Locally advanced nasopharyngeal carcinoma: Current and emerging treatment strategies

Abstract

Although nasopharyngeal carcinoma (NPC) is a widespread malignant tumor, it is particularly frequent in Southeast Asia. Although T1 tumors can be effectively controlled with exclusive radiotherapy, this treatment modality is insufficient for most NPC patients, who present with locally advanced disease at diagnosis. In fact, for stages ranging from T2b N0 to T4 N3, definitive scientific evidence supports the use of concurrent platinum-based chemotherapy with standard external beam radiotherapy. This treatment approach has shown a statistically significant advantage in terms of overall survival, with respect to radiotherapy alone. Several trials have also investigated the use of neoadjuvant and adjuvant chemotherapy in combination with radiotherapy or chemo-radiotherapy. Platinum compounds, anthracyclines and taxanes are among the chemotherapy agents employed. This review focuses on the clinical results obtained in the field of adjuvant/concurrent/neoadjuvant chemotherapy for locally advanced NPC, for which exclusive concurrent chemo-radiotherapy currently represents the standard treatment approach.

Key Words: Chemotherapy, Nasopharyngeal carcinoma, Radiotherapy, Treatment

INTRODUCTION

Nasopharyngeal carcinoma (NPC), a malignant tumor originating from the epithelium of the nasopharynx, is particularly frequent in Southeast Asia and can be divided into three different histological types, that is, non-keratinizing squamous cell carcinoma, keratinizing squamous cell carcinoma and undifferentiated carcinoma[1]. At diagnosis, most NPC patients have locally advanced disease, which includes stages ranging from T2b N0 to T4 N3 (Table 1).

Table 1 Standard approach to nasopharyngeal carcinoma.

Stage	Denomination	Gold standard therapy
T1-2a N0 M0	Early stage	- IMRT alone - Conventional RT alone
From T2b N0 M0 to T4b N3 M0 also every T N2/3 M0	Locally advanced	- Neoadjuvant platinum-based CT followed by IMRT or CCRT (platinum-based) - Concurrent cDDP and RT
Every T every N M1	Metastatic	- Exclusive CT

RT: Radiotherapy; IMRT: Intensity modulated RT; CCRT: Concurrent chemoradiotherapy; CT: Comptued tomography.

Radiotherapy (RT) can control early stage NPC effectively, yielding an excellent 90%-95% 5-year local control rate in clinical trials. However, radiotherapy alone is not the optimal treatment for patients with locally advanced disease, which is the most frequent clinical presentation at diagnosis, since it yields an unsatisfactory 5-year survival rate of about 50%[2]. For this reason, concurrent platinum-based chemotherapy and radiotherapy has become the standard treatment for locally advanced NPC. While in early stage NPC (T1-2a N0), the addition of chemotherapy to standard radiotherapy has not provided a survival advantage in clinical trials[3], a clear superiority has emerged for concurrent chemoradiotherapy when compared to RT alone in patients with locally advanced disease[4-5].

In locally advanced NPC patients, there are presently few data regarding the use of neoadjuvant/adjuvant chemotherapy, as an alternative to concurrent chemoradiotherapy. The role of neoadjuvant chemotherapy before RT or concurrent chemoradiotherapy is a matter of great interest. In fact, induction chemotherapy is an effective way to control subclinical metastatic foci, especially in patients with lymph node metastasis. Moreover, in some patients with large tumors infiltrating the brain stem, it is often difficult to deliver the total required dose to the clinical target volume (CTV) with preservation of critical tissues. Neoadjuvant chemotherapy is often able to provide objective responses in tumor lesions, which offers the possibility to shrink the CTV and reduce toxicity[6].

Retrospective studies that used RT alone for NPC indicated that local control was closely linked to the radiation dose delivered to target tissues[7-8]. Intensity modulated RT (IMRT) is a special type of conformal RT that creates a high dose volume that is precisely shaped around the target volume in order to minimize the radiation dose delivered to surrounding healthy tissues. Investigators compared dosimetric plans of IMRT with conventional RT techniques and concluded that IMRT provided improved tumor coverage and preservation of normal tissues. The proximity of the nasopharynx to critical normal tissues, such as the brainstem and optic structures, makes it challenging for radiotherapists to deliver the optimal radiation dose to the tumor using conventional conformal RT, and underdosing of affected areas is often necessary to preserve healthy tissues. IMRT for locally advanced NPC spares critical portions of the brain stem and of the parotid glands, avoiding neurologic toxicity and permanent xerostomia, respectively. While IMRT has completely replaced conventional conformal RT and has become the standard practice for early stage NPC, its role in the locally advanced setting is not yet well defined[9].

Intracavitary brachytherapy may be used in patients with residual mass after exclusive upfront radiotherapy, especially in the case of a T2b tumor (parapharyngeal infiltration) at initial diagnosis[10]. The combination of external beam RT followed by endocavitary brachytherapy may play an important role in patients with T2b disease. In this review, the treatment of patients with locally advanced NPC is reviewed and discussed, with a special focus on novel experimental therapeutic options.

ROLE OF EXCLUSIVE CONCURRENT CHEMORADIOTHERAPY

In several phase III trials, radiotherapy with concurrent platinum-based chemotherapy has been compared to standard external beam radiotherapy alone in patients with locally advanced NPC. Concurrent chemo-radiotherapy has shown a statistically significant advantage in terms of survival and response rate when compared with radiotherapy alone, but at the expense of more severe toxicity, mainly mucositis and bone marrow suppression[4,5,11]. Results of a large meta analysis carried out by Zhang et al[12] which included 1608 patients enrolled in seven studies confirmed the superiority of concurrent chemo-radiotherapy with respect to RT alone. Of note, this meta-analysis was the first to include studies conducted in endemic areas only.

Another meta-analysis included 18 trials enrolling a total of 1993 patients from China. A comparison between concurrent chemo-radiotherapy and RT alone showed that concurrent chemo-radiotherapy was able to obtain a 3-year overall survival rate of 68.5%, compared with 56.4% in the RT alone arm[13].

More recently, the association of cisplatin and paclitaxel given concurrently with standard radiotherapy was evaluated in a phase II trial. Thirty-one patients with locally advanced NPC received three-weekly 120 mg/m2 of paclitaxel and 75 mg/m2 of cisplatin concurrently with standard 70 Gy external beam radiotherapy. Three-year overall survival rate was 83.9% and the main grade 3/4 toxicity was neutropenia, reported in 12.9% of patients[14]. Another way of improving the effectiveness of standard concurrent chemo-radiotherapy may be to modify the radiotherapy scheme. In a phase II trial, Jian et al[15] investigated the activity of hyperfractionated radiotherapy and concomitant platinum-based chemotherapy. As a result, three-year overall survival rate was 72%, with 73% of patients showing grade 3 mucositis, 31% of patients experiencing severe weight loss and 15% requiring a feeding tube. In view of such an unfavorable toxicity profile, further investigation in this direction does not seem justified.

IMRT is widely employed as an alternative to conventional RT in NPC patients with stage I-II disease, but its role in association with chemotherapy is still unknown. Lu et al[16] evaluated the feasibility and efficacy of a weekly cisplatin (40 mg/m²/wk) regimen given concurrently with definitive IMRT in twenty-one locally advanced NPC patients, obtaining a good safety profile and an excellent one-year overall survival of 95.5%[17]. In another similar trial, the association of three-weekly cisplatin and weekly cetuximab was employed together with standard IMRT in 100 locally advanced NPC patients. The complete + partial response rate achieved was 100% and the toxicity profile was very low, except for a 64% rate of grade 2 acneiform rash. Clinical studies assessing the efficacy and activity of exclusive concurrent chemo-radiotherapy in locally advanced NPC patients are shown in Table 2.

Table 2 Chemo-radiation trials.

Trial	Phase	Pts	Study design	Main end-point	Results
Lin JC et al[4]	III	284	Exclusive RT alone vs cDDP-5FU + RT	5-year DFS	Experimental arm better (P < 0.0012)
Chan AT et al[5]	III	350	Exclusive RT alone vs cDDP-5FU + RT	2-year PFS	Experimental arm better (P < 0.016)
Zhang L et al[12]	III(m)	1608	Exclusive RT alone vs cDDP based CT + RT	5-year OS	Experimental arm better (P < 0.001)
Yang AK et al[13]	III(m)	1993	Exclusive RT alone vs cDDP based CT + RT	5-year OS	Experimental arm better (P < 0.05)
Lu H et al[17]	II	22	IMRT + cDDP	1 year OS	96%
Ekenel M et al[34]	II	100	IMRT+ cDDP-Cet	ORR	100%

RT: Radiotherapy; IMRT: Intensity modulated RT; CT: Comptued tomography; ORR: Overall response rate; DFS: Disease-free survival.

ROLE OF ADJUVANT CHEMOTHERAPY FOLLOWING CONCURRENT CHEMO-RADIOTHERAPY

The Intergroup-0099 was the first randomized trial to compare concurrent chemo-radiotherapy followed by adjuvant chemotherapy with RT alone[18]. In this study, concurrent chemo-radiotherapy consisted of cisplatin (100 mg/m² every 21 d) for three cycles, followed by adjuvant cisplatin (80 mg/m² on day 1) and 5-fluorouracil (1000 mg/m² on days 1-4 every 4 wk). A clear and statistically significant advantage in the chemo-radiation arm was seen in terms of overall survival, disease-free-survival, locoregional failure rate and time to distant metastases. However, these encouraging results did not translate into a change in clinical practice for many Asian oncologists, in view of the high rate of well differentiated carcinomas enrolled in both treatment arms (about 25%) which does not reflect common clinical practice. Furthermore, a particularly low compliance was reported, with only 55% undergoing adjuvant treatment and a particularly poor survival observed in the RT-alone arm.

A comparison between concurrent chemo-radiotherapy followed by adjuvant chemotherapy and RT alone was performed in 316 locally advanced NPC patients enrolled in a phase III trial conducted by Chen et al[19]. Patients were assigned to receive concurrent chemo-radiotherapy, consisting of a standard radiation dose of 70 Gy plus cisplatin followed by three adjuvant cycles of cisplatin and 5-fluorouracil, or RT alone. Concurrent chemo-radiotherapy plus adjuvant chemotherapy yielded better results with respect to RT alone in terms of survival and activity, at the cost of higher toxicity. Similar results were seen in another phase III trial enrolling only non-keratinizing locally advanced NPC patients randomized to concurrent chemo-radiotherapy followed by adjuvant cisplatin and 5-fluorouracil or to RT alone. In this trial, concurrent chemo-radiotherapy was superior in terms of efficacy but also more toxic than RT alone[20].

Park et al[21] carried out a retrospective analysis in forty-three locally advanced NPC patients treated with concurrent chemo-radiotherapy using cisplatin and 5-fluorouracil followed by adjuvant chemotherapy consisting of three cycles of cisplatin, epirubicin and bleomycin. The overall response rate (ORR) was 95% after concurrent chemo-radiotherapy and 100% after adjuvant therapy. The main toxicities observed were grade 3/4 neutropenia and mucositis occurring during concurrent chemo-radiotherapy.

In a prospective phase II trial conducted by Hu et al[22] fifty-four patients were treated with concomitant weekly paclitaxel and external beam radiation therapy (concurrent chemo-radiotherapy) followed by three cycles of cisplatin (30 mg/m² on days 1-3) and paclitaxel (135 mg/m² on day 1), both given every three weeks. An excellent 100% ORR was obtained after the entire treatment with a complete response (CR) rate of 85%. An acceptable toxicity profile was seen with no grade 3/4 side effects.

In view of the conflicting results reported on the role of adjuvant chemotherapy after concurrent chemo-radiotherapy, it is presently unclear whether the addition of adjuvant therapy may improve the efficacy of concurrent chemo-radiotherapy. Interestingly, a combined analysis of two large studies (NPC-9901 and the NPC-9902) revealed that the dose of cisplatin during the concurrent phase of concurrent chemo-radiotherapy had a significant impact on locoregional control, while additional adjuvant chemotherapy with a fluorouracil-containing combination contributed to improving distant control. Table 3 shows the results of clinical trials assessing the efficacy and/or activity of adjuvant chemotherapy following concurrent chemo-radiotherapy.

Table 3 Adjuvant chemotherapy trials.

Trial	Phase	Pts	Study design	Main end-point	Results
Al-Sarraf M et al[18]	III	147	Exclusive RT alone vs CCRT followed by cDDP-5FU	3-year PFS	Experimental arm better (P < 0.01)
Chen Y et al[19]	III	316	Exclusive RT alone vs CCRT followed by cDDP-5FU	2-year OS	Experimental arm better (P < 0.003)
Lee AW et al[20]	III	348	Exclusive RT alone vs CCRT followed by cDDP-5FU	5-year PFS	Experimental arm better (P < 0.035)
Park KH et al[21]	II	43	cDDP-5-FU + RT followed by cDDP-Epi-Ble CT	ORR	100%
Hu W et al[22]	II	54	w Pac + RT followed by cDDP-Pac CT	ORR	100%
Leung TW et al[10]	II	48	HFRT + cDDP based CT followed by cDDP-5FU CT	3-year DFS	71%

RT: Radiotherapy; CT: Comptued tomography; ORR: Overall response rate; CCRT: Concurrent chemoradiotherapy; DFS: Disease-free survival.

ROLE OF NEOADJUVANT CHEMOTHERAPY FOLLOWED BY CONCURRENT CHEMO-RADIOTHERAPY

The role of neoadjuvant chemotherapy followed by concurrent chemo-radiotherapy or RT is a matter of outstanding interest. Several clinical phase III trials from Western countries have proved that induction chemotherapy based on the administration of cisplatin, 5-fluorouracil and taxanes, may significantly improve treatment outcomes in patients with squamous cell carcinoma of the head and neck. An interesting approach may be to employ the same chemotherapy or a similar regimen in locally advanced NPC patients. Amro et al[23] treated 110 patients with induction cisplatin and epirubicin followed by a radical course of radiotherapy with three cycles of concurrent cisplatin, and obtained encouraging results in terms of safety and effectiveness. Italian investigators used the same treatment schedule in 40 patients and obtained an overall response rate of 100% and a 5-year disease-free survival of 77%[24]. In another Italian phase II study, Ferrari et al[25] treated thirty-four patients with three cycles of neoadjuvant cisplatin and 5-fluorouracil followed by concurrent cisplatin and RT. As a result, the overall response rate obtained was a satisfactory 85.3% and the 3-year overall survival rate was 80%.

In the last five years, taxanes have been employed in several phase II and III clinical trials in patients with squamous cell carcinoma of the head and neck, showing a good activity and manageable toxicity profile. Lu et al[26] carried out a trial to compare two different schedules of induction chemotherapy, namely carboplatin-5-fluorouracil (CF) vs docetaxel-carboplatin (TC). Fifty-eight patients with locally advanced NPC were enrolled and randomized to receive CF or TC induction chemotherapy, both followed by concurrent carboplatin and RT. There was no significant difference in terms of response rate and 1-year survival rate. More grade 3/4 neutropenia events were reported in the TC group than in the CF group, whereas less grade 3/4 thrombocytopenia and emesis occurred with the TC regimen than with the CF regimen. An egyptian study enrolled thirty-six patients who were treated with three cycles of induction paclitaxel (175 mg/m²) and cisplatin (80 mg/m²) given every three weeks, followed by concomitant cisplatin-radiotherapy. The overall response rate after the entire treatment schedule was 89% and the 3-year overall survival was 68%. The main toxicity encountered was grade 3/4 neutropenia which was observed in 25% of patients[27]. Hui et al[28] published the results of a randomized phase II trial in which stage III-IVb NPC patients, not previously treated, were randomly assigned to receive either neoadjuvant docetaxel and cisplatin for two cycles followed by concurrent chemo-radiotherapy, or concurrent chemo-radiotherapy alone. A positive impact on survival was observed, since the 3-year overall survival for the neoadjuvant versus the control arm was 94.1% versus 67.7% (P = 0.012). Bossi et al[29] recently presented data of a study on docetaxel, cisplatin and 5-fluorouracil as induction chemotherapy followed by concomitant cisplatin/RT. After completion of treatment, the ORR was 98%, with a complete response rate of 70%. Other authors showed that the same combination had similar results with a 93% response rate and a median time to progression of 39 months[30]. In a phase II study, induction docetaxel, cisplatin and capecitabine followed by chemo-radiation was tested in 40 patients, and resulted in an ORR of 98% and a complete response rate of 48%[31]. In a phase II clinical study, Bae et al[32] treated thirty-three patients with induction cisplatin (70 mg/m²), 5-fluorouracil (1000 mg/m² in i.c of 4 d) and docetaxel (75 mg/m²) followed by cisplatin (100 mg/m²) and RT. Twenty-seven patients achieved a partial response and five patients a complete response. An excellent ORR of 98% was achieved and the three-year overall survival rate was 86.1%. Nevertheless, a 72.7% rate of grade 2/3 neutropenia and a 9.1% rate of febrile neutropenia were reported. Xie et al[33] administered induction cisplatin (80 mg/m²) and docetaxel (70 mg/m²) to fifty-seven patients and randomized them to receive either concomitant RT and single agent cisplatin (80 mg/m²) or concomitant cisplatin (80 mg/m²) and docetaxel (60 mg/m²) with RT. After completion of treatment, the complete response rates were very similar in both treatment arms (about 93%), but the occurrence of grade 3/4 neutropenia was significantly higher in the concomitant docetaxel, cisplatin and RT group (P > 0.05). In a recent phase II clinical study, fifty-nine locally advanced NPC patients were treated with neoadjuvant cisplatin (75 mg/m²), docetaxel (75 mg/m²) and 5-fluorouracil (500 mg/m² on days 1-5 in i.c) for three cycles, followed by concomitant weekly cisplatin (40 mg/m²) and conventional RT or IMRT. The overall response rate three months after RT was 90.2% and the 1-year overall survival was 100%. The rate of grade 3/4 myelosuppression during induction CT was 55.9% and the corresponding rate during concomitant chemotherapy and RT was 11.9%[6]. More recently, Ekenel et al[34] published the preliminary results of a phase II trial in which patients with locally advanced NPC received induction cisplatin (75 mg/m²) and docetaxel (75 mg/m²) for three cycles, followed by definitive RT and concomitant cisplatin (100 mg/m²). Fifty-nine patients were evaluable and the ORR obtained after RT was 95%. Three-year overall survival was 93% and the treatment was generally well tolerated with a 10% rate of grade 3/4 hematologic toxicity.

In the last three years, a significant effort has been made to incorporate IMRT in treatment protocols for locally advanced NPC. In a phase II study, Lin et al[35]treated a total of 370 patients with locally advanced NPC, with stages ranging from IIb to IV, with induction cisplatin-based chemotherapy followed by exclusive IMRT or the association of IMRT and concomitant cisplatin. Drugs more frequently used in combination with cisplatin were paclitaxel and 5-fluorouracil. With a median follow-up of 31 mo, the three-year disease-free-survival and overall survival were 81% and 89%, respectively. A subgroup analysis revealed that concurrent chemotherapy provided no significant benefit to IMRT but was responsible for higher rates of grade 3/4 toxicities[35]. A recent Italian phase II trial carried out by Palazzi et al[36] enrolled 87 patients with locally advanced NPC and treated them with either conventional RT or with IMRT. Of these patients, 26% received only concurrent cisplatin and the other 74% received both induction and concurrent CT. Three-year disease-free survival (DFS) and overall survival were 82% and 90%, respectively. Interestingly, a multivariate analysis revealed that histology, N-stage, RT-technique and total dose of RT had the strongest independent impact on DFS.

Further clinical trials assessing activity, efficacy and toxicity of the combination of induction taxane-based chemotherapy followed by exclusive IMRT in locally advanced NPC are warranted. At the present time, this treatment strategy is recommended only in experienced centers. Table 4 shows clinical trials assessing the activity and efficacy of neoadjuvant chemotherapy followed by radiation or chemo-radiation.

Table 4 Neoadjuvant chemotherapy trials.

Trial	Phase	Pts	Study design	Main end-point	Results
Al-Amro A et al[23]	II	110	Neo cDDP-Epi and followed by cDDP + RT	ORR	100%
Airoldi M et al[24]	II	30	Neo cbdca-Pac followed by RT + cbdca-Pac	ORR	87%
Ferrari D et al[25]	II	34	Neo cDDP-5FU followed by RT + cDDP	ORR	85.3%
Lu X et al[26]	II	58	Neo cbdca-Tax followed by cbdca + RT (arm A) vs neo cbdca-5FU followed by cbdca + RT (armB)	1-year DFS	no difference between arm A and B
Mosatafa E et al[27]	II	36	Neo cDDP-Pac followed by cDDP-RT	ORR	89%
Hui EP et al[28]	II	65	Neo cDDP-Tax followed by cDDP + RT (arm A) vs cDDP + RT (arm B)	3-year OS	Arm A better than arm B (P < 0.012)
Bossi P et al[29]	II	45	Neo cDDP-Tax-5FU followed by cDDP + RT	ORR	98%
Cho S et al[30]	II	19	Neo cDDP-Tax-5FU followed by cDDP + RT	ORR	93%
Bae WK et al[32]	II	33	Neo cDDP-Tax-5FU followed by cDDP + RT	ORR	99%
Kong L et al[6]	II	52	Neo cDDP-Tax-5FU followed by cDDP + RT	ORR	90.2%
Ekenel M et al[34]	II	59	Neo cDDP-Tax followed by cDDP + RT	ORR	95%
Lin S et al[35]	II	370	Neo cDDP based CT followed by IMRT	3-year OS	90%

RT: Radiotherapy; IMRT: Intensity modulated RT; CT: Comptued tomography; ORR: Overall response rate; DFS: Disease-free survival.

CONCLUSION

This review reported in detail the available clinical data regarding the use of chemotherapy in combination with radiotherapy for locally advanced NPC. Although several cytotoxic agents have been used both in the neoadjuvant and adjuvant setting with promising results, exclusive concurrent chemo-radiotherapy remains the recommended approach at the present time, as additional evidence is required to support the use of chemotherapy in the adjuvant/neoadjuvant setting.