Nasopharyngeal carcinoma: Salvage of local recurrence

doi:10.1016/j.oraloncology.2012.02.017

Oral Oncology

Volume 48, Issue 9, September 2012, Pages 768-774

https://doi.org/10.1016/j.oraloncology.2012.02.017 Get rights and content

Summary

Local control of nasopharyngeal carcinoma has substantially improved with advancing radiotherapy technology and appropriate combination with chemotherapy. However, when local recurrence occurs, this is one of the most difficult challenges. Aggressive treatment is indicated because long term salvage is achievable particularly for early recurrence, but high risk of complications is a serious concern. Treatment options include different methods of surgery and/or re-irradiation with/without chemotherapy. Available information in the literature is grossly inadequate; most reports compose of small series of highly selected patients with heterogeneous characteristics and treatment. No randomized trials have been performed to evaluate the therapeutic ratio of different treatment methods. This article reviews available treatment options, their therapeutic benefits and risks of complications; the objective is to provide information for developing treatment recommendations and suggestions for future improvement.

Introduction

Nasopharyngeal carcinoma (NPC) is one of the greatest oncological challenges because of its highly aggressive natural behavior and the anatomical proximity to critical structures. This cancer is radiation-sensitive and chemo-sensitive, but the therapeutic margin is notoriously narrow. With advancing technology in radiation therapy (RT) and appropriate combination with chemotherapy, locoregional control is steadily improving. However, for patients who develop local recurrence, salvage treatment remains a very difficult challenge.

Our current knowledge is based entirely on retrospective studies; most series consisted of small number of highly selected patients and the treatments were often heterogeneous. Furthermore, many studies included both persistent and recurrent disease, distinction should be made because the former generally has substantially better prognosis. Some studies included both local and nodal recurrences; again distinction should be made because the therapeutic considerations and prognosis are different. There is yet no randomized trial to compare the efficacy and toxicities of different treatment methods.

This article reviews the studies listed in PubMed from 1990 to 2011, focusing specifically on data regarding local recurrence from series with actuarial results ⩾2-year; the aim is to provide a more comprehensive and reliable summary of data to develop treatment recommendations and to stimulate exploration for future improvement.

Section snippets

Early detection of local recurrence

The most important prognostic factor for local recurrence is the rT-category.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Vigilant follow-up by physical, endoscopic and radiological examinations are recommended for all patients following the primary treatment. Magnetic resonance imaging (MRI) is superior to computerized tomography (CT), but distinction between early recurrence and irradiation changes is still often difficult. Additional investigation with integrated fluorodeoxyglucose positron emission

Natural history

The latency for nasopharyngeal recurrence varies widely. Different from other head and neck cancers, NPC is notorious for the risk of late recurrence. Those with short latency (<2 years) generally have the worst prognosis.3, 4, 5, 7, 15 Lee et al.¹⁵ showed that the median latency was 1.9 (range, 0.6–11.9) years: 52% of local recurrence were detected within 2 years, 39% between 2 and 5 years, and 9% manifested more than 5 years from primary treatment. Detailed analyses revealed progressive changes in

Decision on salvage methods

Although treatments do incur high risk of complications, aggressive salvage treatment should be attempted as far as possible because long-term survival can be achieved for a substantial proportion of patients, especially those with early recurrence.2, 3, 4, 8 The study by Yu et al.⁸ on 200 patients with isolated local failure showed that those treated with re-irradiation and/or surgery had significantly better overall survival (OS) than those treated by chemotherapy alone or symptomatic support

Salvage by surgery

Surgical salvage by nasopharyngectomy is an option to consider for selected patients. As the nasopharynx is located in the center of the head, adequate exposure for oncological extirpation of the tumor is a great challenge. Different approaches (including infratemporal,¹⁶ transcervico-mandibulo-palatal,¹⁷ transpalatal, transmaxillary and/or transcervical,¹⁸ maxillary swing,¹⁹ facial translocation,²⁰ degloving²¹) have been developed. The choice should be based on the tumor location, size and

Salvage by re-irradiation

Retrospective studies by Chua et al.³ and Yu et al.⁸ showed that the salvage rate achieved by nasopharyngectomy and re-irradiation were similar. On the other hand, Teo et al.⁴ showed that patients with rT1–2 tumor treated by nasopharyngectomy had significantly higher salvage rate than those by external re-irradiation alone (P = 0.02), but it should be noted 70% of the surgical subgroup also had post-operative re-irradiation.

Different re-irradiation methods have been developed, use of the most

Radiation factors affecting the therapeutic ratio

Re-irradiation dose is one of the most important factors affecting the salvage rate; the general consensus is that re-irradiation dose ⩾60 Gy is needed for effective salvage. The risk of late toxicity is a grave concern, and the striving for optimal balance is a great challenge. Pryzant et al.¹ showed that the incidence of severe late toxicity increased significantly when total dose by the 2 courses of RT exceeded 100 Gy versus those with ⩽100 Gy (39% vs. 4% at 5-year).

Lee et al.³⁰ showed that

Brachytherapy

Brachytherapy is an option for treating centrally located non-bulky rT1 tumors. However, the dose distribution depends substantially on the skills of the operator and the anatomy of individual patient. Attractive salvage rates have been reported with special methods. Kwong et al.⁴⁰ achieved a 5-year L-FFR of 63% and OS of 54% by interstitial implants with radioactive gold grains. Common late toxicity included headache, palatal fistula and mucosal necrosis; but in addition 8% had temporal lobe

Stereotactic radiosurgery (SRS)/fractionated radiotherapy (FSRT)

The development of stereotactic RT improves our ability to deliver high dose even to eccentrically located bulky tumors extending beyond the nasopharynx. The sharp dose fall-off and the superb precision in treatment delivery enhance the chance for minimizing the damage to adjacent soft tissues. This is increasingly used in place of brachytherapy.

When first introduced, this was mostly given in a single fraction of large dose and was termed stereotactic radiosurgery (SRS). A matched control study

External radiotherapy

As majority of patients had recurrence extending beyond the nasopharynx at the time of detection, external RT remains a main treatment method. Many combined external RT with a localized boost (using brachytherapy or SRS/FSRT) to achieve high tumor dose with better sparing of adjacent organs at risk.

Series using 2D external RT ± brachytherapy reported 5-year L-FFR ranging from 15%⁴ to 35%,¹ OS ranging from 8%⁴ to 36%.³ Lee et al.² showed that 2D-RT ± brachytherapy to a total equivalent dose ⩾60 Gy

Combined treatment by radiotherapy and chemotherapy

Meta-analyses of treatment for locoregionally advanced primary disease confirmed that addition of chemotherapy, particularly concurrent chemotherapy, could significantly improve tumor control and survival when compared with RT alone.⁵⁵ Four randomized trials have consistently confirmed the therapeutic benefit of concurrent cisplatin followed by adjuvant cisplatin–fluorouracil combination for locoregionally advanced NPC.56, 57, 58, 59 However, the contribution of chemotherapy for treatment of

Particle beam radiotherapy

Particle beam RT (hadrontherapy) with physical advantages of better spatial selectivity and/or higher biological efficacy than photons is an attractive technological alternative. Dosimetric comparisons showed that intensity-modulated proton therapy was superior to IMRT by photon in coverage and conformity for the gross tumor volume, as well as reduction of doses to most organs at risk and integral total body doses. The latter improvement is important for minimizing late damages and carcinogenic

Conclusions and future directions

Management of recurrent NPC remains one of the most difficult challenges. Prevention of recurrence by optimizing primary treatment with state-of-the-art RT and appropriate combination with chemotherapy is vital. Vigilant follow-up is needed to detect recurrence as early as possible. Development of sensitive biomarkers in addition to improvement of imaging facilities would be valuable for early detection of recurrence. Aggressive local treatment is indicated as this might still achieve long-term