诊断

Review

N0-N1 Nasopharyngeal Carcinoma: Can the uninvolved neck be spared?

Sarbani Ghosh Laskar1, G Lavanya 1, Jai Prakash Agarwal1

 

1Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges’ Marg, Parel, Mumbai, Maharashtra, India: 400012

Corresponding author: Sarbani Ghosh Laskar, Email: sarbanilaskar@yahoo.co.in.

 

 

Citation: Laskar SG, Lavanya G, Agarwal JP. N0-N1 Nasopharyngeal Carcinoma: Can the uninvolved neck be spared? J Nasopharyng Carcinoma, 2014, 1(12): e12. doi:10.15383/jnpc.12.

Competing interests:The authors have declared that no competing interests exist.

Conflict of interest: None.

Copyright:image001.gif2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Abstract:Nasopharyngeal cancers (NPC) are characterized by a high predilection for lymph node involvement, mostly orderly. Node negative and N1 NPC comprise around one-third of the cases. Radiotherapy (RT) has been the mainstay of treatment for more than three decades with good results, which has improved further with the use of conformal and precision RT techniques. Despite the large volume of literature on the treatment of NPC, there is a paucity of evidence specifically addressing the volumes and doses to the neck in node negative and N1 disease.

With the availability of better imaging modalities and improved RT delivery and verification systems it is possible today to stage patients with NPC with greater certainty and deliver higher doses to the tumour and spare adjacent critical structures better.

A systematic review was carried out to evaluate the available evidence addressing the issue of sparing the low risk neck regions in patients with N0 and N1 stage.

Available literature reveals that even in the N0 neck, bilateral retropharyngeal group and level II lymph nodes should be considered at risk and cannot be omitted from the radiation portals. The lower neck region is usually at much lower risk of developing metastases in the absence of level II LN involvement and maybe spared.

In the N1 patient, contralateral lower neck is at minimal risk of developing disease, and there is a possibility of not treating these regions. Such a practice warrants a stringent follow-up protocol.

Keywords: Nasopharyngeal Carcinoma; N0-N1; Neck spared

 

 

1. Introduction

Nasopharyngeal cancers (NPC) are a distinct group of head and neck malignancies. They are characterized by a definite geographic distribution, an ethnic/ genetic predisposition, associated with the EBV infection, with a high predilection for lymph node involvement, distant spread and are highly radio and

chemosensitive[1-4]. The disease is characterized by a bimodal incidence in the endemic population. The location and proximity of the nasopharynx to several critical structures also poses a challenge to the oncologist. Due to the high predilection for lymph node involvement, treatment has always aimed at addressing the primary along with the draining lymph node regions. Owing to the sensitivity of these tumors to radiotherapy (RT), it has been used extensively as the sole modality of treatment until the 1990’s, for cure in early cancers and effective palliation of late disease [2, 5-7]. With the results of the Intergroup trial by Al Sarraf et al, combined modality treatment with chemotherapy and radiotherapy was established as the standard of care in advanced disease [8]. This was further endorsed by several meta-analyses [9, 10]. Despite these advances in treatment, several questions remain unanswered. This is especially apparent today when the knowledge of the patterns of failure, the information on natural history of this disease has established certain gaps in the therapeutic approaches [6, 11, 12]. Advances in imaging, availability of effective chemotherapy and leaps in radiotherapy planning and delivery make it possible to better identify patient groups that behave differently from one another, and also enable the oncologist to tailor treatment in an attempt to deliver higher doses to eradicate tumor and reduce antecedent early and late sequelae [11, 13, 14].

One such issue is management of the neck in the node negative group (Group I). The considerations are that do we need to treat the entire neck, with lower doses in the absence of nodal disease or can we do away with treating the uninvolved neck completely. The other issue is whether the lower neck can be spared or at best be given lower doses in the presence of small volume disease in the upper neck (N1) (Group II). In addition to the knowledge about the patterns of lymph node involvement/ spread in NPC, these issues merit consideration for various reasons: availability and ability to image the disease with greater certainty, tailor doses with modern radiotherapy, relatively younger population of patients who would survive to express late sequelae and availability of effective chemotherapy.

The present review attempts to address these issues based on a systematic review of available literature.

 

2. Methodology

We reviewed literature for articles addressing nodal volumes in the management of NPC and reporting outcomes. The standard guidelines used for treatment were also reviewed [15]. The keywords used were nasopharyngeal cancer, radiotherapy, elective nodal irradiation, N0, N1. There was no time limit set for the review. Thirteen such articles were retrieved after extensive search in PUBMED, COCHRANE LIBRARY and GOOGLE SCHOLAR. They were classified into those that addressed group I and those addressing group II.

Only 3 of the articles reviewed were prospective studies, the remaining were retrospective analyses. Two of the articles were available only as abstracts in English. Ten of these articles addressed the question about the N0 group and 3 studies were on the N1 group of which 2 were prospective studies.

 

3. Discussion

3.1. Group I (N0)

3.1.1. Literature Review

One of the early studies which evaluated the role of elective nodal irradiation (ENI) was the retrospective match-pair analysis conducted by Xian et al where regional recurrences of 170 N0 NPC patients treated with conventional radiotherapy with ENI to the upper neck only (4.71%) were compared to 21 matched cases who received whole neck irradiation (4.76%). There was no difference in nodal relapse rates between the two groups. The exact location of the relapses was not available.

Anne WM Lee et al in 1991 reported the results of 189 Stage I (Ho’s staging) patients who were treated during 1980-1984 with radical radiotherapy alone to the primary and retropharyngeal area only. Regional recurrences were observed in 30 % (57/189) patients who did not receive ENI. It was observed that the upper cervical lymphatic group was the most common site of nodal recurrence (50/57, 88%). The overall salvage rate with radiotherapy for these patients was 81% (46/57). However, the 7-year actuarial survival rate was significantly less as compared to the patients with no nodal relapse (70% vs 81%)[16].This study in addition to Ho’s study formed the basis for irradiating the whole neck. However, careful study of the pattern of regional relapse clearly shows that the upper cervical lymph nodes (level II in the present day nomenclature) were the single most common region of nodal relapse. The staging evaluation can be considered suboptimal by present standards in the absence of imaging. Upstaging of the above classified tumors would have been a high probability if imaged, as acknowledged by the authors. Conventional RT techniques were used with a dose per fraction of 4.2 Gy/Fr twice weekly. Though a total BED of 65 Gy was delivered, the effectiveness of such a schedule is uncertain as it does not account for the accelerated repopulation in between the treatments. The results of this study suggest that the retropharyngeal lymph nodes and level II, even when uninvolved cannot be left unaddressed during radiotherapy. It also highlights the importance of imaging for staging in NPC.

It has been subsequently demonstrated that the first echelon of lymph nodes are the upper deep jugulodigastric group (level II) followed by retropharyngeal group [17-19]. From the study by Lee et al and the patterns of regional failure in other studies it has been observed that level II LN is the most common site of nodal relapse.

Tang and colleagues evaluated the patterns of lymph nodal spread in 924 nasopharyngeal carcinoma patients by MRI. Level II and RLN were the most commonly involved lymph nodal regions. They also analyzed the patterns of failure in 138 N0 patients who were treated to the upper neck only against those that received radiotherapy (RT) to the entire neck. The authors suggested the feasibility of omitting level IV and SCF region irradiation in N0 setting. A very low incidence of skip metastasis (0.3%) was observed in this group, which further supports the premise for avoiding RT to the low neck in select group of patients and the necessity of treating the RLN and level II region [20, 21].

Gao et al evaluated the results of 410 patients (T1-T4, N0, AJCC 1997 staging) treated with conventional radiotherapy with omission of ENI to lower neck levels (IV-Vb). Median follow up of this study was 54 months. The dose received to ENI region was 50-56 Gy with conventional fractionation. The 5 year overall survival rate was 84.2%. T stage was the single most important prognostic factor on univariate and multivariate analysis [22].

The above findings are also endorsed by observations made by Li [23], Fang-Yun Xie [24]. The latter also looked into the patterns of nodal recurrence with respect to T stage. No statistically significant differences were found. The 3 year OS and DFS rates were similar in both the groups. MRI, CT and/or PET-CT was used for diagnosis and staging [24]. Chemotherapy was given in 60 patients.

A similar comparative retrospective study published recently by Lei Zeng et al showed excellent regional control rates in 177 patients treated with ENI to the upper neck region only when compared to 99 patients who received entire neck irradiation. IMRT technique was employed in all the patients. The 5 year overall survival in the upper neck group and the whole neck group were 93.6% vs 90.9% , which was not statistically significant. Also, the nodal relapse free rates were similar in both the groups. The proportion of patients who were RLN negative had significantly higher DFS than the RLN positive group. Local recurrence was the most common first failure site [25]. This study addressed the importance of RLN positivity as compared to node negative disease with respect to outcomes. Apart from the retrospective nature, this study has shown that ENI to the whole neck is not necessary in N0 and N1 (RLN+) group.

Chen CZ et al in their retrospective study of 432 N0 patients treated with radical radiotherapy alone analyzed the long term results of patients in whom only upper neck was treated. Median dose received to the upper neck was 50 Gy. The 5 year cervical LN control rate was 96.06%. The rates of neck recurrence alone were 0.93% in the upper necks and 1.62% in the lower neck (p=0.937) [26].

Jian-Da Sun et al evaluated the long term outcomes of 610 N0 patients treated with radiotherapy. The Fuzhou Chinese staging system was used. Elective nodal RT was given to the upper neck only with a median dose of 50 Gy. The 5 and 10 year regional recurrence free rates were 95.8% and 91.8%. Thirty-one (5.1%) patients developed nodal relapse, with 16 (2.7%) patients developing out of field relapse and 13 (2.1%) patients developing in-field relapse. There was no significant difference in relapse rates as per the RT dose received to the neck. T stage was only independent prognostic factor for OS in this group of patients. There was no significant difference in 5 year OS of these subgroups (77.9% vs 79.2%)[27].This study has a long term follow up and study period (1989-2009). It depicts the gradual change in the diagnostic work up from clinical staging of lymph nodes to the use of CT/MRI and also the evolution of radiotherapy techniques.

The only randomized study to address the question was published by Li JZ et al. In this trial, 301 patients with node-negative NPC were randomly assigned to receive primary plus prophylactic upper neck irradiation (153 patients) or primary plus whole-neck irradiation (148 patients). With a median follow-up period of 39 months (range, 6-84 months), no patient in either group had a cervical node relapse [28]. It would be interesting to know the long term results.

3.1.2. Summary

Radiotherapy forms the backbone of treatment of NPC. Despite the evolution of radiotherapy over the years, target volumes have remained constant. The lymphatics irrespective of T stage have been extensively treated, the rationale for which is rooted in the rich lymphatic supply of the nasopharynx. The RTOG consensus also recommends the treatment of levels II-V and supraclavicular lymph nodes. However, it is noteworthy that the nasopharynx has a predictable and orderly fashion of lymphatic spread and the rate of skip metastasis is rare (0.3 -9%)[12, 19, 29]. The treatment of the lower neck is not without its own acute and long term problems [30, 31]. Hypothyroidism is a common condition seen after RT to the neck in long term survivors [32, 33]. Laryngeal sequelae like edema and poor quality of voice have also been reported. Neck fibrosis is also a troublesome complication. Li et al reported carotid artery disease in patients who received whole neck RT to radical doses of 60-70 Gy [14]. Hence, it is a scientific and logical argument not to deliver elective nodal irradiation to the low risk areas. There has been very little exploration in this area and convention has prevailed. This is due to the paucity of literature mingled with the apprehension of recurrence.

The available literature spans a long period of time which corresponds to the evolution of the diagnostic modalities and treatment options. The staging system itself has undergone many changes over the decades with prognostication also varying from the time of Ho’s staging to the latest 2010 AJCC 7th edition [34].

In most of the earlier studies RT was delivered by conventional two dimensional techniques until the recent advent of conformal techniques with good local control rates, lower acute toxicities and better overall survival [35-37].With the use of IMRT, sculpting of doses based on the disease extent is possible, enabling escalation of doses to involved areas, at the same time delivering lower doses to the low risk regions.

Despite differences in staging evaluation and systems, most of the evaluated literature revealed that a dose of 50-56 Gy was delivered to the upper neck region for N0 disease. It was also interesting to observe that despite heterogeneity for other parameters the definition of the upper neck was similar in all the studies which was levels II, III and VA. T stage was the most important factor determining the local recurrences.

The regional relapse rates in the above studies ranged from 0-5.7% as shown in table 1. The most common site of nodal relapse was level II. This is an accessible site for salvage therapy in the form of neck dissection. Isolated neck node recurrences outside the radiotherapy portals have been rare as exemplified by the results of the above studies. Evidence points that most failures occur at distant and local sites as compared to regional recurrences in this stage.

 

 

Table 1. Results of Studies addressing ENI in N0 Patients.

Author

    No

Stage (TNM)

RR (%)

DMFS (%)

OS(%)

Type of Study

Treatment (RT/RT+CT)

WNI

UNI

WNI

UNI

WNI

UNI

WNI

UNI

Xian [41]

21

170

T1-4,N0

4.76

4.71

-

-

-

Retrospective.Match-Pair

NK

Tang [21]

101

37

T1-4,N0

0

0

-

-

-

Retrospective

NR

Gao [22]

0

410

T1-4,N0

NA

0.8

NA

90.6

NA

84.2

Retrospective

RT±CT

Li [23]

99

88

T1-4,N0

1.09

1.14

-

-

71

81

Retrospective

NK

Xie FY [24]

117

88

T1-4,N0

0

2.27

p>0.05

-

-

92

94

Retrospective

RT±CT

Zeng L [25]

99

177

T1-4,N0

1.2

0.6

95

99

91

94

Retrospective

RT±CT

Chen CZ [26]

0

432

T1-4,N0

NA

3.93

NA

-

NA

-

Retrospective

RT

Sun JD [27]

0

610

T1-4,N0

NA

5.1

NA

88.5

NA

78.7

Retrospective

RT±CT

Li JG [28]

148

153

T1-4,N0

0

0

91

91.5

87.4

89.5

ProspectiveRandomized

RT±CT

No: Number of patients, WNI: Whole neck irradiation, UNI:Upper neck irradiation, RR:Recurrence rate, DMFS: Distant Metastasis Free Survival, OS: Overall survival, RT: Radiotherapy, CT: Chemotherapy, NA: Not Applicable, NR: Not Reported, NK: Not Known

 

3.1.3. Recommendations

Based on available evidence, the following recommendations can be made: In the N0 setting, bilateral retropharyngeal group and level II lymph nodes should be considered at risk and should not be omitted from the radiation portals. Doses ranging from 50-56Gy equivalent in conventional fractionation can be employed to the upper neck, with conformal techniques whenever possible. The lower neck region is usually not at risk of developing metastases in the absence of level II LN involvement. It would be logical to avoid treating these regions. Patients with N0 neck are more prone to develop distant metastasis and local recurrences than nodal relapses. This is a function of T stage and not doses received to the neck [7, 23, 39]. It would be ideal to optimize techniques to deliver adequate doses to the primary region and to eliminate micrometastasis rather than treat the low risk nodal basins, which has not shown any improvements in outcomes but carry the probability of adding to the morbidity. These recommendations are based on the premise that optimal current staging protocols have been followed.

 

3.2. Group II (N1)

3.2.1. Literature Review

Literature addressing this issue is sparse.

A prospective study by Hu et al evaluated the results of N1 (unilateral cervical LN) patients in whom the contralateral lower neck (Level IV and Vb) was not addressed. Current staging modalities were used (CT and MRI), AJCC 7th staging system was followed and IMRT technique was used to deliver RT. At a median follow up of 29 months, 3 year nodal recurrence rate was 1.9% (1 patient, II recurrence). No out of field recurrences were observed. Also, chemotherapy was administered to all stage III-IV patients, neoadjuvant chemotherapy followed by concurrent chemotherapy. T stage was a strong prognostic factor for local control rates. However, the number of patients was small (52) and the follow up was short to derive meaningful conclusions, although the results are promising with favourable toxicity profile [40].

Another prospective trial addressing this issue was conducted by Chen JZ et al. Similar results were obtained in patients with N0-N1 disease in whom contralateral levels IV-Vb were not treated. Majority of them had level II involvement. This subset (84) received ipsilateral level IV-Vb irradiation whereas the contralateral level IV-Vb did not receive prophylactic RT. N0 patients (128) did not receive prophylactic RT to bilateral lower neck. Seven patients developed nodal recurrences of which 4 occurred in field and 3 out of field recurrences were noted. Level Vb recurrences were seen in 2 of 3 patients who developed out of field recurrences. The 5 year regional control rates in N0 and N1 patients was 98.2% and 91.3% respectively. IMRT was employed in this study [41].

The role of elective nodal irradiation in RLN only positive disease has been explored in the retrospective comparative analysis by Xiaomin Ou et al in which the results of 30 patients treated with whole neck irradiation were compared to 89 patients treated with ENI to the upper neck only (II,III,VA). At a median follow up of 36.6 months, the 5 year nodal relapse free survival between both

the groups was not significantly different from each other. Four patients in the group who received ENI to the upper neck only developed nodal relapse of which 3 patients developed recurrence in level II region, similar to the other studies. Only 1 patient developed out of field recurrence (level IV). On univariate analysis, IMRT showed better results as compared to 2Dimensional RT. On multivariate analysis, it was observed that the dose to the upper neck of >56 Gy or <56 Gy had a significant impact on nodal recurrence free survival [42].

 

 

Table 2. Results of Studies addressing ENI in N1 Patients.

Author

No

N1 Status

RR (%)

DMFS (%)

OS (%)

Type of Study

Treatment (RT/RT+CT)

Hu [39]

52

Ipsilateral Cervical LN

1.9

94.1

92.2

Prospective

RT±CT

Chen CZ [40]

N0:128

N1:84

Ipsilateral Cervical LN

N0:1.8

N1:4.4

91.4

89.8

Prospective

RT±CT

Ou X [41]

119

Retropharyngeal LN

3.3

91.8

93.6

Retrospective

RT±CT

 

  

 

3.2.2. Recommendations

The involvement of RLN group has been classified variously across the institutions due to its proximity to the primary location, difficulty in detecting the same with a CECT and the problem of differentiating the local spread vs nodal disease. It has been classified as N1 disease and the upstaging to N2 in the presence of bilateral involvement in still controversial.

Ipsilateral cervical LN (N1) disease is slightly different from RLN only metastases, since the ipsilateral neck is at higher risk of harboring the disease and to present day, there has been no study which has omitted treating the lower neck on the same side. However, contralateral lower neck is at minimal risk of developing disease, and therefore there is a possibility of exploring the option of not treating these volumes. Such a practice warrants stringent follow-up protocol. No further recommendations can be made for this group. IMRT has replaced two dimensional techniques in nasopharyngeal carcinoma with sufficient evidence accumulated over the years with significant improvement in local control rates and reduced toxicities [35, 37]. Simultaneous integrated boost (SIB) has been a useful tool in delivering higher doses to the tumor and lower doses to the normal structures. This can be used effectively in dose escalation to the primary while de-escalating the doses to very low risk or no risk areas achieving an optimum therapeutic ratio [36, 42].

 

4. Conclusions

Apart from the above studies, there is sparse literature specifically

addressing these issues, despite the volumes of literature on NPC. Also, there is heterogeneity amongst the various studies. Imaging has not been uniform across the studies. The radiotherapy techniques have ranged from conventional two dimensional RT to IMRT. It is therefore not surprising that most end with a word of caution, pending the availability of results from prospective/ larger studies. However, certain recommendations can still be made from the common findings and we have attempted at doing so. Prospective trials are warranted in this direction which would provide concrete results although there is a body of evidence to suggest that selective nodal irradiation is safe in carefully selected patients, who have been evaluated as per optimal staging guidelines.

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