a significant correlation with survival. In the residue group, 42/70 patients had only a single positive pathological lymph node after neck dissection. These 42 patients had an increased chance of survival. The authors concluded that their study demonstrated that patients with a persistent single lymph node after neck therapy can be treated with selective lymph node dissection. In 2016 Wang et al. ⁵⁶ analysed 153 patients with NPC who had previously undergone RT (with or without CT) and had neck residue or recurrence without evidence of local disease and distant metastases. All patients underwent some variants of ND. Seventeen patients received bilateral simultaneous ND and therefore, in total, 170 neck dissections were performed. The surgical procedures were: 106 modified radical neck dissection (MRND) (including selective neck dissection [SND] in 28, local excision in 9, and parotidectomy in 3), 48 patients received RND, and 16 patients received extended radical neck dissection (ERND). The authors concluded that MRND is suitable for most cases, even if some have ECS.

Distant metastases

As mentioned in part A of this review, distant metastases at presentation are rare (about 5%) ⁸. In contrast, distant post-treatment metastases are quite frequent and represent the first cause of death in patients with NPC. The rates reported by various authors are different. In a series of 352 patients analysed by Khor et al. in 1978, 99 developed distant metastases (28.1%) ⁵⁷. Similar rates were found in other studies of the past century. However, even in the most recent series presented in 2018 by Ai et al., distant metastases appeared in 128/579 NPC patients (22.1%) after chemo-IMRT, and 5-year DMFS was 78.8% ⁵⁸.

The treatment with cisplatin and gemcitabine is the first-line choice and improves OS ^8,20. Because poly-CT is more active than mono-therapy, other regimens include cisplatin or carboplatin plus a taxane, cisplatin/fluorouracil (5-FU), gemcitabine/carboplatin, or carboplatin/cetuximab ²⁰. However, the estimated PFS and OS with second-line therapy are around 5 and 12 months, respectively ⁸. In a recent phase III randomised clinical trial, capecitabine maintenance therapy significantly improved PFS for patients with newly-diagnosed metastatic NPC who achieved disease control after capecitabine-containing induction chemotherapy. Capecitabine exhibited manageable toxic effects ⁵⁹.

A particular category of patients are those who present with local-regional tumour and oligo-metastatic disease (OMD). The NCCN guidelines state that patients with OMD disease can be treated with RT or surgery after systemic CT ²⁰. Two recent studies analysed the results of locoregional radiation therapy (LRRT) in metastatic NPC (mNPC). The authors of the first article carried out a retrospective study in a consecutive cohort of 168 patients with histologically-proven NPC with distant metastasis at initial diagnosis ⁶⁰. Among these patients, 106 and 62 cases were diagnosed with OMD and with polymetastatic disease (PMD), respectively. OMD was defined as no more than five metastatic lesions and no more than two metastatic organs based on pathological examination and/or multiple radiologic imaging, while PMD referred to those had more than 5 tumour lesions and/or more than 2 metastatic organs. All patients underwent platinum-based chemotherapy as a first-line treatment for a minimum of four cycles with or without definitive RT at nasopharynx and neck. The analysis showed that median OS was significantly longer for patients who received CT plus LRRT (69.5 months) than for those who received CT alone (17.8 months, p < 0.001) ⁶⁰. The second study evaluated the efficiency of local RT to metastatic lesions in 109 patients with mNPC after treatment of the nasopharynx and neck, and demonstrated that 2- and 5-year OS were 65.8% and 35.7% for patients who received local radiotherapy (n = 61) and 45.3% and 26.2% for patients who did not receive radiotherapy to metastatic lesions (n = 48) ⁶¹.

Qu et al. ⁶² conducted a thorough retrospective analysis of NPC patients using the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2016. In total, 2,758 patients were included in their study, of whom 332 (12.0%) had distant metastases. Of course, being American patients, the histological composition of the series was different from that of endemic areas. In fact they explain that “a total of 909 of 2,758 tumours (33.0%) were KSCC (keratinizing squamous cell carcinoma), 820 tumours (29.7%) were DNKSCC (differentiated non-keratinizing squamous cell carcinoma), 515 tumours (18.7%) were UNKSCC (undifferentiated non-keratinizing squamous cell carcinoma) and 514 tumours (18.6%) did not belong to any specified groups (other group)”. Regarding the site of metastases, 325 of 332 patients (97.9%) had metastases in five organs [bone, brain, liver, lung, and distant lymph nodes (DL)]. Bone was the most common metastatic organ, followed, in order, by the liver, lung, DL and brain. There were some differences in the metastatic patterns among different histological types: UNKSCC was the most common histological type with bone, brain, liver, and DL metastases, while KSCC was the most common histological type with lung metastases. Some patients had only one metastasis, and others had multiple metastases that occurred simultaneously or sequentially. The incidence of dual-site metastasis was higher than that of single metastasis in all types. Liver metastasis (lmNPC) was associated with a dramatically worse prognosis regardless of the number of metastatic sites. Despite best palliative chemotherapy (PCT), the 3-year survival of patients with lmNPC did not exceed 22% ⁶². Faced with such a poor prognosis, the question of whether definitive radiation therapy (DRT) of the head and neck should be added to PCT in patients with lmNPC remains. Some previous retrospective studies reported contradicting results regarding DRT treatment of patients with lmNPC. In a recent study, Yang et al. ⁶³ analysed 2,213 untreated metastatic patients with pathological confirmed NPC. Among them there were 610 patients with lmNPC (27.5%). The presence of liver metastatic lesions had been confirmed by two different imaging scans and/or biopsy pathological examination. All patients were treated with PCT with or without DRT and liver local therapy (LLT). The various treatments in the liver were radiofrequency ablation (16 patients), surgical resection (21 patients), and trans-arterial embolisation (18 patients). Overall, 395 (64.8%) patients received PCT alone, 160 (26.2%) received PCT +DRT, and 55 (9.0%) received PCT+DRT+LLT. The authors concluded “Our study demonstrated that DRT can be recommended for all patients with lmNPC after PCT because DRT might be beneficial regardless of the tumour response after PCT. For patients who achieved complete response/partial response (CR/PR) after PCT and received DRT, LLT is not recommended because it might have fewer benefits, along with increased cost and side effects. For patients with progressive disease/stable disease (PD/SD) after PCT, DRT +LLT is recommended because it might improve PFS and OS. LLT may be most suitable for patients with liver metastasis only and ≤ 3 metastatic sites” ⁶³.

Regarding immunotherapy Xu et al. stated that “The general immune landscape of nasopharyngeal carcinoma (NPC) renders immunotherapy suitable for patients with NPC” ⁶⁴. “In recent years, immunotherapy has prompted a revolution in the clinical management of many cancers. Immune checkpoint inhibitors (ICIs) based on programmed death-1/programmed death ligand-1 (PD-1/PD-L1) blockade have made a breakthrough and were approved for the treatment of recurrence and/or metastatic NPC (R/M NPC) in 2021 in China” ⁶⁴. The incorporation of ICIs into the treatment paradigms of NPC has become a clinical hot spot and many prospective clinical studies have been performed and are ongoing. Some have been given rather fanciful acronyms (POLARIS-02, CAPTAIN-1st, RATIONALE 309, JUPITER-02, etc.).The most studied ICIs are: camrelizumab, toripalimab, spartalizumab, pembrolizumab, etc. The combination of ICIs and chemotherapy, which can eliminate or modulate immune suppressive cells in the tumour microenvironment (TME), has shown promising synergy. Given the encouraging results of ICI monotherapy and preclinical evidence of the synergy between chemotherapy and ICIs, clinical exploration of the combination of ICIs with chemotherapy is required to promote the management of R/M NPC. Recently, two randomised trials have demonstrated that the addition of camrelizumab or toripalimab to gemcitabine and cisplatin might be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. However, it should be stressed, as the study authors themselves do, that “longer follow-up is needed to confirm this conclusion”.

Those who wish to investigate thoroughly this item may read the paramount paper by Xu et al. ⁶⁴. Table I summarises treatment indications.

Prognostic factors and outcomes

Progressive improvement of treatment results for NPC has been reported both from endemic and non-endemic areas. The average 5-year survival steadily increased from around 35% for patients treated between 1940-60 to 55-60% for those treated between 1970-90. A recent study of patients without distant metastases treated during 1996-2000 showed that 5-year disease-specific survival (DSS) was 81% and OS 75% ⁶⁵. On the contrary, the 5- and 10-year actuarial survivals were 33% and 19%, respectively, in a series of patients with NPC treated between 1958 and 1983 by Haghbin et al. ⁶⁶. In the series of Vikram et al. the observed 5-year survival rate was also 35% for patients treated between 1970 and 1976, and increased to 72% for those treated between 1977 and 1980. They remarked that “The two patient populations were similar except that the dose of irradiation to the primary site was 6,000 rad during 1970-1976 and 7,000 rad during 1977-1980” ⁶⁷. A retrospective analysis was performed by Yeh et al. on 326 consecutive NPC patients treated between 2004 and 2015. The 5-year OS and DFS rates of these patients were 77.9% and 70.5%, respectively ⁶⁸. Another analysis of a very large series of 2,070 NPC treated by RT alone in Hong Kong between 1996 and 2000 showed that the 5-year progression-free, overall, and cancer-specific survival rates were 63%, 75%, and 80%, respectively; the OS decreased from 90% for stage I to 58% for stage IVA-B ⁶⁹. After the almost routine use of the association of CT-RT in the various combinations, the results improved further. In the series of 488 patients with stage II-IVa NPC reported by Yang et al, the 5-year LRFS, DMFS, OS, and PFS rates were 87.7%, 81.7%, 81.2%, and 69.3%, respectively ⁷⁰.

Many studies have analysed the various prognostic factors that affect the ultimate cure rate of patients with NPC. By doing a search on PubMed, using the keywords “nasopharyngeal carcinoma” and “prognostic factors”, you can find 5,394 articles. Over the past decade, nomograms have become very popular for predicting the chances of cure for patients with NPC; using the keywords “nasopharyngeal carcinoma” and “nomogram”, you can find 147 studies on PubMed.

It is often difficult to compare the results of the various studies because some have taken into consideration the entire series of NPCs treated in a single centre or all those present in the SEER or National Cancer Database (NCDB), while others have considered only some specific categories (for example, stage II ⁷¹ or only patients after IC ²⁸). However, the most accepted prognostic factors that worsen prognosis are male sex, older age, advanced T-N categories, and the presence of distant metastases ^72-75. Regarding sex, OuYang et al. ⁷⁴ demonstrated that females showed significant advantage over males in both early and advanced stage groups. However, this advantage persisted at premenopausal age, declined during menopause, and totally disappeared at postmenopausal age. According to the authors probably, “Intrinsic biologic traits appear to be the exact explanation according to the declining magnitude of sex effect with age” ⁷⁴.

Other important prognostic factors are histological type and ethnicity, which are strictly dependent on each other. As mentioned earlier, the proportion K-NPC/NK-NPC among all NPC is very different between endemic and non-endemic areas. Since many studies have shown that K-NPC has a worse prognosis than NK-NPC, the different healing rates between one race and another are explained ^76-79. Moreover, comprehensive national data base analyses evaluating epidemiological factors associated with outcomes of NPC in the USA found that Asian patients had a survival advantage relative to Caucasian patients even after adjusting for disease histology ^76,77. In the study by Stepan et al., stratifying by race and disease histology, Asian patients with K-NPC and DNK-NPC had significantly improved survival relative to Caucasian patients after controlling for covariates. In contrast, there was no significant relationship between race and OS for those with UNK-NPC ⁷⁶. These authors concluded that their results suggest “interesting interactions between race and histological types of NPC that may reflect distinct biology” ⁷⁶.

Another prognostic factor worsening the prognosis reported in various studies is EBV-DNA level, both pre-treatment (≥ 4,000 copies/ml) and post-IC (positive) ⁷⁰. Yang et al. analysed 488 patients with stage II-IVa NPC, all of whom were treated with ICT. Among these, 124 patients received ICT followed by IMRT alone, and 364 patients received ICT followed by CRT. Pre-treatment and post-ICT EBV DNA were independent predictive factors of OS and PFS. The authors developed a nomogram, integrating TNM stage, post-ICT plasma EBV DNA, age, and treatment regimens (IMRT alone or CRT) and achieved a satisfying value in a validation cohort for predicting OS and PFS. Yang et al. concluded “It is possible to guide clinicians to conduct personalized therapy in clinical practice, including early treatment modification for high-risk patients, which implies that they should receive therapeutic intensification” ⁷⁰. However, the authors correctly admit that a nomogram based on plasma EBV DNA is limited by the large interlaboratory variability. In this regard, the ESMO-EURACAN Clinical Practice Guidelines ⁸ also stated “Plasma EBV DNA is a promising marker for the diagnosis of recurrence and should be evaluated at least every year”. But, in the same guidelines there are the following statements “Due to the variability in assessments between laboratories, EBV DNA measurement needs further harmonization” … “However, more research is needed to refine the role of plasma EBV DNA in the management of NPC and to identify additional molecular markers which could lead to advances in personalised medicine in NPC” ⁸.

It is now a certain concept that systemic immunity and inflammation play a crucial role in the processes of tumour elimination, regression, and metastasis ^80-82. Lin et al. performed a comparative analysis of 12 pre-treatment immune-related indices in a double-centre retrospective cohort of patients with NPC ⁸². The most significant were: absolute neutrophil count (ANC), absolute lymphocyte count (ALC), platelet count (PLT), levels of albumin (ALB), C-reactive protein (CRP), haemoglobin, and lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (MON), and platelet-to-lymphocyte ratio (PLR). In a meta-analysis on the prognostic significance of haematological markers for patients with NPC, Yang et al. ⁸³ analysed 23 studies encompassing 23,417 patients. The results of this meta-analysis suggested “that inflammatory cells (such as neutrophils, monocytes, lymphocyte and platelets) and proteins (such as ALB, CRP and HDL-C) have the capacity to predict survival in cancer, including NPC. As widely available and inexpensive biomarkers, haematological parameters may facilitate prognosis prediction in patients with solid tumors” ⁸³. Among these immune-related indices, one of the most widely verified on large series has been the NLR ^73,83,84. Zengh et al. wrote “Recently, immune-inflammation indexes including the systemic inflammatory response index (SIRI) based on three types of white cells (peripheral neutrophils, monocytes and lymphocytes) and the systemic immune-inflammation index (SII) based on three types of white cells (peripheral neutrophils, platelet and lymphocytes) were investigated in various cancers. These inflammation indexes are also considered to be independent prognostic factors for cancers, and their prognostic value is higher than that of only white blood cells” ⁸⁵. The SIRI is defined as neutrophil count × monocyte/lymphocyte count. The SII is defined as neutrophils × platelets/lymphocytes. Jin et al. ⁸⁶ retrospectively analysed 287 children and adolescents with locoregionally advanced NPC. They found that elevated SIRI (≥ 1.53) and EBV DNA (≥ 4000 copy/ml) were significantly associated with inferior OS, and concluded that the combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination. Chen et al. also agreed that “the pre-treatment SIRI value is a novel systemic inflammatory marker for patients with NPC, and its value is significantly more than that of conventional systemic inflammatory markers” ⁸⁷.

A controversial prognostic factor is pre-treatment lymph node biopsy. Two older studies demonstrated that pre-irradiation lymph-node biopsy consistently resulted in poorer survival ^88,89. Dickson ⁸⁸ presented a racially balanced North American series of 209 patients with NPC. When the nodes were mobile, 5-year absolute (NED) survival was 46.9% in the non-biopsied group and 25% when nodes were excised prior to primary irradiation therapy. Cai et al. ⁹⁰ found that for patients with fixed and partially fixed neck nodes, the interval between the first biopsy and radiotherapy and the type of biopsy done on the lymph node did not influence prognosis. On the contrary, for patients with movable neck nodes, the interval between the first biopsy and radiotherapy influenced the final outcome. Moreover, patients who received radiotherapy within 14 days after biopsy had a 5-year survival of 61%, which is better than that of the patients who started their treatment beyond the 15^th day (47.5%). These authors also showed that “For patients with movable lymph nodes, partial excision of the node gave a poorer five year survival (22%) than that of patients on whom complete excision was done (50%). Therefore, complete excision of the node is advised for patients with movable neck node metastasis” ⁸⁹.

It should be pointed out that these series referred to patients treated in the pre IMRT era. However, the analysis of more recent series also demonstrated that diagnostic excision of lymph nodes may worsen prognosis ^63,90. Qu et al. found that biopsy without complete removal of the lymph node increased the likelihood of distant metastasis ⁶³. Lv et al. analysed 2,910 patients with NPC from the SEER; 416 patients underwent pre-treatment lymph node biopsy. After control for patient, tumour, and demographic characteristics, biopsy was not associated with impaired OS or DSS but, in the subgroup analysis, the unfavourable effect of biopsy was observed for patients with differentiated non-keratinising squamous cell carcinoma (but not for other histologic types) ⁹¹.

In contrast, other studies demonstrated that cervical biopsy was not related to a higher risk of death, distant metastasis, or nodal relapse ⁹².

Two prestigious guidelines also report a different attitude towards lymph node biopsy. The Clinical Practice, published in 2010 by the EHNS-ESMO-ESTRO (European Head and Neck Society-European Society for Medical Oncology-European Society for Radiotherapy & Oncology), state that “This procedure is not recommended since it may reduce cure probability and have an impact on late treatment sequelae” ⁹³. Regarding the diagnostic work-up, the NCCN guidelines are more permissive, allowing both biopsy of the primary and FNA of the neck ²⁰.

An association between prolonged waiting time to start the best therapy and worsening of prognosis has been demonstrated for many cancers. Obviously, NPC does not escape this rule. Chen et al. found that a prolonged waiting time (> 4 weeks) between diagnosis and primary radical radiotherapy (WRT) is a disadvantage for NPC patients ⁹⁴. These data were subsequently confirmed by other studies ²⁹. The conclusion of these studies was that WRT of NPC should be as short as reasonably achievable.

Finally, among the variety of prognostic factors that significantly influence OS in NPC there is one that has rarely been considered in most studies, namely the “hospital” and “physician” factor. Eskander et al. ⁹⁵ analysed 17 studies examining a volume-outcome relationship in the treatment of patients with head and neck cancer with meta-analysis for long-term survival results, and found that high-volume hospitals have better OS than low-volume hospitals. As for NPC specifically, a study from an endemic country (Taiwan) demonstrated that patients with NPC treated by high-volume physicians (case load ≥ 35 patients per year) had better survival rates (p = 0.001) after adjusting for comorbidities, hospital, and treatment modality ⁹⁶. These data have also been confirmed in a non-endemic country (USA) ^97,98. Both of these studies queried the NCDB for patients with NPC. In the study by Goshtasbi et al. ⁹⁷ a total of 8,260 patients were included. The 1,114 unique facilities were categorised into 854 low-volume (treating 1-8 patients per year), 200 intermediate-volume (treating 9-23 patients), and 60 high-volume (treating 24-187 patients) facilities. Kaplan-Meier log-rank analysis demonstrated significantly improved OS with high-volume facilities (p < 0.001). The study by Yoshida et al. ⁹⁸ included 3,941patients with stage II-IVB NPC treated at 804 facilities, including 1025 patients (26.0%) treated at high volume facilities. The latter had a significantly improved OS on multivariable analysis. Interestingly, among patients treated at high volume facilities, those treated at academic centres had better 5-year OS. These data support the concept of centralisation of tumours that require complex treatments at centres that are able to meet minimum volume thresholds to improve patient outcomes. Table II summarises what has been described about prognostic factors and outcomes.

Conflict of interest statement

The author declares no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical consideration

Not applicable.

Figures and tables

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