Retreatment in locally recurrent nasopharyngeal carcinoma: Current status and perspectives

Abstract

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells that cover and line the nasopharynx. While it is considered a rare cancer globally, it is commonly observed in South China and a few other ethnically distinct racial groups. Due to its propensity to spread early through the submucosal tissue and the highly infiltrative nature of this disease, NPC spreads easily through areas of lesser resistance within the pharyngobasilar fascia with a tendency for neural infiltration [1-3]. Radiation therapy (RT) is the most suitable modality for primary curative treatment and can be complemented with either induction, concurrent, or adjuvant chemotherapy in the more advanced cases. The overall predominant cause of treatment failure is distant metastases. However, on average, 10% to 20% of NPC patients present with local recurrence after primary curative treatment. The 5-year local failure-free rate decreases depending on the initial stage of the primary tumor. For T1 disease, this can range from 88% to 100%, whereas for T4 disease, this can drop to 55% to 86% [4-8]. For patients with first local failure, the majority of them have only local recurrence without distant metastases [9]. Recurrent disease is defined as a biopsy-proven disease that recurs after a period of remission following completion of initial treatment, occurring more than 3 months post-treatment [10]. Thus, the prospect of offering salvage treatment to these patients is to achieve control of local disease in order to have a chance of cure, as well as alleviate any current and potential symptoms, remains a worthwhile option. Local recurrence in NPC remains a difficult topic, presenting many challenges in management. As a result of the numerous complex issues arising, recurrent NPC is best treated in an experienced center with expertise in multidisciplinary care. In this article, we consolidated the available literature on retreatment in cases of locally recurrent NPC, highlighting the role of surgery, patient selection for RT retreatment, RT dose fractionation and constraints, modalities of RT delivery, the role of chemotherapy in re-irradiation cases, and the role of immunotherapeutic advances in re-irradiation cases. Initial RT at first presentation involves extensive coverage of the nasopharyngeal and parapharyngeal tissues, as well as the skull base and its foramina to a high dose, due to the high tissue-infiltrative and neural-infiltrative nature of NPC [2-3, 11]. Thus, for cases of locally recurrent NPC, nasopharyngectomy is the preferred modality of treatment if amenable, either via an open approach, or more commonly, an endoscopic approach. The primary goal is to achieve negative margins with minimal postoperative morbidity. However, surgery remains feasible only for smaller recurrent tumors in an accessible location. Contraindications to surgery include [1] extensive indurated invasion, [2] cavernous sinus involvement, [3] pharyngobasilar fasciae invasion, [4] extensive skull base involvement, especially with the involvement of neural foramina, [5] perineural involvement, and [6] dural or intracranial involvement [12-14]. Thus, recurrences amenable to surgery with favorable outcomes and a high likelihood of negative margins include the majority of recurrent T1 (rT1; based on the 8th TNM staging edition of the American Joint Committee on Cancer) and early rT2 disease, and a very selected group of rT3 disease with small disease volume and minimal skull base involvement [12-14]. Studies on the local failure patterns of NPC after initial treatment with intensity-modulated radiation therapy (IMRT) showed that the recurrent disease was rT1 to early rT2 in only approximately 22% to 29% of patients and of the remaining patients, approximately 50% presented as rT3 disease and the other 50% as rT4 disease [15, 16]. A retrospective analysis by Zou et al. [17] showed that only 22.4% out of the 410 patients recruited over a time period of 10 years with local NPC recurrence were eligible for surgery. There have also been conflicting results regarding the addition of adjuvant radiotherapy after nasopharyngectomy with resultant positive margins. King et al. [18] found that there was a significant improvement in survival and tumor control with the addition of postoperative radiotherapy. However, it must be noted that this was a study done many years ago with recruitment completed in the year 1997. In addition, the surgical approaches were all via the open technique, and the sample size was small (n = 31 patients). A later study by Willard E Fee et al. [14] found no benefit from adjuvant radiotherapy in this group of post-nasopharyngectomy patients with positive margins, with around 60% of the cases recurring locally but this result was a subset analysis and the details regarding the extent of positive margins, adjuvant radiotherapy coverage, doses and techniques were not elaborated. Thus, the need for adjuvant irradiation after salvage nasopharyngectomy should be taken on a case-by-case basis, with discussion at a multidisciplinary tumor board; bearing in mind that adjuvant irradiation should not be taken as a replacement for careful case selection of eligible surgical candidates. The 5-year overall survival (OS) rates for patients with locally recurrent NPC who undergo nasopharyngectomy surgery, considering that a proportion of deaths result from distant metastases, especially for those presenting with later stage recurrent disease, may range from 25.9% to 60%, depending on the center where the treatment was offered and the rT stage [9, 14, 19]. The 5-year local control rates similarly show a decreasing trend with increasing rT stage. For instance, Willard E Fee et al. [14] found that the 5-year local control rates for rT1, rT2, rT3, and rT4 diseases were 77%, 40%, 57%, and 0%, respectively. Thus, surgery should be the choice of treatment for cases with early recurrent disease where clear margins can be confidently obtained with minimal morbidity. In cases with inadvertent resultant positive or close margins less than 5 mm, the role of adjuvant treatment should be evaluated on a case-by-case basis in a multidisciplinary tumor board. For the majority of patients with local recurrence not amenable to surgery, re-treatment with radiotherapy remains the only option available to offer the patient another chance of cure. Compared to primary RT treatment for initially diagnosed NPC, which can lead to 5-year local control rates of 80% to >90% [7-9], re-irradiation, even with IMRT, may lead to considerably lower short-term local control and survival rates. Both Qiu et al. [20] and Chua et al. [21] observed an average 1- to 2-year local progression-free rates of approximately 56% and OS rates of 63%. A meta-analysis looking at the 5-year outcomes after NPC re-irradiation, pooling together 12 studies, also found a trend towards similar outcomes, with a 5-year local progression-free survival (PFS) rate of 72% (95% confidence interval [CI], 66%-78%), and a 5-year OS rate of 41% (95% CI, 36%-47%) [22]. However, putting a patient through a second round of high-dose irradiation can result in severe acute and long-term toxicities, as well as potentially exacerbating any resultant complications from the initial course of radiotherapy. For optimal outcomes, proper patient selection, as well as appropriate re-RT dose prescription and fractionation are key. Equally crucial is the accurate determination and setting of dose constraints for organs at risk (OARs). Here, we will briefly discuss the different modalities of RT delivery, as well as the role of chemotherapy in re-RT cases. Appropriate patient selection is the first critical step for ensuring good outcomes in re-irradiation cases. Table 1 summarizes postulated and known patient factors which may determine prognosis and outcomes from available published literature [23-31]. Factors found to be significant in influencing treatment outcomes include age at recurrence, with an OS difference found between patients of younger and older than 46 to 50 years old and hazard ratio ranging from 1.02-1.48, depending on the source paper [23-31]. Another important factor is the patient's Karnofsky performance status (KPS), with a hazard ratio of 2.65 for those with KPS ≤70 compared to those with KPS >70 [23-31]. Whether the patient suffered from any grade 3 or higher late toxicities from initial RT was also found to be a significant factor, with a hazard ratio ranging from 1.90 to 2.36 [23-31]. This may be correlated with their performance status, nutritional status, and overall fitness and health status during treatment, which may reflect their ability to tolerate and complete re-irradiation with minimal unscheduled breaks. Disease characteristics at recurrence are similarly important in influencing prognosis. Patients with early recurrent rT0 to rT2 disease show a 5-year OS rate range of 73.2%-75.8% with re-RT treatment. However, this can decrease to 32.4%-35.1% for rT3 to rT4 disease. Tumor volume of the recurrent disease is another important factor influencing prognosis. Various studies have used different volume cut-offs, ranging from 30 cm3 to 38 cm3, with the hazard ratio for larger volumes of recurrent disease ranging from 1.57 to 1.96. For example, taking the higher volume cut-off of 38 cm3, the 5-year OS rate range for tumor volume ≤38 cm3 was found to be 48.7%-55.9%, whereas for tumors >38 cm3, it can decrease to 15.2%-30.1%. Furthermore, patients with rT3-4 tumors or gross tumor volume (GTV) >30 cm3 may exhibit a significantly higher rate of mucosa necrosis than patients with rT1-2 stage tumors (36.8% vs. 26.1%, P = 0.04) or with GTV >30 cm3 (38.7% vs. 23.0%, P < 0.01) [26]. NPC tumor histology classification also plays a role in prognostication, with WHO type III tumors generally having a better prognosis with retreatment compared to types I and II, due to their more radiosensitive tumor biology. Other factors that influence outcomes for re-treatment cases include the disease-free interval (DFI) before recurrence, with a hazard ratio of 1.05 for patients whose disease recurred within 25 months. This is likely to be a reflection of the biology of the tumor, suggesting increased radio-resistance. High plasma EBV DNA titer at recurrence is another negative prognostic factor. A recent study found that patients with advanced clinical T and N stage locally recurrent NPC had higher levels of pre-retreatment plasma EBV DNA, and this was further shown to be significant in locoregional recurrence-free survival (LRRFS) (54.2% vs. 75%, P < 0.001), implying such patients were at greater risk of subsequent relapses [31]. Lastly, high previous RT doses delivered to critical OARs could also lead to poorer outcomes after retreatment, likely secondary to limitations on retreatment dose deliverable. There have been a number of prognostic models published that aimed to correlate the above patient characteristics with survival outcomes and treatment-related morbidity and mortality, in order to more objectively ensure appropriate patient selection [25, 32]. These models used weighted hazard ratios of various parameters to stratify the patients into 2 to 3 risk subgroups, with re-irradiation recommended for the low- to intermediate-risk groups, but more clinical evaluation and caution are needed before offering re-irradiation for the high-risk groups. These prognostic tools can be applied clinically to aid in offering suitable treatment recommendations. Currently, there is still no established definitive gold standard dose and fractionation for NPC re-irradiation cases. The available studies are highly variable in terms of timing, technique, and radiation doses; as well as in their use of concurrent chemotherapy and drugs used, and many are retrospective or single-arm, making comparison across different studies difficult. However, available literature largely points to the need for a total EQD2 (Equivalent dose in 2 Gray fractions) dose of at least 60 Gy or more to achieve adequate local control [21, 33-36]. Lee et al. [34] found that the hazard of local failure increased by 1.7% per Gy10 biological effective dose (BED) drop during re-irradiation (assuming an alpha/beta ratio of 10). For rT1 to rT2 recurrences, the 5-year local control rate for patients given >70 Gy10, 60 Gy10-70 Gy10, and <60 Gy10 doses were 40%, 35%, and 14%, respectively. When compared with the group given 60 Gy10-70 Gy10 doses, the local salvage rate in those given <60 Gy was significantly inferior (P = 0.001), but the superiority in local control of those given >70 Gy failed to reach statistical significance (P = 0.229). A similar trend was also observed for patients with rT3 disease [34]. On the other hand, total EQD2 doses greater than 70 Gy (assuming an alpha/beta ratio of 3) could be associated with increased late toxicities, most commonly mucosal necrosis (30.8% to 50%), trismus and dysphagia (∼17.3% to 18.9%), temporal lobe necrosis (17.3% to 22%), and hemorrhage (11.5% to 31%) [34, 36, 37]. Thus, it appears that the optimal EQD2 dose range should lie within a range of 60 Gy to 70 Gy. The other issue to consider is the optimal fractionation for dose delivery. For most irradiation treatments, including that of initial de-novo NPC treatment, the standard of care is dose delivery at 2 Gy to 2.2 Gy per fraction. In recent years, attention has turned to the consideration of hyperfractionated dose delivery in head and neck re-irradiation cases, including NPC. Hyperfractionated regimens involve delivering a small fraction size of 1.1 Gy to 1.5 Gy, given twice a day with a break of at least 6 hours. This is radiobiologically advantageous for late responding organs such as the spinal cord, brain, mucosa, and other OARs, thus reducing late toxicities of re-irradiation, while still allowing sufficiently high curative doses to be delivered. There have been a number of clinical studies using hyperfractionated radiation doses in head and neck malignancies demonstrating the feasibility of this approach, with no differences in local disease control and acceptable acute and late adverse effects [38-45]. In addition, there are a number of studies looking at locoregional control and late sequelae using hyperfractionation in recurrent head and neck cancers [46-48]. In these studies, a median dose of 60 Gy to 68 Gy was delivered in fractions of 1.2 Gy to 1.5 Gy twice a day, with grade 3 and above toxicities ranging from 14% to 29%. Lee et al. [49] conducted a non-randomized prospective study comparing hyperfractionation with standard fractionation in locally advanced recurrent NPC. All patients in the study received induction chemotherapy with cisplatin and gemcitabine, as well as weekly cisplatin during the concurrent phase. The hyperfractionated dose delivered was 64.5 Gy at 1.2 Gy per fraction twice a day, while the historical cohort received a standard dose of 60 Gy at 2 Gy per fraction daily. The median local failure-free survival (LFFS) showed a trend in favor of hyperfractionation (28.2 vs. 16.6 months, P = 0.164), though there was no significant difference in overall survival. Grade 3 and above late toxicities were similar, with treatment-related hemorrhage showing a significant in the group hyperfractionated Another retrospective by et al. also showed that re-irradiation for recurrent NPC, delivered with hyperfractionated IMRT, in local disease control of with acceptable Grade 3 and above late of with the use of RT et al. showed in their small case study that were to doses of Gy to Gy in 1.1 Gy to 1.2 Gy per fraction doses twice good local control with minimal late Another is the use of radiotherapy to recurrences with high doses of is only suitable for small recurrent where high doses can be delivered without the critical This has the of more to of tumor cells compared to which is to be cause of local disease used in the literature range from fractions of Gy to Gy, Gy in 3 30 Gy in 5 to Gy in 6 In most studies had small patient and of 1 to 3 local control rates from to with generally acceptable late rates However, a number of late toxicities were with study patients hemorrhage and In the optimal EQD2 dose range delivered in NPC re-irradiation should lie within a range of 60 Gy to 70 Gy, with hyperfractionated doses of 1.1 to 1.5 Gy delivered twice a day at least 6 remains a with more studies needed to determine the re-treatment volumes and doses at retreatment, in order to significant late The head and neck a number of radiosensitive organs which can with high doses of radiation to de-novo and recurrent NPC and may lead to tissue complications after Thus, it is important to determine suitable dose constraints to to these OARs, especially on that may result in severe morbidity if These include the cord, and the temporal For late considerably in their to from radiation such as the mucosa, spinal cord, and have the ability to from to a on the size of the initial dose, as well as the interval between irradiation Table 2 summarizes the from literature for critical head and neck The spinal cord, and were as constraints while the and temporal were as dose constraints A discussion of dose constraints is the of this Gy Gy Gy for of with patient for NPC challenges to Due to the dose range in head and neck retreatment, acute and late toxicities may be more severe and careful and management. available we found that re-irradiation was associated with a to of grade 3 and above acute toxicities, most commonly with a smaller proportion of patients severe the most acute adverse effects were grade and as well as The late toxicities are more in comparison to the acute The late toxicities were to significant trismus to and to such as temporal lobe necrosis or other on from to and the presentation in such patients from to and the more late toxicities were mucosal necrosis from to to and from On average, a range of to of retreatment patients was found to have or more of these late The most cause of from was hemorrhage which from to and could be a reflection of case selection and early on at RT can be delivered via or through more advanced such as IMRT, therapy or or via of the it is crucial to ensure that an experienced and are on as well as before dose delivery. For cases of NPC re-irradiation, the should be to achieve the most thus allowing dose coverage to the volume while good In this the current advanced delivery techniques are to techniques and should be the of choice in such retreatment cases. The is increased dose, especially with as compared with therapy and which exhibit dose the may be used to further dose without coverage, potentially reducing complications by re-irradiation and of There have been a few retrospective the outcomes and toxicities of these techniques in head and neck re-irradiation over that of IMRT, with results For example, et al. OS and rates of with therapy with late grade 3 and toxicities of and larger sample further the role of these irradiation modalities in NPC In cases of NPC re-irradiation, the role of chemotherapy remains to be As with initial treatment, of chemotherapy be as induction, concurrent with or less as adjuvant treatment. The role of concurrent chemotherapy with irradiation is to as a In a of the literature that there is with to its in NPC re-irradiation cases. The used was largely either cisplatin or or with A number of retrospective studies have shown that the use of concurrent chemotherapy together with re-irradiation either showed no benefit or poorer local control than those on RT et al. showed that either as induction or concurrent, had prognostic significance in but not in However, a in these studies be that a majority of these studies are retrospective in nature and exhibit of selection of the patients who received chemotherapy had more adverse prognostic more advanced rT or may have a role as induction treatment before re-irradiation for selected can be used to tumor recurrences, allowing RT to be delivered more to high dose volume or to decrease the dose delivered to critical can also as a to RT treatment for patients with tumor recurrences occurring within months to 1 where from the initial irradiation may not be for a second round of RT to be A number of studies looking at induction chemotherapy before re-irradiation have generally shown good especially with the of cisplatin and Chua et al. observed a rate with 3 of cisplatin and gemcitabine, while Lee et al. [49] observed a rate of with and with cisplatin or with The addition of chemotherapy at any is associated with significant toxicities of grade 3 and toxicities such as temporal lobe toxicities, mucosal toxicities, and long-term were all increased compared to re-RT of retreatment with techniques or with IMRT, thus careful patient selection is There has also been in the role of in NPC, with outcomes In the recurrent and the use of or with chemotherapy have shown good rates of and in early with to the of in locally recurrent cases for retreatment, the a clinical in in where a of adjuvant following salvage treatment for locally recurrent NPC was The and outcomes of this are and may a in we these especially with the use of more irradiation such as and can result in long-term disease control and survival for a proportion of patients with recurrent NPC. from the literature that the optimal dose received by the recurrent tumor should lie within a range of 60 Gy to 70 Gy with an shown for hyperfractionated dose delivery, especially in terms of acute and late effects on OARs such as the spinal cord, brain, temporal and The use of chemotherapy in re-irradiation cases to be considered in of the significantly increased chemotherapy with re-irradiation should not be in very selected cases after discussion at multidisciplinary tumor chemotherapy may have a role to tumor recurrences RT can be delivered more to the high dose to decrease the dose delivered to critical OARs, or to as treatment between of in these cases appears to and further treatment in retreatment cases should be There are a number of together the of head and neck this very and critical topic, which are prospective studies are also needed to further the outcomes of using different dose and treatment and optimal and All to the The no of the for their to the NPC in The discussion of re-irradiation in NPC was

Topics & Concepts