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Malignant Nasopharyngeal Tumors Treatment & Management

  • Author: Ho-Sheng Lin, MD, FACS; Chief Editor: Arlen D Meyers, MD, MBA  more...
 
Updated: Feb 03, 2016
 

Medical Therapy

Previously untreated nasopharyngeal carcinoma

Nasopharynx

External beam radiation therapy is the primary mode of management of nasopharyngeal carcinoma (NPC), both at the primary site and in the neck. This is mainly because of this tumor's high degree of sensitivity to radiation as well as the anatomical constraints for surgical access to the highly complex nasopharyngeal region. Recent advances in imaging capabilities (eg, the ability to more accurately define tumor location) and improved radiotherapy techniques (eg, stereotactic radiotherapy boost) have helped to improve the locoregional control rate. At the same time, complications associated with radiation therapy have been reduced. Various sophisticated fractionation schema and boosting techniques have been advocated, with a minimum of 65-75 Gy of radiation delivered to the primary site.

Although radiation therapy alone is a well-accepted management of stages I and II NPC, the administration of chemotherapy adjunctive to radiotherapy in advanced NPC (stages III-IV) has remained a controversial issue because of conflicting reports in the literature. When interpreting these data, the inherent difference in disease type in endemic areas (eg, Southeast Asia) and nonendemic areas (eg, North America and Western Europe) must be noted. WHO type 1 makes up fewer than 5% of all NPC cases in Southeast Asia, while it accounts for 25% of tumor types in the Intergroup Study from North America.[29] WHO type 1 NPC is generally considered to be less radiosensitive than WHO type 2 and 3 NPC; therefore, WHO type 1 NPC is associated with the worst prognosis. Not surprisingly then, the locoregional control and survival rates reported from Southeast Asia are, in general, better than rates reported from the West.

Another important thing to remember is that the radiation regimens reported in Asian studies are typically more aggressive than ones reported in nonendemic areas in the West.[30] This may account for the better outcome in the radiation-alone arm seen in Asian studies, making it harder to show survival benefit with the addition of chemotherapy. Finally, many different types of chemotherapeutic regimens (different drugs, concentrations, and different timing) were used in these trials, which may also account for some of the differences in outcome.

Chemotherapy can be delivered before (neoadjuvant), during (concurrent), or following (adjuvant) radiation therapy. Active chemotherapeutic agents include cisplatin, 5-fluorouracil (5-FU), doxorubicin, epirubicin, bleomycin, mitoxantrone, methotrexate, and vinca alkaloids. Various chemotherapeutic approaches have been devised to improve the response rates while minimizing toxicities.

In 1998, a landmark study (Intergroup Study 0099) was reported by Al-Saraaf et al.[29] This was a large, prospective, randomized trial from North America that demonstrated that concomitant chemoradiation (cisplatin 100 mg/m2 infused on days 1, 22, and 43) followed by adjuvant chemotherapy with cisplatin (80 mg/m2) and 5-FU (1 g/m2) every 4 weeks for 3 cycles improved overall survival (OS) at 3 years for patients with advanced stages of NPC over radiation therapy alone (75% vs 46%).

In an updated report, Al-Saraaf reported that patients treated with chemoradiation continued to have superior OS rates over patients treated with radiation alone at 5 years (67% vs 37%).[31] This study was the first large randomized trial that demonstrated a significant improvement in OS with the addition of chemotherapy to radiation. Following this landmark study, a major change in the treatment paradigm for patients with advanced stage NPC occurred in the United States. Most centers now treat patients who have advanced-stage NPC with a combination of chemotherapy and radiation. However, this treatment regimen is certainly not routinely practiced in other parts of the world, especially in endemic regions in Asia.

In contrast to the Intergroup Study 0099, several large, prospective, randomized trials failed to show any survival benefit with the addition of chemotherapy for treatment of advanced NPC (see Table 5 below). Most of these earlier studies from Asia, however, used chemotherapy either in the neoadjuvant or adjuvant fashion instead of the concurrent and adjuvant regimen used in Intergroup Study. Using chemotherapy in an adjuvant setting, the Taiwan Cooperative Oncology Group Trial failed to demonstrate any survival benefit from the addition of adjuvant chemotherapy in advanced stages of NPC. The 5-year OS for the chemoradiation group was 61% versus 55% survival for radiation alone group.[32]

Studies using chemotherapy in a neoadjuvant setting also failed to show survival advantage. A randomized trial from the Asian-Oceanian Clinical Oncology Association compared induction chemotherapy followed by radiotherapy versus radiotherapy alone.[33] The 3-year OS rate was 78% for the induction chemotherapy group, which was not significantly different from the 3-year OS of 71% for the radiation alone group.

In a similar large, randomized trial, Ma et al reported a 5-year OS of 63% for the group that received induction chemotherapy followed by radiation versus a 5-year OS of 56% for the group that underwent radiation alone.[34] Statistical significant improvement in survival was not achieved (P =0.11). Finally, Chan et al evaluated the addition of both neoadjuvant and adjuvant chemotherapy and reported a 5-year OS rate of 80% for the chemoradiation group and 81% for the radiation alone group with P =0.1.[35]

Unfortunately, the disparate results in these well-conducted large, prospective, randomized trials are difficult to interpret, for several reasons. First, the difference in the proportion of the 3 types of NPC in each of these studies may contribute to some of the disparities in the effect of chemotherapy in these different studies. As stated previously, most of the NPC cases (>95%) in Southeast Asia involve type 2 NPC and type 3 NPC, which are extremely radiosensitive. Treatment with radiation alone usually results in an excellent 5-year OS rate, ranging from 60-80%. Improving on this excellent survival rate is difficult with the addition of chemotherapy. Although fewer than 5% of patients in these studies from Southeast Asia have type 1 NPC, a large proportion of patients (25%) in the Intergroup Study have type 1 NPC, which is less radiosensitive and is associated with a much lower survival rate than radiation alone.[29]

The possibility exists that the significant improvement in survival reported from the Intergroup Study may be more applicable to patients with type 1 NPC than patients with type 2 or 3 NPC.[29] Subgroup analysis of the Intergroup Study seems to support the significant beneficial effect of adding chemotherapy for patients with WHO type I NPC (see Table 6 below). In patients with WHO type I treated by radiation alone, the 5-year OS rate is only 14%. The survival rate increased to 59% in the same group of patients treated with chemoradiation. However, one must be cautious in drawing conclusion from subset analysis, especially given the small number of patients in this subset of WHO type I (n = 36).

The debate over whether chemotherapy is beneficial in the treatment of advanced NPC is further complicated because different trials used different chemotherapeutic agents (eg, vincristine, cisplatin, bleomycin, epirubicin, 5-FU, methotrexate) as well as different delivery schedules (ie, neoadjuvant, concurrent, adjuvant, combination). The improved survival rate from the Intergroup Study may result from the concurrent use of chemotherapy with radiation, whereas many prior studies from Asian countries mainly use chemotherapy in the adjuvant setting, neoadjuvant setting, or both.

To test this hypothesis, several phase III randomized trials were conducted in Asia using chemotherapy in the concurrent fashion with radiotherapy. Unfortunately, the results were again inconclusive. Chi et al reported that the concurrent use of cisplatin, 5-FU, and leucovorin with radiation failed to improve 5-year overall survival in stage IV NPC patients when compared with radiation alone (61% versus 55%). On the other hand, Chan et al reported on a phase III randomized study comparing concurrent use of weekly infusion of cisplatin (40 mg/m2) during radiation versus radiation alone.[35] They demonstrated that for patients with stage II and III NPC, the 5-year OS rate is better in patients treated with concurrent chemoradiotherapy (70.3%) than for patients treated with radiation alone (58.6%).

Another study from Taiwan reported by Lin et al also demonstrated that the use of concurrent chemoradiotherapy is superior to radiotherapy alone.[36] In that study, patients were treated with 2 cycles of cisplatin and 5-FU during radiation. The 5-year OS rate in the chemoradiation group (72.3%) was significantly better than that for the radiation alone group (54.2%).

Two published randomized phase III clinical trials, using the exact same treatment schema that was used in the Intergroup Study 0099, however, gave contradictory results. Using concurrent chemoradiation with cisplatin followed by adjuvant chemotherapy with cisplatin and 5-FU, Wee et al reported a statistically significant (P =0.008) improvement in 5-year OS rate in patients who received chemoradiotherapy (67%) versus patients who received radiation alone (49%).[37, 38] However, using this same regimen, Lee et al reported no statistical significant difference (P =0.22) in 5-year OS rate in patients treated with chemoradiotherapy (68%) versus patients treated with radiation alone (64%) (see Table 5 below).[39, 40] Nonetheless, the locoregional control rate in the chemoradiation group (92%) is statistically significantly (P =0.027) better than that for the radiation alone group (82%).

Further, this was the first randomized trial to include a more contemporary standard of radiation, with approximately 60% of patients receiving some form of intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT). As stated earlier, radiation regimens used in Asian studies are typically more aggressive and treatment with radiation alone usually results in an excellent 5-year OS rate. Thus, it may be more difficult to improve on this excellent survival rate (using radiation alone) with the addition of chemotherapy.

Finally, a recently published randomized phase III trial from Chen et al involved 316 patients from Chinese mainland.[41, 42] Patients in the combined treatment arm were given concurrent cisplatin (40 mg/m2) weekly during 7 weeks of radiation followed by cisplatin (80 mg/m2 on day 1) and fluorouracil (800 mg/ m2 on days 1-5) every 4 weeks for 3 cycles after radiation. The 5-year OS for the chemoradiation arm and radiation-alone arm were 72% and 62%, respectively (hazard ratio, 0.69; 95% CI, 0.48-0.99; P =0.043.[42]

A meta-analysis involving 1,528 patients from 6 randomized studies comparing combined chemotherapy-radiation therapy versus radiation therapy alone in locally advanced NCP showed that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the OS increased by 20% at 2 years, 19% at 3 years, and 21% at 4 years with chemotherapy plus radiation therapy.[43]

A report from the Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) reviewed individual patient data from 8 well-designed randomized trials that compared chemotherapy plus radiotherapy versus radiotherapy alone in locally advanced NPC.[44] A total of 1753 patients were included in this review. All trials used conventional radiotherapy and cisplatin-based chemotherapy. The authors found that the addition of chemotherapy improved 5-year OS from 56% to 62% (absolute survival benefit, 6%) and improved EFS from 42% to 52% (absolute benefit, 10%).

They also observed a significant interaction between chemotherapy timings and OS (P =.005), which explained the heterogeneity of clinical trial results previously noted. The use of concurrent chemotherapy with radiation was found to result in the highest survival benefit. In the sensitivity analysis, chemotherapy was found to be more efficient against WHO type 1 disease than other types. The authors concluded that the addition of chemotherapy to standard radiotherapy provides a small but significant survival benefit in patients with nasopharyngeal carcinoma. This benefit is especially observed when chemotherapy is administered concomitantly with radiotherapy. The role of induction chemotherapy and adjuvant chemotherapy is more questionable.

A recent large, phase 3, multicenter, randomized control trial[45] compared the effect of the addition of adjuvant chemotherapy (cisplatin and 5-FU) to concurrent chemotherapy with cisplatin in locoregionally advanced NPC. This trial involved 7 institutions in China and enrolled patients with stage III or IV NPC, except for T3-4N0. A total of 251 patients were randomized to the concurrent chemoradiation plus adjuvant chemotherapy (C+A) group, while 257 were randomized to the concurrent chemoradiation alone (C) group. After a median follow-up of 37.8 months, the estimated 2 year failure-free survival rate was 86% (95% CI, 81-90) in the C+A group and 84% (95% CI, 78-88) in the C group (hazard ratio 0.74; 95% CI, 0.49-1.10; P =0.13).

Similarly, in a meta-analysis of 5 studies involving 394 patients in the C+A group and 399 patients in the C only group, Liang et al showed that the addition of adjuvant chemotherapy to concurrent chemoradiation did not improve outcome compared with concurrent chemoradiation alone. Risk ratios of 1.02 (95% CI, 0.89-1.15), 0.93 (95% CI, 0.72-1.21), 1.07 (95% CI, 0.87-1.32), and 0.95 (95% CI, 0.80-1.13) were observed for 3 years OS, 5 years failure-free survival, 5 years locoregional failure-free survival, and 5 years distant metastasis failure-free survival, respectively.[46]

In his recent review paper, Al-Sarraf[31] commented on reversing the sequence of chemotherapy from adjuvant to neoadjuvant. Using this protocol of induction chemotherapy with 3 courses of cisplatin and 5-FU followed by concurrent chemoradiation using 3 courses of cisplatin, he reported an unpublished 5 year OS of approximately 90%. Kong et al[47] recently reported on the use of neoadjuvant chemotherapy consisting of a taxane, cisplatin, and 5-FU (TPF regimen) followed by concurrent chemoradiation in 52 stage III and 64 stage IVA/IVB NPC patients. The 3-year OS was 94.8% (95% CI, 87.6-100%) for stage III patients and 90.2% (95% CI, 81.8-98.6%) for stage IVA/IVB patients. This excellent result is very encouraging and warrants randomized controlled trials.

Table 5. Prospective Randomized Clinical Trials of Chemoradiation Versus Radiation Alone in the Treatment of Locally Advanced NPC (Open Table in a new window)

 



Author, Year



Stage Number



of



Patients



Treatment Arms Survival Rate P Value
Neoadjuvant Chemotherapy Followed by Radiation
VUMCA, 1996[48] IV n=171 Bleomycin/epirubicin/cisplatin X 3



Radiation



60% (3 yr OS) P > .05
n=168 Radiation alone 54% (3 y OS)
Hareyama, 2002[49] I-IV n=40 Cisplatin/5-FU X 2



Radiation



60% (5 y OS) P > .05
n=40 Radiation alone 45% (5 y OS)
Chua, 1998[33] T3



N2-3



n=167 Cisplatin/epirubicin X 2-3



Radiation



78% (3 y OS) P = .57
n=167 Radiation alone 71% (3 y OS)
Ma, 2001[34] III-IV n=224 Cisplatin/bleomycin/5-FU X 2-3



Radiation



63% (5 y OS) P = .11
n=225 Radiation alone 56% (5 y OS)
Concurrent Chemotherapy and Radiation
Lin, 2003[36] III-IV n=141 Cisplatin/5-FU X 2 +



Radiation



72.3% (5 y OS) P = .002
n=143 Radiation alone 54.2% (5 y OS)
Chan, 2005[35] II-IV n=174 Cisplatin weekly and



Radiation



70.3% (5 y OS) P = .048
n=176 Radiation alone 58.6% (5 y OS)
Radiation Followed by Adjuvant Chemotherapy
Rossi, 1988[50] I-IV n=113 Radiation



Vincristine/cyclophosphamide/Adriamycin X 6



59% (4 y OS) P > .05
n=116 Radiation alone 67% (4 y OS)
Chi, 2002[32] IV n=77 Radiation



Cisplatin/5-FU/leucovorin X 9



61% (5 y OS) P = .5
n=77 Radiation alone 55% (5 y OS)
Neoadjuvant Chemotherapy Followed by Radiation Followed by Adjuvant Chemotherapy
Chan, 1995[35]   n=34 Cisplatin/5-FU X 2



Radiation



Cisplatin/5-FU X 4



80% (5 y OS) P = .1
n=40 Radiation alone 81% (5 y OS)
Concurrent Chemotherapy and Radiation Followed by Adjuvant Chemotherapy
Al-Sarraf, 1998[29] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



78% (3 y OS) P < 0.001
n=92 Radiation alone 47% (3 y OS)
Al-Sarraf, 2002[31] ; 2001[51] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P < 0.001
n=92 Radiation alone 37% (5 y OS)
Wee, 2004[37, 38] III-IV n=111 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P = 0.008
n=110 Radiation alone 49% (5 y OS)
Lee, 2005[39] ; 2010[40] T1-4



N2-3



n=172 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



68% (5 y OS) P = 0.22
n=176 Radiation alone 64% (5 y OS)
Chen, 2013[42] III-IV n=158 1) Cisplatin weekly + radiation



2) Cisplatin/5-FU X 3



72% (5 y OS) P = 0.043
n=158 Radiation alone
62% (5 y OS)

Table 6. Intergroup Study 0099. Subgroup Analysis of 5-Year Overall Survival Based on WHO Types[29] (Open Table in a new window)

Treatment WHO I, II, III



(n=147) OS, %



WHO II and III



(n=111, 75) OS, %



WHO I



(n=36, 25%) OS, %



Radiation 37 45 14
Chemoradiation 67 70 59

Neck

Radiation therapy more readily controls neck disease that arises from NPC than comparable neck disease from other head and neck carcinomas. Regional control remains a possibility even with extensive nodal disease. Delivery of radiation at a minimum of 65-75 Gy to the clinically positive neck node is recommended. Given the high propensity of NPC to metastasize to the neck, most authors recommend elective treatment of the N0 neck. Furthermore, treatment of both sides of the neck is recommended. The retropharyngeal and parapharyngeal lymph nodes are included in the treatment volume of the primary tumor.

Persistent or recurrent nasopharyngeal carcinoma (locoregional failures)

Despite recent advances in the management of NPC, locoregional failure is still significant, with reported rates of 15.6-58% (median, 34%).[4, 5, 6, 7]

Nasopharynx - Local failure

The frequency of local failure is reported to range from 18-58%.[52, 53] Management of locally recurrent diseases can be accomplished with either re-irradiation or salvage nasopharyngectomy. Re-irradiation is associated with a high frequency of complications, including temporal lobe necrosis, brainstem damage, cranial neuropathy, endocrine dysfunction, visual and hearing impairments, osteonecrosis, soft tissue necrosis, and trismus. These complications can be reduced with the use of brachytherapy or stereotactic radiotherapy. Although the potential for these complications is high, only 10-30% of patients achieve local control after the second course of irradiation.[54, 55] A survival rate of 34-48% at 3 years has been reported, although only about 15-23% of patients achieve disease-free survival.[54, 55]

Neck - Regional failure

The frequency of persistent or recurrent neck disease is reported to range from 8-34%.[56] Patients whose treatment failed regionally can be treated with either re-irradiation or salvage neck dissection. The control rate after re-irradiation is reported to be between 28% and 33%.[55] In contrast, Wei et al reported a regional control rate of 66% after radical neck dissection.[57] Despite a relatively good chance of regional control, these patients who presented with recurrent or persistent neck disease usually have a high risk of distant metastases.

Distant metastases

A high prevalence of distant metastases has been observed for patients with NPC, with a substantial number eventually experiencing distant failure despite lasting locoregional control. The distant failure rate was reported to range from 18-35%. At the time of initial presentation, 5-10% of patients may already have distant metastases. The occurrence of distant disease does not appear to be associated with the size of the primary tumor. However, a strong association exists between nodal disease and the development of distant disease, with 38% of patients with N+ neck disease exhibiting distant metastases versus 11% of patients with N0 neck disease. Some series have reported a rate of up to 80% of distant metastasis in patients with N3 neck disease.

The lung is the most common site of metastasis, followed by bone and the liver. Currently, available treatment modalities are ineffective in curing distant metastases. Palliative treatment is directed toward pain relief, symptom control, and prolongation of life. Radiation can be extremely effective in palliating pain from bone metastasis. Although the use of palliative chemotherapy in a patient who experiences symptoms is reasonable, the use of palliative chemotherapy in a patient without any symptoms is not as clear. The desire for prolongation of life must be balanced against the patient's quality of life, which should be the first priority.

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Surgical Therapy

Previously untreated nasopharyngeal carcinoma

Because of the tumor's high degree of sensitivity to radiation and the anatomical constraints for surgical access to the highly complex nasopharyngeal region, nasopharyngectomy is reserved only for treatment of recurrent NPC with limited disease.

Persistent or recurrent nasopharyngeal carcinoma (locoregional failures)

Nasopharynx - Local failure

Although nasopharyngectomy can achieve slightly better local control and a lower rate of complication as compared with re-irradiation, this surgery is only applicable in patients with limited disease such as rT1, rT2, rT3. A recurrent or residual disease that involves the middle cranial fossa may be amenable to resection through the craniofacial approach. Most surgeons consider the involvement of the cavernous sinus, the cranial nerves, and the carotid artery as a contraindication for surgical intervention. Even though tumors in these areas are technically resectable, salvage surgery is not advised because of the high morbidity associated with resection of the internal carotid artery and the cranial nerves in the setting of a very low probability of cure. A recent meta-analysis of 779 patients from 17 published studies showed a 5-year overall survival of 51.2% following salvage surgery with or without reirradiation for recurrent nasopharyngeal carcinoma.[58]

Various surgical approaches to the nasopharyngeal region have been described. Each approach has its own merit, and no single approach has clearly been shown to be superior to the other approaches. Because of the nature of the disease process, which involves an extremely complex anatomical region, the surgeon needs to be familiar with all of these surgical approaches. The operation performed must be tailored to the areas involved by the tumor and may involve a combination of approaches, thus allowing maximal exposure while minimizing associated morbidity.

Neck - Regional failure

Radical neck dissection can be used to treat recurrent or residual disease in the neck after radiation treatment with a good probability of regional control. Wei et al reported a regional control rate of 66% after radical neck dissection.[57] On serial sectioning of the entire radical neck dissection specimen, 27.5% of the specimen was found to have tumors lying in close proximity to, or even infiltrating, the spinal accessory nerve. Based on this finding, Wei et al recommended radical neck dissection as the salvage procedure of choice.[57] If the retropharyngeal or parapharyngeal space is involved, neck dissection is extended to include this region.

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Preoperative Details

A detailed assessment of the extent of tumor involvement is extremely important. Most surgeons consider the involvement of the cavernous sinus as a contraindication for surgery. A clear appreciation of the tumor in relation to the internal carotid artery is essential. Metastatic workup must be performed to exclude distant metastases.

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Intraoperative Details

Fee describes a transpalatal, transmaxillary, and transcervical approach.[23] This approach to the nasopharynx provides excellent exposure to both sides of the nasopharynx with minimal morbidity to the patient. Isolation and protection of the internal carotid artery through the transcervical approach allow resection of the lateral nasopharyngeal wall with minimal risk to the internal carotid artery and the cranial nerves. Disease that extends to the pterygomaxillary space can be exposed via a transmaxillary approach through the posterior wall of the maxillary sinus. Then, the clivus and vertebral body bone are drilled with a large cutting burr. Fee reported on his experience with 33 patients who had recurrent NPC and were monitored for 2-17 years after nasopharyngectomy. A 5-year local control rate of 67% with a 5-year disease-free survival rate of 52% and an OS rate of 60% were achieved.

Fisch describes the infratemporal fossa approach, and Gross and Panje describe the lateral temporal approach.[59, 60] Both approaches provide excellent exposure of tumors that extend into the infratemporal fossa and the parapharyngeal space. A major disadvantage of these approaches is that entry into the nasopharynx is performed on the side of the lesion, making complete excision difficult if the tumor extends to the contralateral nasopharynx. Furthermore, the morbidity following this approach is significant and may include sensorineural hearing loss, cerebrospinal fluid (CSF) leak, unilateral laryngeal paralysis, and facial nerve deficit.

Wei et al suggested a new idea for exposure of the nasopharynx through the maxillary swing (facial translocation).[61] This approach involves a Weber-Fergusson incision. After achieving the necessary bone cuts, the entire osteocutaneous complex is swung laterally to provide exposure of disease in the ipsilateralpterygomaxillary and paranasopharyngeal space. However, the control of the internal carotid artery is less than optimal. Wei reported a local control rate of 42% at 3.5 years.[61]

Biller and Krespi describe the transcervico-mandibulo-palatal approach. This approach provides a wide-field exposure of the nasopharynx and excellent protection of the internal carotid artery. Morton et al reported a 67% local control rate at 2 years with this approach.[62] King et al reported on a series of 31 patients who were treated with a variety of surgical approaches followed by postoperative radiation.[63] They reported a 5-year survival rate of 47% with a 5-year disease-free survival rate of 42%.

With the increasing interest in minimally invasive surgery in the field of head and neck, endoscopic approach for resection of recurrent nasopharyngeal carcinoma has been described. Chen et al. reported on a series of 6 patients with recurrent T1 or T2a disease who underwent endoscopic nasopharyngectomy with a local control rate of 83% at a mean follow-up duration of 29 months.[24]

Finally, the introduction of the da Vinci robot provided another technological advancement that enables surgeons to reach and operate in areas such as the nasopharynx, which are difficult to access. Tsang et al[64] reported on 12 patients who underwent robotic nasopharyngectomy with 2-year local control rate of 86% and 2-year OS of 83%.

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Postoperative Details

The nasopharyngeal defect is covered with a split-thickness skin graft. The graft is held in place with packing. A 14F Foley catheter is then placed through the nose, and the balloon is inflated to keep the packing in place. Bilateral or unilateral myringotomy and tube placement are performed at the end of the surgery. The Foley catheter is usually removed on the third postoperative day, and the nasopharyngeal packing is removed on the 10th postoperative day. The patient is instructed to irrigate the nasopharynx with normal saline until healing is complete.

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Follow-up

Unlike other head and neck cancers, NPC is known for its continued risk of late recurrences, and long-term follow-up care is required. Although most recurrences occur within 5 years, 5-15% of recurrences may manifest between the 5th and 10th year. Therefore, patients with NPC should be monitored for at least 10 years after treatment. Some authors have suggested that a 10-year, rather than the 5-year, survival rate is needed to assess the effectiveness of a particular treatment of NPC.

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Complications

Radiation

Recent advances in imaging capabilities (which more accurately define tumor volumes) and improved radiotherapy have helped in improving the locoregional control rate while, at the same time, reducing the complications associated with radiation therapy. However, in an attempt to improve locoregional control and survival rates, a higher radiation dose, a more radical fractionation schedule, and the addition of chemotherapy have, in some cases, increased the frequency and severity of complications.

Complications associated with radiation therapy to the nasopharynx and the neck can be classified according to the following organ systems:

  • Brain - Pituitary dysfunction, brainstem encephalopathy, temporal lobe necrosis, cranial nerve palsy
  • Ear - Sensorineural hearing loss, otitis media with effusion, eustachian tube dysfunction
  • Eye - Dry eye syndrome, ischemic retinopathy
  • Thyroid - Hypothyroidism
  • Gastrointestinal system - Severe mucositis, xerostomia, nausea, vomiting, dysphagia, dehydration, esophageal stricture
  • Musculoskeletal system - Excessive fibrosis, trismus, radiation myelitis, osteoradionecrosis, soft tissue necrosis, osteomyelitis
  • Vascular system - Stenosis of common carotid artery or internal carotid artery (Cheng et al reported a 16% incidence of critical stenosis of either the common carotid artery or the internal carotid artery. [65] )

Surgery

Surgical complications can be divided into those associated with nasopharyngectomy and those associated with neck dissection. Because surgery is usually performed after a course of radical radiotherapy, complications from poor wound healing are commonly observed. These complications include palatal fistula, nasopharyngeal wound infection, osteonecrosis, osteomyelitis of cervical vertebrae or skull base, nonunion or malunion of osteotomy sites, and wound edge or flap necrosis. Other complications include damage to the internal carotid artery or the cranial nerves, dural violation at the skull base, and death.

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Outcome and Prognosis

The prognostic factors for patients with nasopharyngeal carcinoma (NPC) include the extent of the primary tumor (ie, skull base invasion, cranial nerve involvement, parapharyngeal infiltration), the level of the disease in the neck, the histologic subtype, the age and the sex of the patient, and the type and technique of radiotherapy. Survival rates are generally better in females than in males.

Some of the largest studies have reported a 5-year disease-free survival rate of 40-60% with primary radiation treatment. The 5-year overall survival (OS) rate is 85-95% for stage I NPC and 70-80% for stage II NPC treated with radiation alone. For stages III and IV NPC treated with radiation alone, the 5-year OS rate ranges from 24-80%, with better results generally occurring in patients from Southeast Asia. The Intergroup Study 0099 demonstrated that North American patients with advanced NPC benefited from concurrent chemotherapy with an improved 5-year OS rate of 67% compared with the 5-year OS rate of 37% for patients treated with radiation alone.

WHO type 3 NPC or undifferentiated carcinoma has the most favorable prognosis because of its high degree of radiosensitivity. The 5-year OS rate is 60-80%. In contrast, WHO type 1 NPC has the worst prognosis, with a 5-year OS rate of 20-40% because of its low radiosensitivity.

Unlike other head and neck carcinomas, some NPCs have a long, protracted course. Some patients can live with their recurrent disease for many years before succumbing to the disorder.

A literature review by Liao et al indicated that in patients with NPC, overexpression of matrix metalloproteinase-9 correlates with a poor prognosis for overall survival and disease-free survival.[66]

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Future and Controversies

Several areas continue to be debated regarding the management of nasopharyngeal carcinoma (NPC).

The role of chemotherapy in advanced nasopharyngeal carcinoma

Unfortunately, the literature is conflicting regarding the role of chemotherapy in the management of advanced NPC. This discrepancy in the literature may result from differences in the proportion of NPC WHO types, the types of chemotherapeutic agents, and delivery schedules in these various clinical trials. The significant improvement in survival with the addition of chemotherapy reported from the Intergroup Study may be because of the large proportion of patients with type 1 NPC in this study and the concurrent use of chemotherapy. Other large clinical trials, most notably from Asia, include a large proportion of patients with type 2 or 3 NPC who received chemotherapy in the neoadjuvant or adjuvant fashion. These trials failed to demonstrate improvement in overall survival (OS) with the addition of chemotherapy.

Several clinical trials from Asia that incorporated the use of concurrent chemoradiotherapy for locoregionally advanced NPC did show statistically significant improvement in OS. However, results are still conflicting. Using the same regimen as the one used in Intergroup Study 0099, Lee et al reported no statistically significant difference in 3-year OS in patients treated with chemoradiotherapy (76%) versus patients treated with radiation alone (77%). Nonetheless, the locoregional control rate in the chemoradiation group (93%) is statistically significantly better than the radiation alone group (82%).

Most recently, a report from the Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) reviewed individual patient data from 8 well-designed, randomized trials comparing chemotherapy plus radiotherapy with radiotherapy alone in locally advanced NPC. A total of 1753 patients were included in this review. The authors found that the addition of chemotherapy improved 5-year OS from 56% to 62% (absolute survival benefit, 6%) and improved EFS from 42% to 52% (absolute benefit, 10%). The authors concluded that the addition of chemotherapy to standard radiotherapy provides a small but significant survival benefit in patients with nasopharyngeal carcinoma. This benefit is essentially observed when chemotherapy is administered concomitantly with radiotherapy. The role of induction chemotherapy and adjuvant chemotherapy is more questionable.

Treatment recommendations for type and schedule of chemotherapeutic agents

Even if the decision is made to add chemotherapy to the treatment, the type and the schedule of chemotherapeutic agents must be determined. The goal is to determine the optimal timing and regimen, thereby maximizing the effectiveness of the treatment while minimizing the adverse effects. Numerous clinical trials to address this issue are ongoing.

Conventional versus altered fractionation, stereotactic radiation boost, and brachytherapy

The goal of these therapies is to find the optimal radiation regimen, thereby maximizing the effectiveness of this treatment while minimizing the adverse effects. The general recommendation for treatment of a primary tumor is a radiation dosage of at least 66 Gy. Stereotactic radiotherapy and brachytherapy may be used to boost dosage as well as to minimize surrounding tissue damage. Various clinical trials that involve different radiation regimens have been reported, and many more clinical trials are ongoing.

Salvage nasopharyngectomy or re-irradiation for local recurrence

The choice of therapy for local recurrence is another area of ongoing controversy. Fee concluded that the results of surgical resection are probably only slightly better than retreatment with radiotherapy. However, Fee believes that surgery is associated with fewer long-term complications when compared with re-irradiation. With the continued improvement in radiation delivery techniques such as intensity-modulated radiation therapy (IMRT) and stereotactic boost, complications associated with re-irradiation may decrease.

The best approach for performing nasopharyngectomy

None of the surgical approaches for resection of recurrent NPC is ideal. Because of the nature of the disease process, which involves an extremely complex anatomical region, the surgeon needs to be familiar with all of the surgical approaches. The operation must be tailored to the areas involved by the tumor and may involve a combination of approaches, thus allowing maximal exposure while minimizing associated morbidity.

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Contributor Information and Disclosures
Author

Ho-Sheng Lin, MD, FACS Professor and Interim Chair, Department of Otolaryngology-Head and Neck Surgery, Faculty, Sleep Fellowship Program, Divison of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine; Chief, Section of Otolaryngology, Department of Surgery, John D Dingell Veterans Affairs Medical Center

Ho-Sheng Lin, MD, FACS is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Association of University Professors, American College of Surgeons, American Head and Neck Society, Association of VA Surgeons, Chinese American Medical Society, SWOG, American Academy of Sleep Medicine, Triological Society

Disclosure: Received consulting fee from Intuitive Surgical for proctoring; consultant for Checkpoint Surgical.

Coauthor(s)

Willard E Fee, Jr, MD Edward C and Amy H Sewall Professor Emeritus, Chairman Emeritus, Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine

Willard E Fee, Jr, MD is a member of the following medical societies: American College of Surgeons, American Laryngological Association, American Medical Association, California Medical Association, The Triological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nader Sadeghi, MD, FRCSC Professor, Otolaryngology-Head and Neck Surgery, Director of Head and Neck Surgery, George Washington University School of Medicine and Health Sciences

Nader Sadeghi, MD, FRCSC is a member of the following medical societies: American Head and Neck Society, American Thyroid Association, American Academy of Otolaryngology-Head and Neck Surgery, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;SymbiaAllergySolutions<br/>Received income in an amount equal to or greater than $250 from: Symbia<br/>Received from Allergy Solutions, Inc for board membership; Received honoraria from RxRevu for chief medical editor; Received salary from Medvoy for founder and president; Received consulting fee from Corvectra for senior medical advisor; Received ownership interest from Cerescan for consulting; Received consulting fee from Essiahealth for advisor; Received consulting fee from Carespan for advisor; Received consulting fee from Covidien for consulting.

Additional Contributors

Benoit J Gosselin, MD, FRCSC Associate Professor of Surgery, Dartmouth Medical School; Director, Comprehensive Head and Neck Oncology Program, Norris Cotton Cancer Center; Staff Otolaryngologist, Division of Otolaryngology-Head and Neck Surgery, Dartmouth-Hitchcock Medical Center

Benoit J Gosselin, MD, FRCSC is a member of the following medical societies: American Head and Neck Society, American Academy of Facial Plastic and Reconstructive Surgery, North American Skull Base Society, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Rhinologic Society, Canadian Medical Association, Canadian Society of Otolaryngology-Head & Neck Surgery, College of Physicians and Surgeons of Ontario, New Hampshire Medical Society, Ontario Medical Association

Disclosure: Nothing to disclose.

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Axial T2-weighted image shows a left-sided cervical nodal metastasis resulting from nasopharyngeal cancer.
Table 1. Diagnostic profiles of IgA to EA and IgA to VCA [11]
Serology Status Sensitivity Specificity PPV NPV
IgA to EA 80.2% 100% 100% 83.5%
IgA to VCA 97.3% 46.8% 64.7% 94.5%
Table 2. Predictive Value of Epstein-Barr Virus Serology Combinations
IgA Antibody to EA IgA Antibody to VCA Probability of NPC
+ + 100%
+ 100%
5.5%
+ 37.8%
Table 3. Diagnostic Values of the 4 EBV Antibodies [12]
Serology Status Sensitivity Specificity Area Under ROC Curve (95% CI)
IgA to EA 89.1% 98.5% 0.94 (0.92-0.96)  
IgA to VCA 98.1% 82.8% 0.98 (0.96-0.99)    
IgG to Rta 90.5% 85.2% 0.92 (0.89-0.95)    
IgA to EBNA1 87.2% 84.2% 0.92 (0.89-0.95)    
Table 4. Diagnostic Accuracy based on Different Combination of the 4 EBV Antibodies
Combination Sensitivity Specificity Area Under ROC Curve (95% CI)
IgG to Rta +



IgA to EBNA1



93.4% 90.6% 0.97 (0.95-0.98)  
IgA to VCA +



IgA to EA



92.4% 98.5% 0.98 (0.96-0.99)    
IgA to VCA +



IgA to EBNA1



94.3% 98.0% 0.98 (0.97-0.99)    
IgA to VCA +



IgG to Rta



94.8% 98.0% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgA to EBNA1



97.2% 95.6% 0.98 (0.97-0.99)    
IgA to VCA +



IgA to EA +



IgG to Rta



92.9% 99.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgG to Rta +



IgA to EBNA1



94.8% 98.5% 0.99 (0.98-1.00)    
IgA to VCA +



IgA to EA +



IgG to Rta +



IgA to EBNA1



96.7% 97.0% 0.99 (0.98-1.00)    
Table 5. Prospective Randomized Clinical Trials of Chemoradiation Versus Radiation Alone in the Treatment of Locally Advanced NPC
 



Author, Year



Stage Number



of



Patients



Treatment Arms Survival Rate P Value
Neoadjuvant Chemotherapy Followed by Radiation
VUMCA, 1996[48] IV n=171 Bleomycin/epirubicin/cisplatin X 3



Radiation



60% (3 yr OS) P > .05
n=168 Radiation alone 54% (3 y OS)
Hareyama, 2002[49] I-IV n=40 Cisplatin/5-FU X 2



Radiation



60% (5 y OS) P > .05
n=40 Radiation alone 45% (5 y OS)
Chua, 1998[33] T3



N2-3



n=167 Cisplatin/epirubicin X 2-3



Radiation



78% (3 y OS) P = .57
n=167 Radiation alone 71% (3 y OS)
Ma, 2001[34] III-IV n=224 Cisplatin/bleomycin/5-FU X 2-3



Radiation



63% (5 y OS) P = .11
n=225 Radiation alone 56% (5 y OS)
Concurrent Chemotherapy and Radiation
Lin, 2003[36] III-IV n=141 Cisplatin/5-FU X 2 +



Radiation



72.3% (5 y OS) P = .002
n=143 Radiation alone 54.2% (5 y OS)
Chan, 2005[35] II-IV n=174 Cisplatin weekly and



Radiation



70.3% (5 y OS) P = .048
n=176 Radiation alone 58.6% (5 y OS)
Radiation Followed by Adjuvant Chemotherapy
Rossi, 1988[50] I-IV n=113 Radiation



Vincristine/cyclophosphamide/Adriamycin X 6



59% (4 y OS) P > .05
n=116 Radiation alone 67% (4 y OS)
Chi, 2002[32] IV n=77 Radiation



Cisplatin/5-FU/leucovorin X 9



61% (5 y OS) P = .5
n=77 Radiation alone 55% (5 y OS)
Neoadjuvant Chemotherapy Followed by Radiation Followed by Adjuvant Chemotherapy
Chan, 1995[35]   n=34 Cisplatin/5-FU X 2



Radiation



Cisplatin/5-FU X 4



80% (5 y OS) P = .1
n=40 Radiation alone 81% (5 y OS)
Concurrent Chemotherapy and Radiation Followed by Adjuvant Chemotherapy
Al-Sarraf, 1998[29] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



78% (3 y OS) P < 0.001
n=92 Radiation alone 47% (3 y OS)
Al-Sarraf, 2002[31] ; 2001[51] III-IV n=93 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P < 0.001
n=92 Radiation alone 37% (5 y OS)
Wee, 2004[37, 38] III-IV n=111 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



67% (5 y OS) P = 0.008
n=110 Radiation alone 49% (5 y OS)
Lee, 2005[39] ; 2010[40] T1-4



N2-3



n=172 Cisplatin X 3 +



Radiation



Cisplatin/5-FU X 3



68% (5 y OS) P = 0.22
n=176 Radiation alone 64% (5 y OS)
Chen, 2013[42] III-IV n=158 1) Cisplatin weekly + radiation



2) Cisplatin/5-FU X 3



72% (5 y OS) P = 0.043
n=158 Radiation alone
62% (5 y OS)
Table 6. Intergroup Study 0099. Subgroup Analysis of 5-Year Overall Survival Based on WHO Types [29]
Treatment WHO I, II, III



(n=147) OS, %



WHO II and III



(n=111, 75) OS, %



WHO I



(n=36, 25%) OS, %



Radiation 37 45 14
Chemoradiation 67 70 59
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