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Keywords:

  • nasopharyngeal carcinoma (NPC);
  • gemcitabine;
  • paclitaxel;
  • docetaxel;
  • oxaliplatin;
  • capecitabine;
  • irinotecan

Abstract

  1. Top of page
  2. Abstract
  3. THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?
  4. CHEMOTHERAPY IN METASTATIC DISEASE
  5. CONCLUSIONS AND RECOMMENDATIONS
  6. REFERENCES

BACKGROUND

Recent advances in the treatment of nasopharyngeal carcinoma (NPC) have transpired into better treatment outcomes for patients with locoregionally advanced NPC, and have broadened the chemotherapeutic options for patients with metastatic disease.

METHODS

Data for this review were identified through searches of articles published in PubMed, MEDLINE, and abstracts from selected conference proceedings up to 2004.

RESULTS

The results of two meta-analyses and at least six randomized trials supported a survival benefit with the use of concurrent chemotherapy (e.g., platinum, tegafur-uracil [UFT)] and standard fractionated radiotherapy (with or without adjuvant chemotherapy) in the management of patients with locoregionally advanced NPC (nonmetastatic Stage III/IV disease, according to the staging system of the International Union Against Cancer). For those patients with metastatic NPC, platinum-based doublets using newer agents such as gemcitabine and the taxanes are reported to be better tolerated and can yield response rates comparable to those obtained with older, multidrug regimens.

CONCLUSIONS

The current study reviewed the latest literature and pertinent issues concerning the role of chemotherapy in the treatment of patients with metastatic and locoregionally advanced NPC. Cancer 2005. © 2004 American Cancer Society.

Nasopharyngeal carcinoma (NPC) is endemic to Southern China, North Africa, and parts of the Mediterranean basin. The prevalence is reported to be highest in Southern China, where, on average, 80 cases per 100,000 population are reported each year,1 with nonkeratinizing, poorly differentiated, and undifferentiated (World Health Organization [WHO] types 2 and 3)2 being the most common subtypes of NPC. These subtypes differ from WHO type 1 NPC with regard to their heightened sensitivity to chemotherapy and association with the Epstein–Barr virus (EBV) in > 90% of cases.1 The prognosis of patients with metastatic disease is reported to be poor, with a median survival of < 12 months. Likewise, patients with locoregionally advanced NPC (i.e., American Joint Committee on Cancer/International Union Against Cancer [AJCC/UICC] Stage III and Stage IV disease) are reported to have a 5-year survival rate of only 40% despite treatment with standard radiotherapy (RT), with the majority of patients dying of distant recurrences (Figure 1).3 This article examines the pertinent issues and latest studies concerning the incorporation of chemotherapy as part of the armamentarium against locoregionally advanced and metastatic NPC.

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Figure 1. Overall Kaplan–Meier survival curve of patients with advanced nasopharyngeal carcinoma based on American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) stage of disease. Reprinted with permission from Cooper JS, Cohen R, Stevens RE. A comparison of staging systems for nasopharyngeal carcinoma. Cancer. 1998;83:213–219.

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THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?

  1. Top of page
  2. Abstract
  3. THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?
  4. CHEMOTHERAPY IN METASTATIC DISEASE
  5. CONCLUSIONS AND RECOMMENDATIONS
  6. REFERENCES

The integration of chemotherapy with standard RT in the treatment of patients with nonmetastatic Stage III/IV NPC is based on the following rationale/hypotheses: 1) to minimize the risk of distant recurrence through eradication of micrometastases; 2) to use chemotherapy as a radiosensitizer; and 3) to facilitate planning of RT and to improve local disease control by reducing the tumor volume prior to RT. Two recently presented meta-analyses have demonstrated a survival advantage for the addition of chemotherapy to RT compared with RT alone in the treatment of patients with locoregionally advanced NPC. Huncharek et al. pooled together data from 6 randomized trials (1500 patients) published in the English database between 1988–2002 and analyzed the impact of adding chemotherapy to RT at any sequence.4 An improvement in progression-free survival of 34% and in overall survival of 20% at 4 years was reported.

Another more comprehensive meta-analysis evaluated published data from 78 randomized trials (9279 patients; breakdown according to AJCC/UICC stage of disease was not presented). This analysis compared the impact on patient survival of adding chemotherapy to RT at any sequence. Published studies from both English and non-English databases were selected according to the quality of the randomization procedure, the use of intention-to-treat analysis, and the completeness of follow-up.5 Presented in an abstract form, this analysis found that concurrent chemoradiation improves 5-year overall survival by an odds ratio of 0.68 (95% confidence interval [95% CI], 0.46–0.99), and that concurrent chemoradiation followed by adjuvant chemotherapy improves the 5-year disease-free and overall survival rates with an odds ratio of 0.30 (95% CI, 0.16–0.55) and 0.30 (95% CI, 0.17–0.53), respectively.

In these meta-analyses, the survival benefit was predominantly observed with concurrent chemoradiation using platinum-based agents, whereas to our knowledge the benefit of induction and adjuvant chemotherapy remains unclear. This observation is strengthened further by the recently presented positive results of several randomized trials that favor the strategy of concurrent chemoradiation.6–8

Concurrent Chemoradiation for Locoregionally Advanced NPC

To our knowledge to date, 6 randomized trials have been published in the English database over the past 6 years, with the majority demonstrating a superiority of concurrent cisplatin plus RT over RT alone in terms of survival or locoregional control among patients with locoregionally advanced NPC (Table 1). The Intergroup 0099 study was to our knowledge the first to demonstrate a 31% improvement in 3-year overall survival with concurrent high-dose cisplatin (100 mg/m2, every 3 weeks) and RT, followed by adjuvant cisplatin plus 5-fluorouracil (5-FU), compared with RT alone.9 However, this trial has been criticized for the unexpectedly poor survival rate reported in the RT arm compared with the historic control arm. Furthermore, it is difficult to extrapolate this result to countries outside the U.S. because only 45% of patients in the study had undifferentiated histology compared with > 90% of patients from endemic countries. Compliance with adjuvant chemotherapy was suboptimal with only 55% of patients completing treatment as planned. Nevertheless, this trial is pivotal with regard to its influence on the standard of practice in the U.S. for this category of patients.10

Table 1. Randomized Trials of Chemoradiation in Patients with Locally Advanced NPC
ReferenceYear of publicationNo.Stage of diseaseTreatment armsResult (all stages)
 CRT %RT %P-value
  • NPC: nasopharyngeal carcinoma; CRT: chemoradiation; RT: radiotherapy; Gy: grays; PFS: progression-free survival; OS: overall survival; C: cisplatin; adj: adjuvant; 5-Fu: 5-fluorouracil; muco: mucositis; Tegafur-Uracil:; B: bleomycin; M: methotrexate; V: vinblastine; FFS: failure-free survival; DM: distant metastases; DFS: disease-free survival; LCR: local control rate.

  • a

    Abstract only.

Al-Sarraf et al.91998147III–IVRT, total 70 Gy3-yr PFS6924< 0.001
    RT + C (100 mg/m2, every 3 wks) for 3 cycles [RIGHTWARDS ARROW] adj C + 5-FU3-yr OS78470.005
Grade 3–4 muco37.127.9
Chan et al.112002 (update 2004a)350II–IIIRT, total 66 Gy5-yr OS70.358.60.048
    RT + C (40 mg/m2/week)5-yr PFS60.252.10.059
     Grade 3–4 muco48.935.8
Lin et al.132003284III–IVRT, total 70–74 Gy; some patients received altered fractionation.5-yr PFS71.653.00.001
    RT + C + 5-FU (Days 1–4) for 2 cycles5-yr OS72.354.20.002
Grade 3–4 muco45.435
Kwong et al.82004219II–IIIRT, total 70 Gy.3-yr OS86.576.80.06
    RT + UFT3-yr FFS69.357.80.14
    RT + UFT [RIGHTWARDS ARROW] adj C + 5-FU-B-M-V    
RT [RIGHTWARDS ARROW] adj C + 5-FU-B-M-VGrade 3–4 muco46.424.8
Wee et al.72004a221III–IVRT, total 66 Gy.2-yr DFS76620.1
    RT + C (25 mg/m2/day on Days 1–4) [RIGHTWARDS ARROW] adj C + 5-FU2-yr OS85770.02
Grade 3–4 muco7538
Lee et al.62004a348T1-4RT, total 66 Gy3-yr PFS69610.24
   N2-3RT + C (100 mg/m2, every 3 wks) [RIGHTWARDS ARROW] adj C + 5-FU3-yr OS76770.76
LCR93820.01
     Grade 3–4 muco6346

Two Asian studies with a design similar to the Intergroup 0099 study have been completed and the results recently were presented as abstracts. Wee et al. attempted to confirm the results of the Intergoup 0099 study and randomized 221 patients with nonmetastatic Stage III/IV NPC to undergo RT, with or without concurrent cisplatin administered over 4 days at a dose of 25 mg/m2/day every 3 weeks.7 An 8% (P = 0.02) improvement in the overall survival rate and a trend toward a 14% (P = 0.1) improvement in the disease-free survival rate was observed at 2 years, affirming the findings of the Intergroup 0099 study. Compliance with chemotherapy in this trial was as challenging as in the Intergroup study, such that 40% of patients required a dose reduction or omission during concurrent cisplatin therapy, and 58% did not receive the planned adjuvant chemotherapy at the full dose. In the second study by Lee et al., patients were treated with a chemotherapy schedule that was identical to that of the Intergroup 0099 study.6 At a median follow-up of 25 months, a significant improvement in the 3-year locoregional control rate (93% vs. 82%; P = 0.01) and a trend toward an absolute improvement of 8% in the 3-year progression-free survival rate (P = 0.24) was reported, favoring the chemoradiation arm. It is interesting to note that the incidence of Grade 3 and Grade 4 mucositis in the chemoradiation arm encountered in these Asian studies (75% with Grade 3 mucositis only and no Grade 4 mucositis in the study by Wee et al.7 and 63% of patients with Grade 3 mucositis in the study by Lee et al.6) significantly exceeded that reported by the Intergroup 0099 study (37.1%). Therefore, longer follow-up is needed before definitive conclusions can be drawn from these Asian studies with regard to long-term survival and the late toxicities of chemoradiation.

To our knowledge, the largest and the most mature Asian Phase III data published to date are derived from the study of Chan et al. in Hong Kong.11 To improve the treatment compliance rate and ease of administration, an outpatient regimen of weekly low-dose cisplatin (40 mg/m2/week without adjuvant chemotherapy) was combined with RT in the treatment of patients with AJCC/UICC Stage II to Stage IV NPC. At the time of this study's first publication, a 7% improvement in the 2-year progression-free survival was noted, with the benefit being more pronounced among patients with T3 and T4 disease.11 In a recent update with a median follow-up of 5.5 years, a borderline significant 13% improvement in overall survival (P = 0.048) and a nonsignificant trend of a 10% improvement in progression-free survival (P = 0.059) was reported favoring the chemoradiation arm for all disease stages. This improvement reached statistical significance in patient subgroups with T3 to T4 disease (the hazard ratio [HR] for overall survival was 0.51, with a 95% CI, 0.30–0.87 [P = 0.014]; and the HR for progression-free survival was 0.53, with a 95% CI, 0.33–0.88 [P = 0.014]).12

In a published Taiwanese trial of 284 patients with Stage III/IV NPC, RT alone was compared with RT with concurrent cisplatin and infusional 5-FU given for 2 cycles.13 Heterogeneity in RT delivery was noted because 14% of the patients were treated with hyperfractionated accelerated RT whereas the majority of patients received standard RT, which was delivered by a telecobalt unit or modern linear accelerator. Furthermore, there was a slight predominance of patients with Stage IV disease in the RT alone arm (84.6% vs. 75.9%). At a median follow-up of > 5 years, an improvement of 18.1% was noted in both the 5-year overall and progression-free survival rates, thus favoring the chemoradiation arm. The addition of 5-FU to cisplatin during RT did not appear to significantly increase the incidence of Grade 3 to Grade 4 mucositis (45.4%) or neutropenia (4.3%) compared with studies by the Intergroup and Chan et al.,9, 11 which used cisplatin alone.

Using a 2 × 2 factorial randomized trial design, Kwong et al. addressed the question of whether a nonplatinum agent (UFT) can achieve results that are comparable to concurrent treatment with cisplatin and RT, and whether adjuvant chemotherapy is of value.8 Unlike the abovementioned studies, split-course RT was used in 30–35% of patients in the study by Kwong et al.8 The investigators described nonsignificant improvements in the 3-year overall and failure-free survival rates favoring the chemoradiation arm, without any improvement reported with regard to the rates of distant or local recurrence. This negative result might be due to the study being underpowered from a poor accrual rate, because only 63% of the target sample size was attained over 6 years of accrual.

The randomized trials discussed earlier share similar characteristics in terms of demonstrating a better treatment outcome with concurrent chemoradiation, at the expense of a higher incidence of acute mucosal and hematologic toxicities. Although the benefit observed applied principally to survival endpoints, it could not be explained entirely by improvements in local or distant disease control because only some studies reported a decrease in the rates of locoregional recurrence,6, 13 and distant recurrence.7, 13 Another notable observation is that the margin of benefit reported by Chan et al.11 appeared to be much smaller when compared with that reported by the Intergroup 0099 study and Lin et al.9, 13 This might have resulted from a “dilutional” effect by Chan et al.11 of including patients with Stage II disease because these patients enjoy a better prognosis, even when treated with RT alone. Another explanation is that the weekly cisplatin schedule used by Chan et al.11 could not achieve the same dose intensity as the 3-weekly high-cisplatin schedule used in the other trials. Despite these differences, the types of salvage treatment and the incidence of Grade 3–4 mucositis (range, 50–64%) were comparable in the studies by the Intergroup 0099, Chan et al., and Lin et al.9, 11, 13

In summary, concurrent chemoradiation should be adopted as the standard therapy for medically fit patients with Stage III/IV NPC. In the future, investigators should adequately report the incidence of late toxicities of concurrent chemoradiation (e.g., neurologic and otologic). In addition, efforts should be focused on evaluating novel and less toxic agents that can potentiate the antitumor effect of RT without exacerbating toxicities to normal tissues. For example, concurrent RT with cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has been evaluated recently in patients with locoregionally advanced, non-NPC head and neck malignancies with promising results. Compared with the use of RT alone, concurrent cetuximab and RT was reported to result in a 13% advantage in the 3-year survival without significantly increasing the incidence of RT-related Grade 3–4 mucositis.14 Such strategy may be applicable to NPC given its high prevalence of tumoral EGFR expression15 and the known activity of cetuximab in patients with metastatic NPC.

Induction Chemotherapy

Compared with studies on adjuvant chemotherapy, Phase II trials regarding induction chemotherapy described better patient tolerance and treatment compliance, as well as a high locoregional response of 72–100%.13, 16–20 Despite these promising results, none of the five randomized trials we studied demonstrated an overall survival advantage for all disease stages with this approach compared with RT alone (Table 2).21–25 Some of the postulated explanations include the potentially detrimental effect of RT interruptions because of toxicities from induction chemotherapy, and accelerated repopulation of viable tumor clones occurring during the treatment break before the initiation of RT.26 Nevertheless, these randomized studies should be interpreted with caution because some were underpowered,21, 25 and the majority used older and more toxic regimens such as the combination of cisplatin, bleomycin, and epirubicin. It is interesting to note that two of these studies reported a trend toward better recurrence-free survival with the use of induction chemotherapy among subgroups with advanced N classified disease.23, 24 This is supported by an update on pooled data from 2 previously reported Phase III studies totaling 784 patients.23, 24 In this analysis, the use of induction chemotherapy resulted in an absolute improvement of 8.2% in the recurrence-free survival rate (P = 0.014) and 5.4% in the disease-specific survival rate (P = 0.029) over 5 years.27

Table 2. Randomized Trials of Induction Chemotherapy
ReferenceYear of publicationSample sizeTreatment armsDFSOS
  1. DFS: disease-free survival; OS: overall survival; RT: radiotherapy; C: cisplatin; 5-FU: 5-fluorouracil; adj: adjuvant; chemo: chemotherapy; NS: not significant; B: bleomycin; E: epirubicin.

Chan et al.21199577RTNSNS
   C + 5-FU [RIGHTWARDS ARROW] RT [RIGHTWARDS ARROW] adj chemo  
Roussy221996339RTNS
   CBE [RIGHTWARDS ARROW] RT  
Chua et al.231998286RT3-yr 46%NS
   CE for 2–3 cycles [RIGHTWARDS ARROW] RT3-yr 58% 
Ma et al.242001449RT5-yr 49%NS
   CB + 5-FU for 3 cycles 3 [RIGHTWARDS ARROW] RT5-yr 59% 
Hareyama et al.25200280RTNSNS
   C + 5-FU for 2 cycles [RIGHTWARDS ARROW] RT  

More recently, investigators expanded the concept of induction therapy by combining it with chemoradiation rather than using RT alone. Newer agents such as paclitaxel,28 the “ECF” regimen (epirubicin, cisplatin, and infusional 5-FU),29 interferon,30 docetaxel,31, 32 and gemcitabine33 have all been evaluated. Chan et al. used the combination of carboplatin and paclitaxel followed by cisplatin given concurrently with RT in 31 patients with Stage III/IV NPC. Although treatment tolerance was reported to be good, local response to induction chemotherapy was only 16% compared with 58% in the regional lymph nodes. Nevertheless, the 2-year overall survival and progression-free survival rates were promising at 91.8% and 78.5%, respectively.28 In this study, in which plasma EBV DNA was evaluated as a response monitoring tool, 78% of patients demonstrated a serologic response as indicated by a decrease in levels to ≤ 500 copies/mL after induction therapy.28

Docetaxel also has been tested with promising results. Johnson et al. reported a 88% response rate (2 complete responses) to 3 cycles of docetaxel (80 mg/m2) and carboplatin (area under the dose response curve [AUC] of 6 mg/mL/minute) administered every 3 weeks in 18 patients with Stage III/IV NPC, followed by RT or chemoradiation.31 Similarly, Yamouni et al. treated 75 patients with Stage IV NPC with 3 cycles of 3-times weekly cisplatin (75 mg/m2) and docetaxel (75 mg/m2) prior to RT, with a response rate of 89% (37% complete responses).32 Within these 2 studies, the incidence of Grade 3–4 neutropenia appeared to be higher with the combination of carboplatin and docetaxel (51%)31 compared with the cisplatin and docetaxel combination (12%).32

Rischin et al. used the ECF regimen prior to concurrent chemoradiation in predominantly Asian patients with Stage III/IV NPC.29 In their study, the overall tumor response rate was 86% as assessed by magnetic resonance imaging (MRI) and computed tomography (CT). Despite using a lower total RT dose (60 grays) than most studies, the 3-year overall and progression-free survival rates (94% and 88%, respectively) were excellent for this cohort compared with historic data (Table 1). In a third study that took 9 years to complete, a combination of cisplatin, 5-FU, leucovorin, and –interferon-α-2b were given prior to treatment with concurrent 5-FU and hydroxyurea and RT. In this study, 37% of the patients had squamous cell histologic type, in contrast to the studies by Chan et al. and Rischin et al., in which 85–100% of patients had poorly or undifferentiated subtypes.28, 29 The overall survival rates at 3 years and 5 years were 88% and 77%, respectively, rates which are comparable to those of the other 2 studies.30

The role of induction therapy remains controversial. Prompted by the encouraging results reported by Chan et al.28 and Rischin et al.,29 a randomized Phase II trial recently was completed at the current study center that compared concurrent chemoradiation with or without induction taxane-based chemotherapy. Results are expected to be presented by early 2005.

Adjuvant Chemotherapy

To our knowledge, only two randomized trials to date have specifically compared RT alone with or without adjuvant chemotherapy.34, 35 Rossi et al.34 randomized 229 patients with nonmetastatic NPC (some had T1 or N0 disease) to undergo RT with or without adjuvant treatment with the combination of vincristine, doxorubicin, and cyclophosphamide for 6 months. No survival benefit was observed.34 Similarly, no benefit was reported in an Asian trial that randomized 157 patients with Stage IV NPC to undergo RT, with or without 9 cycles of adjuvant cisplatin, 5-FU, and leucovorin.35 In light of the lack of benefit with adjuvant chemotherapy as reported in the 2 × 2 factorial study by Kwong et al.8 and the meta-analysis performed by Thephamongkhol et al.,5 it is possible that the concurrent component as opposed to the adjuvant component of the Intergroup 0099 study accounted for the observed survival benefit. Poor patient compliance to adjuvant chemotherapy also limits its broader application.

CHEMOTHERAPY IN METASTATIC DISEASE

  1. Top of page
  2. Abstract
  3. THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?
  4. CHEMOTHERAPY IN METASTATIC DISEASE
  5. CONCLUSIONS AND RECOMMENDATIONS
  6. REFERENCES

Older Agents–Singles or Combination

Platinum chemotherapy is a cornerstone in the management of metastatic NPC, and both cisplatin and carboplatin are reported to have a respective response rate of 28% and 22%, respectively.1 Studies performed in the 1980s have shown that platinum-based combinations result in higher response rates (approximately 50–90%, with complete response rates of 5–30%) compared with monotherapy or nonplatinum therapy (e.g., the combination of ifosfamide, 5-FU, and leucovorin36) (Table 3). Of these combinations, cisplatin and −5-FU is a popular first-line regimen for metastatic NPC in Asian centers, and in Phase II trials, cisplatin (at a dose of100 mg/m2) administered together with a 3-day to 5-day infusion of 5-FU (at a dose of 1 g/m2) reportedly yielded a response rate of 66–78% with a median survival of 11 months.37, 38

Table 3. Newer Agents and Platinum-Based Doublets in Metastatic NPC
ReferenceYear of publicationSample sizeRegimenOR (%)CR (%)
  1. NPC: nasopharyngeal carcinoma; OR: overall response; CR: complete response; C: cisplatin; 5-FU: 5-fluorouracil; I: ifosfamide; carbo: carboplatin; pac: paclitaxel; doce: docetaxel.

Wang and Tan37199125C + 5-FU768
Au and Ang38199424 6613
Stein et al.62199618C + I5915
Yeo et al.63199642Carbo + 5-FU3817
Yeo et al.45199827Carbo + pac5911
Tan et al.46199932Carbo + pac753
McCarthy et al.4920029C + doce220
Foo et al.53200225 pretreatedGemcitabine284
  27 untreated 483.7
Ngan et al.54200244C + G7320
Poon et al.57200430Irinotecan170

In the 1990s, multidrug (three or more agents) combinations were used to optimize treatment response (Table 4). Although the reported response rates were impressive in some Phase II studies, toxicities were significant with reports of septic deaths. Durable response rates reaching 80% (complete response rate of 20%) were reported in 1 European study using a combination of cisplatin, bleomycin, and 5-FU,39 but this was not confirmed by an Asian study that reported a 36% rate of Grade 3 or 4 neutropenia that was complicated by 3 septic deaths.40 Three additional studies that used 4–5 drugs in combination reported response rates between 52–86%, associated with a sharp increase in the incidence of Grade 3 to 4 neutropenia in > 80% of patients and treatment-related death rates of up to 9%.41–43 Nevertheless, the reported response rates were no better than those obtained with platinum-based triplets, as outlined in Table 4. Nonhematologic toxicities such as bleomycin-related lung fibrosis,41–43 cardiotoxicity from epirubicin,43 and radiation recall from mitomycin43 also were found to be problematic.

Table 4. Platinum-Based Combination with ≥ 3 Agents
ReferenceYear of publicationSample sizeRegimenOR (%)CR (%)Toxic deaths
  1. OR: overall response; CR: complete response; C: cisplatin; B: bleomycin; 5- FU: 5-fluorouracil; LV: leucovorin; CAPABLE: cyclophosphamide, bleomycin, doxorubicin, cisplatin, and methotrexate; E: epirubicin; M: mitomycin; Carbo: carboplatin; G: gemcitabine; pac: paclitaxel.

Boussen et al.39199149C + B + 5-FU7919
Su et al.40199325C + B + 5-FU403Yes
Chi et al.64199435C + 5-FU + LV80–10013–15
Siu et al.42199890CAPABLE40–866–22Yes
Taamma et al.41199926C + B + E + 5-FU7835Yes
Hasbini et al.43199944C + E + 5-FU + M5213Yes
Leong et al.55200333Carbo + G + pac7612Yes

Taken together, the impressive response rates observed with combination chemotherapy using older agents in patients with metastatic NPC has not appeared to significantly improve survival. Durable responses can be noted with doublets as well as the more toxic multidrug combinations. Furthermore, the significant toxicity observed cannot justify the use of these multidrug combinations within the clinical context of palliation for metastatic NPC.

Newer Agents–Taxanes, Gemcitabine, Capecitabine, Oxaliplatin, and Irinotecan

Taxanes

Paclitaxel is active alone or in combination with platinum in the first-line or second-line treatment of patients with metastatic NPC. As monotherapy, doses of 135–175 mg/m2 given every 3 weeks are well tolerated with a reported response rate of 22% and a response duration of 7.5 months.44 When combined with carboplatin (AUC of 6 mg/mL/minute), paclitaxel at a dose of 135–175 mg/m2 reportedly yielded a response rate of 60–72% (complete response rate of 3–11%) and a median time to disease progression of approximately 7 months in the first-line setting.45, 46, 47 Attempts to dose-escalate paclitaxel have only been found to exacerbate toxicity.46 In another study, carboplatin (AUC of 7 mg/mL/minute) and paclitaxel (at a dose of 200 mg/m2) were given using growth factor support. Response rate (57%) and time to disease progression (4.3 months)48 did not appear to exceed that of more conventional doses of carboplatin and paclitaxel as described.45

As discussed earlier, docetaxel has activity as induction chemotherapy31; however, to our knowledge, experience with this agent in patients with metastatic NPC has been disappointing. A Phase II trial of docetaxel (at a dose of 75 mg/m2) and cisplatin (at a dose of 75 mg/m2) as first-line therapy was prematurely terminated because of modest activity and 100% Grade 3–4 neutropenia.49

Capecitabine

Capecitabine is an oral fluoropyrimidine with an efficacy similar to infusional 5-FU in the treatment of colon carcinoma. In the preliminary report of a Phase II trial, Chinese patients with platinum-refractory advanced NPC were treated with capecitabine (at a dose of 1250 mg/m2 twice daily) in a 3 times weekly cycle. The overall response rate was 24%, with a median time to disease progression of 5 months. Hematologic toxicities were mild except that Grade 1–2 hand-foot syndrome was common (59%).50 Capecitabine has been evaluated concurrently with RT in a Phase I study published in the Chinese language database. Diarrhea and hand-foot syndrome were dose-limiting, and the recommended Phase II dose was 1700 mg/m2/day for 14 days at a 3 times weekly schedule.51

Gemcitabine

To our knowledge, there are retrospective and Phase II data supporting the use of gemcitabine alone or in combination with cisplatin in metastatic NPC. In a retrospective review of 32 patients, 35% of predominantly platinum-refractory patients with metastatic NPC responded to gemcitabine alone. Of those who were chemotherapy-naïve and treated with cisplatin and gemcitabine, the response rate was reported to be 64%. Tolerance was reported to be good among patients with poor performance status.52

In the Phase II setting, 52 Asian patients with metastatic NPC were given gemcitabine at a dose of 1250 mg/m2 on Days 1 and 8, every 21 days, with an overall response rate of 28% reported in the chemotherapy-naïve group and 48% in the pretreated group. Although toxicity was minimal, response was not durable and the median time to disease progression was found to be 3–5 months.53 In another Phase II trial by Ngan et al.,54 44 Chinese patients with metastatic NPC (54% of whom had received prior platinum therapy) were treated with gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at a dose of 50 mg/m2 on Days 1 and 8, every 28 days. An impressive response rate of 73% (complete response rate of 20%) was observed, a finding that was comparable to that reported with older, multidrug combinations. The median duration of response was 5.3 months with a 1-year survival rate of 64%, whereas 78% of the patients experienced an improvement in cancer-related symptoms.54

Leong et al.55 explored the merits of a platinum-based triplet using carboplatin (AUC of 5 mg/mL/minute) on Day 1, and on Day 1 and 8 paclitaxel (at a dose of 70 mg/m2), and gemcitabine (at a dose of 100 mg/m2). Presented in an abstract, an overall response rate of 76% was observed, similar to that reported by Ngan et al. with a cisplatin-gemcitabine doublet.53 Hematologic toxicity with this triplet was severe with Grade 3–4 neutropenia reported to affect 83% of the patients, complicated by 1 septic death.55

Oxaliplatin

Oxaliplatin is a third-generation platinum that is reported to have far fewer renal and ototoxicity complications than cisplatin. To our knowledge, its efficacy in NPC is limited and only one randomized Phase II study has been reported in abstract form to date, comparing RT with or without concurrent oxaliplatin in 77 patients with Stage III/IV NPC.56 Oxaliplatin was given at a dose of 70 mg/m2 on a weekly schedule for 6 cycles, and more patients in the oxaliplatin and RT arm experienced Grade 1–2 nausea and emesis and neuropathy compared with the RT arm. At the study center, a Phase II study of oxaliplatin and gemcitabine given on a biweekly schedule for the treatment of metastatic NPC currently is underway.

Irinotecan

In a Phase II trial of 25 evaluable patients with metastatic undifferentiated NPC who developed disease progression within 3 months of treatment with platinum-based and/or taxane-based chemotherapy, irinotecan was given at a dose of 100 mg/m2 on Days 1, 8, and 15, every 28 days.57 Preliminary results reported 4 partial responses (17%) and toxicity was mild.

CONCLUSIONS AND RECOMMENDATIONS

  1. Top of page
  2. Abstract
  3. THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?
  4. CHEMOTHERAPY IN METASTATIC DISEASE
  5. CONCLUSIONS AND RECOMMENDATIONS
  6. REFERENCES

Platinum-based chemotherapy is an integral part of treatment for patients with advanced NPC, whether in the metastatic or curative setting. Although a high response rate can now be achieved in the metastatic setting thanks to more tolerable, modern agents such as gemcitabine and taxanes, a therapeutic plateau appears to have been reached because patient survival remains poor and the majority of patients invariably become refractory to chemotherapy. Future research should focus on biologic agents that can overcome resistance to, or potentiate the efficacy of, chemotherapy without exacerbating toxicity. For example, our team has shown that cetuximab, the monoclonal antibody against EGFR, enhances the cytotoxic effect of platinum and paclitaxel in NPC cell lines.58 We have also shown in a Phase II study that the addition of cetuximab to carboplatin in patients with platinum-refractory metastatic NPC has clinical benefit.59

For patients with locoregionally advanced NPC, there is now substantial evidence supporting the use of concurrent chemoradiation as the standard treatment, and the challenge now is to explore means of minimizing distant recurrences and RT-related toxicities to normal tissues. This may involve the broader application of intensity-modulated RT and the identification of molecular predictors of response to chemoradiation, as well as augmenting the efficacy of RT with biologic agents such as cetuximab60 or the hypoxic cytotoxin, tirapazamine.61 Further studies also are needed to validate plasma EBV DNA as a tool with which to assess early response to induction chemotherapy or residual disease after RT.

REFERENCES

  1. Top of page
  2. Abstract
  3. THE ROLE OF CHEMOTHERAPY IN LOCOREGIONALLY ADVANCED NPC–HOW TO BEST INCORPORATE CHEMOTHERAPY WITH RADIOTHERAPY?
  4. CHEMOTHERAPY IN METASTATIC DISEASE
  5. CONCLUSIONS AND RECOMMENDATIONS
  6. REFERENCES
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