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- MATERIALS AND METHODS
- FUNDING SOURCES
- CONFLICT OF INTEREST DISCLOSURE
Radiotherapy is the mainstay of treatment for patients with nasopharyngeal carcinoma (NPC). Because of the rich submucosal lymphatic network of the nasopharynx, NPC has a propensity for early cervical node metastases. A retrospective study showed that up to 40% had nodal recurrence if the neck irradiation was withheld in patients without clinically palpable cervical nodes. Although most of the nodal relapses could be successfully salvaged by therapeutic irradiation, these patients had significantly more distant metastases than those without nodal recurrence. Therefore, it has long been accepted that the bilateral cervical regions should be electively irradiated for potentially metastatic nodes.[4, 5] Currently, most clinical protocols, such as RTOG-0225 (Radiation Therapy Oncology Group-0225), recommend the routine elective irradiation of node groups II to V and the supraclavicular nodal areas, regardless of the nodal status. However, this recommendation is based on retrospective data where the evaluation of node status was largely based on clinical palpation alone. With the routine use of modern imaging in the staging of NPC, the exact volumes that need to be irradiated to obtain the optimal outcomes became controversial, especially for patients with node-negative disease.[7, 8]
It has long been documented that metastases to the cervical lymph nodes from NPC follow an orderly pattern, from the upper neck inferiorly to the lower neck and then the supraclavicular fossa.[9-11] Skip metastases to the IV, Vb, and supraclavicular fossa regions without corresponding higher level involvement are relatively rare, with an incidence that ranges from 0.5% to 7.9%. In addition, computed tomography (CT) and magnetic resonance imaging (MRI) scans have been commonly used in the evaluation of nodal spread in patients with NPC, and the sensitivity of such imaging for the detection of cervical nodal metastases appears to be higher than that of clinical palpation.[13, 14] More recent studies, including one prospective phase 2 study based on CT or MRI, show that the relapse rate in the neck after upper neck irradiation alone is acceptably low, and recurrence outside the irradiated lower neck is extremely rare.[9, 15]
Therefore, we have conducted this randomized clinical trial to verify our hypothesis that omitting the lower neck during prophylactic node irradiation will not significantly increase the rate of lower neck nodal relapse.
- Top of page
- MATERIALS AND METHODS
- FUNDING SOURCES
- CONFLICT OF INTEREST DISCLOSURE
Our results confirmed the hypothesis that the probability of lower neck occult metastases by subclinical nodes was extremely low in patients who had node-negative NPC, and the omission of the lower neck during prophylactic node irradiation did not decrease the rate of lower neck control. At a median follow-up period of 39 months, there was no case of confirmed cervical nodal relapse. This exceptionally low neck relapse rate might be partly due to the 10-Gy boost to the suspicious nodes, which could have improved the treatment of subclinical disease. Our result was similar to those of the several recently reported trials in which node metastases were diagnosed on the basis of imaging studies. Chen et al demonstrated that the regional control of 128 patients with node-negative (N0) NPC was 98.2% with no relapse in the IV and Vb regions, which were omitted during elective node irradiation. In a study by Gao et al, 410 patients with N0 NPC were given prophylactic irradiation to the upper neck region only. Four of these 410 patients developed neck recurrences, but only 1 had a lower neck relapse outside the irradiation field. Another study by Tang et al presented a series of 138 patients who underwent selective irradiation to the upper neck alone (37 patients) or to the entire neck (101 patients), with no neck relapse in either group.
Although the prophylactic irradiation of the whole neck has been recommended in patients with NPC, irrespective of nodal status, this was based on clinical observations and a small number of retrospective studies. The nodal volume needed for prophylactic irradiation in patients with N0 NPC remains controversial. The only randomized clinical trial concerning this question was reported by Ho et al in 1978. In this study, patients with N0 NPC were randomized to receive either upper neck prophylactic irradiation to both sides or no irradiation if the node was not palpable. The results of the patient with stage I disease as described by Ho et al demonstrated that although 5 of the 32 patients in the nonirradiation group developed palpable nodes during the follow-up period, all of them were successfully cured by salvage radiotherapy, and the survival and tumor control rates did not significantly differ between the 2 arms. The authors of that study recommended that irradiation of the neck should be withheld until clinical metastases become evident. However, 2 later retrospective studies from the same center demonstrated that the rate of node recurrence was unacceptably high in patients who did not receive prophylactic node irradiation (30%-40%), and although most of the regional relapses could be successfully rescued, distant metastases were higher in those patients with regional recurrence.[3, 21]
Our randomized trial differed from the former cited research in 2 main respects: first, nodal status was evaluated on the basis of modern imaging techniques (MRI or CT) in our study, whereas the diagnoses of nodal spread in previous studies were mainly based on clinical palpation. CT or MRI scans are more sensitive in detecting nodal metastases in patients with NPC, and some of the node-negative patients in older studies would already have had subclinical metastases, resulting in the overdiagnosis of “node-negative” patients by palpation. These would have eventually manifested as nodal recurrence when the nodal drainage areas were left untreated. The second and probably most important difference was that the entire neck of patients in former studies was not irradiated, whereas only the lower neck in our UNI arm was omitted from the prophylactic irradiation protocol. Because nodal spread occurs in an orderly pattern, the upper neck would be at a relatively high risk of subclinical node metastases, even though no nodal metastases were considered to be present after a complete clinical and radiographic study. Because the aforementioned study showed that more than 95% of recurrent node disease occurred in the upper neck region, the omission of UNI would certainly result in a higher rate of regional relapse.
Although lower neck irradiation is relatively safe and well-tolerated, it is not without its adverse effects. The soft tissues, part of the thyroid gland, carotid, and apex of the lungs were inevitably irradiated when the lower neck region was treated, which could damage these tissues. Although no significant differences existed in the overall toxicities between the 2 groups, more than two-thirds of the patients in the WNI group had faint erythema during radiotherapy in the lower neck regions, and 13.5% and 4.7% of patients had grade I skin atrophy in the lower neck regions and fibrosis of the lung apex, respectively. Whereas the long-term effect of these mild complications on the quality of life of patients remained unclear, based on our relatively short follow-up period, reducing the irradiated volume would surely be beneficial provided that tumor control and survival were not negatively affected.
The OS, RFS, and MFS rates did not significantly differ between groups. The results were comparable to those found in recent studies, despite a relatively higher rate of advanced local disease in our study. Xie et al reported a 3-year OS of 94.2% for patients treated with UNI and 91.9% for those treated with WNI. Results of 2 studies with longer follow-up periods were also reported recently.[15, 25] The 5-year OS rates were 78.7% and 89.8%, 5-year RFS rates were 81.2% and 88.6%, and 5-year MFS rates were 88.5% and 90.6%, for the studies by Chen et al and Sun et al, respectively, when the prophylactic irradiation volume included only the upper neck region. These results suggest that tumor control and survival are not adversely affected when the lower neck is omitted during WNI in the treatment of patients with N0 NPC.
A major concern about our study was the relatively slow enrollment of the patients, because the enrollment period lasted for more than 6 years. Most patients were treated by conventional radiotherapy before 2009 and by IMRT thereafter, which could bring a potential bias into interpreting the results of treatment. However, the comparability of the treatment groups because of the randomized nature of our study, the identical lower margins (which was at the inferior margin of the cricoid bone) whether by conventional radiotherapy or IMRT during the upper neck irradiation, the same imaging techniques used in detecting nodal metastases, and the lack of cervical nodal relapse in the 2 groups make us confident that omitting the lower neck would not increase the regional relapse.
In conclusion, UNI is sufficient as prophylactic node irradiation for patients with N0 NPC.