Nasopharyngeal Carcinoma: Salvage of Residual or Recurrent Tumor
Incidence and Diagnosis
As nasopharyngeal carcinoma is radiosensitive and it has a high incidence of metastases to the cervical lymph nodes, the field of external radiation covers both the nasopharynx and the neck. Despite the improved efficacy of concomitant chemoradiotherapy in the management of nasopharyngeal carcinoma, there were still some patients who developed local or regional failure. The incidence of local failure was around 8.3%1 and patients may present with residual or recurrent tumor. Regional recurrence in the cervical nodes was around 4.7%1 and this might be associated with tumor recurrence in the nasopharynx or distant metastasis. Most reported series on treatment failures are from single-center experiences with small numbers of patients. The Hong Kong NPC Group reported a comprehensive review on outcome of NPC after primary treatment in the contemporary era of chemoradiotherapy.2 There were 319 local failures as the first failure for 2,915 patients treated between 1996 and 2000. Among these 319 patients, 275 (86%) had isolated local failure. The incidence of isolated failure in the neck nodes reduced from 10% in 1978 to 5% in 1985,3 and in more recent years it has been around 1.6%.4
Early detection of residual or recurrent disease is essential in achieving a successful salvage. Regular clinical examination is important; and whenever there is suspicion of disease, investigation should be performed. Copies of Epstein-Barr virus DNA in blood have been reported to increase in number before the manifestation of macroscopic disease. Imaging studies such as CT and MRI cannot give unequivocal evidence of disease but a progressive enlarging mass would be worrisome. These imaging studies also provide information on the extent of the recurrent disease. PET scan has also been shown to be superior to the conventional imaging studies in the diagnosis of disease,5 especially for tumor lying below the mucosa. However, endoscopic examination of the nasopharynx with biopsy of the tumor remains the “gold standard” in confirming the presence of disease. Sequential biopsy of the nasopharynx after treatment has shown that it takes ~10 weeks for the primary tumor to regress completely after radiotherapy. Thus only tumor that has persisted for 12 weeks after treatment is considered to be residual disease.
It is notoriously difficult to confirm residual or recurrent tumor in the cervical lymph nodes after radiotherapy. Fine needle aspiration is not helpful as the fibrosis developed after radiation reduces the yield of the aspiration and also in some of the recurrent lymph nodes only clusters of tumor cells are present.6 Sometimes even Tru-cut biopsies may not be able to obtain enough tissue for definitive diagnosis. Imaging techniques such as CT or MRI may have features that are suggestive of disease, such as the hypodense center of the node or evidence of central necrosis. They also evaluate the local extent of the neck disease (Fig. 26.1). The probability of disease escalates when the node increases in size on sequential imaging. The definitive diagnosis, however, still depends on histological confirmation and sometimes this is only available after salvage surgery.
Management of Residual or Recurrent Disease
Salvage treatment, even by aggressive procedures for locally recurrent NPC, is indicated especially when the disease is confined to the nasopharynx. The survival after salvage treatment for extensive disease remains poor, but it is still higher than in patients receiving supportive treatment only. Even for those patients who develop synchronous locoregional failures, aggressive treatment should be considered for selected patients.7
Disease in the Neck
When further doses of external radiotherapy were employed to treat these cervical lymph node metastases, the 5-year actuarial control rate of local disease for lymph nodes smaller than 4 cm in diameter was 51% and the overall 5-year survival rate was 19.7%.8 Excision of the lymph node followed by second course of radiotherapy as the salvage treatment was employed by others but the results were not conclusive because of the small patient numbers.9 The associated morbidities of radiotherapy were also significant.
Radical neck dissection has been employed for salvage of recurrent metastatic neck lymph node in nasopharyngeal carcinoma. The 5-year actuarial control rate of disease in the neck was 66%, and the 5-year actuarial survival for this group of patients was 38%.10 Whether such an extensive operation such as radical neck dissection is necessary to achieve control of the neck disease is debatable, as frequently the cervical metastasis presents clinically as a solitary node and, sometimes, subsequent examination of the radical neck dissection specimen reveals no tumor in any of the lymph nodes removed.6
The optimal management of localized metastasis in the neck lymph nodes depends on the pathological behavior of the tumor and a prospective study was performed to clarify this point. Classical radical neck dissection specimens were obtained from 43 nasopharyngeal carcinoma patients who developed localized disease in the neck after radiotherapy. The whole radical neck dissection specimen was fixed and sequentially sliced at 3-mm intervals. A histological slide was made from each tissue slice. From these 43 radical neck dissection specimens, a total of 1,075 histological sections were obtained and a total of 2,137 lymph nodes were examined, of which 294 contained tumor. In three patients, no malignant cells were identified in any of the neck nodes examined; there was only reactive hyperplasia with fibrosis.
For the remaining 40 patients, significantly more tumor-bearing lymph nodes were identified histologically than detected clinically. The tumor-bearing lymph nodes were found mostly in the upper part of the neck and in the posterior triangle. The distribution of the neck nodes was level I 5% (15/294), level II 34% (99/294), level III 16% (48/294), level IV 7% (19/294), and level V 38% (113/294). Surgical clearance of lymph nodes at all levels in the neck is important, especially in the upper neck. These tumor-bearing lymph nodes also showed extracapsular spread in 46% (135/294). In view of the extensive nature of these lymph node metastases (Fig. 26.2), a radical neck dissection is recommended as the salvage treatment for cervical nodal metastasis after radiotherapy in patients with NPC. However, a recent review suggested that as the neck nodes in level I were frequently not affected in these patients, a less extensive neck dissection, sparing level I might be applicable in patients with localized involvement of the neck lymph nodes.11
When the residual or recurrent disease in the neck is extensive, such as when the nodes have infiltrated the floor of the neck or the overlying skin, then brachytherapy should be applied in addition to the radical neck dissection as a salvage procedure. During the radical neck dissection the skin over the tumor in the neck is removed with the specimen (Fig. 26.3) and hollow nylon tubes are placed over the operative site for after-loading brachytherapy with iridium wire (Fig. 26.4). The cutaneous defect in the neck is covered with either a deltopectoral flap or a pectoralis major myocutaneous flap (Fig. 26.5). With this additional brachytherapy, the 3-year actuarial control rate of neck disease was around 60%12 and this was similar to the disease control rate when a radical neck dissection was performed for less extensive neck disease.
Disease in the Nasopharynx
When residual or recurrent tumor is detected in the nasopharynx after radiation or concurrent chemoradiotherapy, it can be managed with a second course of external radiotherapy. The recommended radiation dosage has to be greater than the initial dose to eradicate those tumor cells that survived the initial irradiation. In an early report, survival of up to 50% has been reported.13 The response of the surrounding tissues to further radiation limits the radiation dose. The neuroendocrine injury,14 temporal lobe necrosis,15 cranial nerve palsies, and other problems such as trismus and deafness, can be incapacitating. However, with the development of precision radiotherapy, such as intensity-modulated radiotherapy (IMRT) and stereotactic radiotherapy, a second course of external radiotherapy could be given with sufficient efficacy and acceptable side effects. In a report, following a second course of radiation, a salvage rate of 32% was achieved, the cumulative incidence of late post-reirradiation sequelae was 24%, with treatment mortality of 1.8%.16 Stereotactic radiotherapy for the treatment of recurrent disease has been reported to achieve a 2-year local tumor control rate of 72%.17 The number of patients treated with this method was small and long-term follow-up information is not available.18
External Beam Reirradiation
Retreatment of nasopharyngeal carcinoma by external beam radiation is difficult and poses special challenges to the clinician and the patient. Reirradiation of nasopharyngeal carcinoma is difficult due to the large numbers of critical structures in the vicinity of the recurrent disease that were already irradiated to a high dose during the primary course of radiotherapy. Whenever possible, brachytherapy or stereotactic radiosurgery should be considered first for retreatment of the nasopharynx. The reported 5-year survival rates after external beam reirradiation using conventional technique ranged from 8% to 36%.19,20 A high incidence of late complications, mostly neurologic damage and soft tissue fibrosis, has commonly been observed after external beam reirradiation.
The use of three-dimensional conformal radiotherapy and more recently IMRT has improved the outlook of patients receiving external reirradiation. In one study using three-dimensional conformal radiotherapy for retreatment of nasopharyngeal carcinoma, the 5-year local control rate was 71% but the actuarial incidence of major late toxicities was still high with all patients developing at least grade 3 toxicities and nearly half had grade 4 toxicities at 5 years.21 Several preliminary reports using IMRT for reirradiation of nasopharyngeal carcinoma reported good short-term control with a relatively low incidence of severe late toxicities, but long-term outcome is not yet available.22,23
Prognostic Factors with Reirradiation
Important prognostic factors in patients receiving external reirradiation for recurrent NPC include T stage, time to recurrence, and the reirradiation dose for local control and/or survival. The most consistent prognostic factor reported has been the T stage of the recurrence, and patients treated for advanced T stage have had poor local control and survival after reirradiation. There appears to be an important relationship between reirradiation dose and treatment outcome, with most series reporting poor tumor control with a dose below 60 Gy,23,24 although the optimal dose has yet to be defined.
Chemoradiotherapy may also improve treatment outcome in locally recurrent nasopharyngeal carcinoma in settings similar to those of newly diagnosed cases. One study employed induction chemotherapy to shrink the tumor volume followed by reirradiation using IMRT, and reported 75% local control rate at 1 year.25 Another study employed concurrent chemoradiotherapy and reported a 1-year progression-free rate of 42%.26 In patients with advanced local recurrence in which treatment planning for reirradiation is difficult, induction rather than concurrent chemotherapy is preferred as induction may allow tumor shrinkage to take place and facilitate subsequent radiotherapy planning and whole-target coverage but there is no evidence of improved survival.
Stereotactic Radiosurgery
Stereotactic radiosurgery is the technique in which a small target is stereotactically localized and irradiated by multiple convergent beams using a large single dose of radiation. The technique was originally developed for treatment of functional neurologic disorders, but was later found to be useful for vascular malformations, benign intracranial/skull base neoplasms, and cerebral metastases. Stereotactic radiosurgery has also been employed in nasopharyngeal carcinoma to deliver a boost dose after a second course of radiotherapy or as a salvage treatment of local recurrence. Stereotactic radiosurgery alone has been reported to achieve a crude local control rate of 53 to 86% for locally recurrent nasopharyngeal carcinoma.27,28 For recurrent disease confined to the nasopharynx or adjacent soft tissues, the reported local control rate at 2 years was 72%.17 When stereotactic radiosurgery was administered as a boost dose after reirradiation, the 3-year control rate ranged from 52% to 58%.29,30
The same technique may also be used to deliver multiple fractions of radiation and is termed “stereotactic radiotherapy” (Fig. 26.6), but the control rates appeared to be similar to those with radiosurgery. These results indicate that radiosurgery is an effective salvage treatment for local failures of nasopharyngeal carcinoma, although there are no data comparing the relative efficacy and complications of radiosurgery with other salvage treatments. In practice, selection of treatment modalities depends mainly on extent of disease and expertise available. For recurrent disease confined to the nasopharynx or adjacent soft tissues, the results of radiosurgery appear to be comparable to those of brachytherapy or surgery, and can be considered as a treatment option. The advent of IMRT appeared to improve the outcome of recurrent nasopharyngeal carcinoma, and reirradiation using modern techniques is recommended for patients with extensive local recurrence while reserving radiosurgery as a boost treatment or for further recurrence.
Complications
Although most studies report a relatively low risk of late complications following radiosurgery, massive hemorrhage remains the most severe form of complication with a potential fatal outcome.18 Massive hemorrhage that developed after radiosurgery is usually due to radiation damage to the carotid artery as a result of using large fraction dose and a high cumulative dose. To minimize the risk of hemorrhage, radiosurgery should only be used in the absence of direct tumor encasement of the carotid artery, otherwise the patient should be treated by fractionated radiotherapy using a small fraction dose.
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