Abstract

Background

Capecitabine monotherapy had activity in recurrent/metastatic nasopharyngeal carcinoma (NPC) as demonstrated previously in a small pilot study. We conducted a retrospective review of patients who received capecitabine for recurrent and metastatic NPC to further evaluate its clinical benefits.

Methods

Forty-nine patients with recurrent and metastatic NPC received capecitabine at a dose of 1–1.25 G/m2 twice daily for 14 days in 3-week cycles. Disease sites were locoregional in 29%, distant in 45% and locoregional plus distant in 26%. All except one had prior platinum-based chemotherapy for relapse or as adjunctive treatment. Median follow-up was 10 months (range: 3–41).

Results

Treatment was generally well tolerated. Hand-foot syndrome was common and occurred in 86% (25% Grade 3). Grade 3 hematological toxicity occurred in 6%. Partial response rate was 31% (95% CI: 18%, 44%) and complete response rate was 6% (95% CI: 0%, 13%), for an overall response rate of 37% (95% CI: 23%, 50%). Median time-to-progression was 5 months and median survival was 14 months. One- and two-year survival rates were 54 and 26%, respectively. Significantly better survival was observed in patients treated for locoregional recurrence and those with severe hand-foot syndrome.

Conclusions

Capecitabine has single agent activity in NPC and severe hand-foot syndrome predicts favorable outcome. Based on our experience, capecitabine monotherapy should be considered in patients with recurrent/metastatic NPC.

INTRODUCTION

Nasopharyngeal carcinoma (NPC) is highly responsive to chemotherapy and effective palliation of symptoms, and prolongation of survival can often be achieved after chemotherapy for recurrent and metastatic disease with occasional observation of long-term survivors after treatment (1,2). Platinum-based chemotherapy regimens are among the most effective regimens for NPC and they are often used as first-line chemotherapy for recurrent or metastatic disease. For those with disease recurrence or progression after prior platinum-based chemotherapy, there is no standard second-line chemotherapy although several regimens have been reported to achieve a response rate of 29–56% in platinum-pretreated patients (3–5). In patients who received multiple lines of chemotherapy, toxicity became a major issue and the identification of active regimen with a favorable toxicity profile is important.

Capecitabine is a novel oral tumor-activated and -elective fluoropyramidine carbamate. The drug exploits the significantly higher thymidine phosphorylase activity of malignant cells as compared with healthy cells for preferential conversion of capecitabine to 5-fluorouracil in malignant cells. The selective tumor-activation of capecitabine allows continuous tumor exposure to 5-fluorouracil while reducing side effects by reducing exposure of normal tissues to the drug. The convenience of oral administration provides an added advantage. We have previously conducted a Phase II trial using capecitabine in 17 patients with recurrent or metastatic NPC pretreated with platinum-based chemotherapy, and we observed a response rate of 23.5% with a median time-to-progression of 4.9 months (6). On the basis of the results of this trial, capecitabine monotherapy was used as palliative chemotherapy for advanced NPC in our institution. To further explore the efficacy of capecitabine and to identify possible predictive factors of response, we conducted a retrospective review of the outcome of our patients who received capecitabine for recurrent or metastatic NPC.

PATIENTS AND METHODS

Between January 2004 and December 2006, 49 patients received capecitabine monotherapy for recurrent and/or metastatic NPC at Queen Mary Hospital. The ratio of male to female was 2.3:1, and the median age was 46. All patients except one, who refused intravenous chemotherapy, had previously received platinum-based chemotherapy as adjunctive treatment or palliative treatment for relapse. Disease sites were local and/or regional in 29%, distant only in 45% and locoregional plus distant in 26%. About 22% of patients received capecitabine as first-line chemotherapy for relapse, 45% as second-line and 33% as ≥third-line treatment. Table 1 summarizes the patient and disease characteristics.

Table 1.

Characteristics of patients who received capecitabine for recurrent and/or metastatic nasopharyngeal carcinoma

Gender (n 
 Male 34 (69%) 
 Female 15 (31%) 
Age (years)  
 Median 46 
 Range 29–2 
Karnofsky performance score  
 Median 75 
 Range 60–100 
No. of relapse (n 
 First relapse 31 (63%) 
 Second relapse 15 (31%) 
 Third relapse 3 (6%) 
Relapse pattern (n 
 Locoregional 14 (29%) 
 Distant 22 (45%) 
 Locoregional and distant 13 (26%) 
Previous chemotherapy received (n 
 Platinum 48 (98%) 
 Taxane 10 (20%) 
 Gemcitabine 11 (22%) 
 Ifosfamide 14 (29%) 
 5-fluorouracil 38 (78%) 
No. of chemotherapy regimens received (n 
 One 24 (49%) 
 Two 21 (43%) 
 ≥ three 3 (6%) 
Gender (n 
 Male 34 (69%) 
 Female 15 (31%) 
Age (years)  
 Median 46 
 Range 29–2 
Karnofsky performance score  
 Median 75 
 Range 60–100 
No. of relapse (n 
 First relapse 31 (63%) 
 Second relapse 15 (31%) 
 Third relapse 3 (6%) 
Relapse pattern (n 
 Locoregional 14 (29%) 
 Distant 22 (45%) 
 Locoregional and distant 13 (26%) 
Previous chemotherapy received (n 
 Platinum 48 (98%) 
 Taxane 10 (20%) 
 Gemcitabine 11 (22%) 
 Ifosfamide 14 (29%) 
 5-fluorouracil 38 (78%) 
No. of chemotherapy regimens received (n 
 One 24 (49%) 
 Two 21 (43%) 
 ≥ three 3 (6%) 

Capecitabine was administered orally at a dose of 1–1.25 G/m2 twice daily in 3-week cycles consisting of 2 weeks of treatment followed by rest period of 1 week. Thirty-seven patients (75.5%) received capecitabine at a standard dose of 1.25 G/m2 twice daily. Since a high proportion of patients treated with the standard dose developed severe hand-foot syndrome requiring dose modification, the starting dose of capecitabine was subsequently reduced to 1 G/m2 twice daily and 12 patients were treated using the reduced dose. In the event of severe hand-foot syndrome, capecitabine dose was modified as follows: no dose change for Grade 1 toxicity; for Grade 2 toxicity, no dose change at first occurrence of event, 25% dose reduction at second occurrence and 50% dose reduction at third occurrence; for Grade 3 toxicity, 25% dose reduction at first occurrence of event and 50% dose reduction at second occurrence. Treatment was interrupted when patient developed Grade 2–3 hand-foot syndrome and resumed after resolution of toxicity to Grade 0–1.

Complete blood picture and serum biochemistry were routinely tested before each cycle. Patients were assessed for toxicity before each cycle of treatment. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 3.0. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors by imaging before treatment, after third and sixth cycles, and thereafter every 3–4 cycles. Patients who had treatment discontinued but without disease progression had follow-up imaging at 2 and 4 months after treatment and every 3–4 months thereafter. Treatment was continued until disease progression, presence of unacceptable toxicity, or patient refusal.

All patients were included in efficacy and safety analysis. The following endpoints were used in the evaluation of efficacy: response rate, progression-free survival (PFS) and overall survival (OS). PFS and OS probabilities were calculated by the Kaplan–Meier method. Time-to-progression was calculated from the date of first dose of capecitabine to the date of documented progression or most recent follow-up in patients without disease progression. Survival time was calculated from the date of first dose of capecitabine to the date of death or most recent follow-up for surviving patients. Univariate analysis was performed to study the predictive value of different variables on PFS and OS, using log rank test to compare the differences between actuarial curves. Response rates among different subgroups were compared using chi-square test or Fisher's exact test as appropriate. A value of P < 0.05 was considered to be statistical significant.

RESULTS

Treatment Outcome

Patients received 1–10 cycles of capecitabine with a median of four cycles. Median follow-up time was 10 months (range: 3–41). Treatment was discontinued in 16 patients (33%) due to disease progression. In the remaining 33 patients (67%), treatment was discontinued in the absence of disease progression due to patient decision, either because of lack of further response or financial issue since capecitabine cost was not covered by the hospital budget. Best response to capecitabine was complete response in three patients (6%; 95% confidence interval (CI): 0%, 13%), partial response in 15 patients (31%; 95% CI: 18%, 44%), stable disease in 21 patients (43%; 95% CI: 29%, 57%) and progressive disease in 10 patients (20%; 95% CI: 9%, 32%). Overall response (OR: complete + partial) rate was 37% (95% CI: 23%, 50%). OR rate according to disease sites was 46% for local disease, 36% for regional disease and 31% for distant metastases. PFS rate was 37% at 6 months and 9% at 12 months (Fig. 1), with a median time-to-progression of 5 months. OS rate was 54% at 1 year and 26% at 2 years (Fig. 2), with a median survival of 14 months.

Figure 1.

Progression-free survival curve in recurrent and metastatic nasopharyngeal carcinoma patients treated with capecitabine.

Figure 1.

Progression-free survival curve in recurrent and metastatic nasopharyngeal carcinoma patients treated with capecitabine.

Figure 2.

Overall survival curve in recurrent and metastatic nasopharyngeal carcinoma patients treated with capecitabine.

Figure 2.

Overall survival curve in recurrent and metastatic nasopharyngeal carcinoma patients treated with capecitabine.

Toxicity of Treatment

Treatment was generally well tolerated. Table 2 summarizes the toxicity of capecitabine treatment. Hematological toxicity was mild with only three patients developing Grade 3 toxicity (6%), including Grade 3 anemia in two patients and Grade 3 thrombocytopenia in one patient. The most common non-hematological toxicity was hand-foot syndrome, which occurred in 42 patients (86%), with Grade 3 toxicity in 12 patients (25%), despite the use of prophylactic topical emollient creams and pyridoxine at a dose of 100 mg/day. Patients with hand-foot syndrome were treated with topical emollient creams +/− antibiotic creams. Thirteen patients (27%) had dose modification during treatment, all due to hand-foot syndrome. There was no significant difference in the percentage of patients, who developed severe hand-foot syndrome using a starting dose of 1.25 or 1 G/m2 (58 versus 57%), and the percentage of patients with dose modification was similar with a starting dose of 1.25 or 1 G/m2 (25 versus 27%). Not all patients with Grade 2–3 hand-foot syndrome had dose modification due to unwillingness of some patients to have their treatment dose reduced. Although the incidence of hand-foot syndrome was high, none of our patients had treatment discontinued due to this toxicity alone. None of the patients developed any Grade 4 toxicity and there were no treatment-related deaths.

Table 2.

Summary of toxicity of capecitabine treatment in patients with nasopharyngeal carcinoma

 Number of patients 
 Grade 0 Grade 1 Grade 2 Grade 3 
Anemia 33 
Neutropenia 39 
Thrombocytopenia 44 
Diarrhea 42 
Stomatitis 36 11 
Hand-foot syndrome 14 16 12 
Nausea 35 12 
Vomiting 42 
Fatigue 35 10 
Rash 47 
 Number of patients 
 Grade 0 Grade 1 Grade 2 Grade 3 
Anemia 33 
Neutropenia 39 
Thrombocytopenia 44 
Diarrhea 42 
Stomatitis 36 11 
Hand-foot syndrome 14 16 12 
Nausea 35 12 
Vomiting 42 
Fatigue 35 10 
Rash 47 

Additional Treatment After Capecitabine

Sixteen patients (33%) received further intravenous chemotherapy after discontinuation of capecitabine, usually at the time when disease progression was documented. The remaining 33 patients (67%) did not receive further chemotherapy after capecitabine and were put on supportive care only.

Predictive Factors of Treatment Outcome

Treatment outcome was analysed according to different disease and treatment factors and the results were summarized in Table 3. No significant difference in OR rate was observed among patients treated for different relapse patterns. Both PFS and OS rates were, however, significantly better in those treated for locoregional recurrence only (Fig. 3). No significant difference in OR and OS rates was observed among patients who received capecitabine as first, second or greater than or equal to third-line of chemotherapy for relapse, but PFS rate was lower when capecitabine was used as first-line treatment for relapse. No significant difference in treatment outcome was observed in patients with and without prior treatment with 5-fluorouracil. Patients with Grade 2–3 hand-foot syndrome had significantly better OR and OS rates than those with Grade 0–1 toxicity (Fig. 4). Treatment outcome in patients treated with the reduced starting dose of capecitabine was not significantly different from those treated with the standard dose.

Figure 3.

Comparison of overall survival curves in recurrent and metastatic nasopharyngeal carcinoma patients with different relapse pattern.

Figure 3.

Comparison of overall survival curves in recurrent and metastatic nasopharyngeal carcinoma patients with different relapse pattern.

Figure 4.

Comparison of overall survival curves in recurrent and metastatic nasopharyngeal carcinoma patients with and without severe hand-foot syndrome to capecitabine.

Figure 4.

Comparison of overall survival curves in recurrent and metastatic nasopharyngeal carcinoma patients with and without severe hand-foot syndrome to capecitabine.

Table 3.

Summary of treatment outcome according to disease and treatment factors

 Overall response rate Progression-free survival rate (6-month) Overall survival rate (1-year) 
Gender    
 Male (%) 41 38 52 
 Female (%) 27 36 57 
P value 0.33 0.54 0.45 
Age    
  ≤ 45 (%) 33 26 52 
  > 45 (%) 40 48 54 
P value 0.63 0.26 0.80 
Relapse pattern    
 Locoregional only (%) 50 62 79 
 Distant only (%) 32 36 45 
 Locoregional + distant (%) 31 15 40 
P value 0.48 0.023 0.014 
Capecitabine as    
 First-line Rx (%) 36 18 53 
 Second-line Rx (%) 23 34 45 
 ≥ third-line Rx (%) 56 63 65 
P value 0.11 0.040 0.44 
Prior 5-fluorouracil Rx    
 Yes (%) 32 41 46 
 No (%) 55 27 80 
P value 0.29 0.33 0.46 
Hand-foot syndrome    
 Grade 0/1 (%) 19 33 32 
 Grade 2/3 (%) 50 40 71 
P value 0.026 0.13 0.002 
Capecitabine dose    
 2 G/m2 daily (%) 25 31 57 
 2.5 G/m2 daily (%) 41 39 53 
P value 0.49 0.68 0.35 
 Overall response rate Progression-free survival rate (6-month) Overall survival rate (1-year) 
Gender    
 Male (%) 41 38 52 
 Female (%) 27 36 57 
P value 0.33 0.54 0.45 
Age    
  ≤ 45 (%) 33 26 52 
  > 45 (%) 40 48 54 
P value 0.63 0.26 0.80 
Relapse pattern    
 Locoregional only (%) 50 62 79 
 Distant only (%) 32 36 45 
 Locoregional + distant (%) 31 15 40 
P value 0.48 0.023 0.014 
Capecitabine as    
 First-line Rx (%) 36 18 53 
 Second-line Rx (%) 23 34 45 
 ≥ third-line Rx (%) 56 63 65 
P value 0.11 0.040 0.44 
Prior 5-fluorouracil Rx    
 Yes (%) 32 41 46 
 No (%) 55 27 80 
P value 0.29 0.33 0.46 
Hand-foot syndrome    
 Grade 0/1 (%) 19 33 32 
 Grade 2/3 (%) 50 40 71 
P value 0.026 0.13 0.002 
Capecitabine dose    
 2 G/m2 daily (%) 25 31 57 
 2.5 G/m2 daily (%) 41 39 53 
P value 0.49 0.68 0.35 

Rx, treatment.

DISCUSSION

Chemotherapy remains an important palliative treatment for recurrent and/or metastatic NPC. Although no randomized trial comparing different chemotherapy regimens in NPC has ever been reported, platinum/5-fluorouracil combination was commonly employed due to the high response rate observed in chemotherapy-naïve patients. Combined chemo-radiotherapy has now been accepted as standard treatment for locoregionally advanced NPC, and many centers also routinely offer chemo-radiotherapy for patients with Stage II disease. As a consequence, most patients with recurrent or metastatic disease nowadays have already been pretreated with platinum in the adjunctive setting. For these patients, as well those who progressed after prior platinum-based chemotherapy, there is no agreement on standard chemotherapy regimen that should be used. Taxane- or gemcitabine-based doublet combination was commonly employed, with reported response rate of 22–75% in the former (3,7–9) and 36–75% in the latter (5,10,11), but hematological toxicity was common and dose-limiting.

Palliative chemotherapy using triplet or more combination has also been explored. In one report, combination of cyclophosphamide, doxorubicin, cisplatin, methotrexate and bleomycin was used for chemotherapy-naïve NPC patients (12). The response rate in patients with recurrence and metastatic disease was 41 and 80%, respectively. The corresponding median survival was 16 and 14 months. Toxicity was, however, severe with 41% patients requiring admission for management of toxicity and treatment-related deaths occurred in 11%. In another report, combination of paclitaxel, carboplatin and gemcitabine was used in 32 metastatic NPC patients and yielded a response rate of 78%, but Grade 3–4 neutropenia was common and occurred in 78% of patients (13).

Single agent chemotherapy other than platinum was generally considered to be of limited benefit in NPC. In heavily pretreated patients, single agent chemotherapy is likely to be more tolerable and acceptable to patients. Agents, such as mitoxantrone (14) and irinotecan (15), have been studied but the response rate was low. Even when the active agent gemcitabine was used alone, the response rate appears to be lower than that of the combination regimen containing the same drug (16). A Phase II study using capecitabine alone as palliative chemotherapy in pretreated NPC patients was conducted by us previously, and a response rate of 23.5% was observed. The current report represents our experience of using capecitabine in routine clinically setting, and the response and survival rates observed were similar to our previous report.

Most of our patients found capecitabine to be convenient and tolerable. Hand-foot syndrome, however, was common and the toxicity had significant impact on patient compliance, although it was reversible and always improved after dose interruption and modification. Owing to the relatively mild toxicity, capecitabine can actually be administered for prolonged cycles in the absence of disease progression. In the current series, most patients had treatment discontinued in the absence of disease progression, and it is uncertain whether prolonged treatment can further improve the outcome.

Our observation of improved outcome in patients treated for locoregional recurrence only was likely due to the different clinical course in this group compared with patients treated for distant metastases. Similar to the findings of our previous Phase II trial, we also observed the association of response to capecitabine with severe hand-foot syndrome in the current series. This association was not related to capecitabine dose or treatment duration, as most patients developed the worst reaction by the end of third cycles before assessment of response. In view of the observed association of severe hand-foot syndrome and subsequent tumor response, it is important to reassure patient and not to discontinue treatment prematurely if severe toxicity occurs early in the course of treatment.

Table 4 summarizes the results of using different chemotherapy regimens for recurrent and metastatic NPC reported in the literature. Although one should be careful in making direct comparison of these results due to different patient and disease characteristics, the data listed are in agreement with clinical experience. Capecitabine monotherapy compares favorably with other chemotherapy regimens in terms of efficacy, even if majority of our patients did not receive further chemotherapy after capecitabine and almost all were platinum pretreated. On the other hand, resistant clones are more likely to emerge early with single agent than combination chemotherapy, patients with newly diagnosed relapse should benefit more from combination chemotherapy as initial treatment. The significantly poorer PFS rate, when capecitabine was used as first-line treatment observed in our study, suggests that capecitabine should be reserved for second- or third-line treatment for recurrent/metastatic NPC, and combination chemotherapy should be employed instead as first-line treatment.

Table 4.

Summary of reported response rate and treatment outcome after chemotherapy using different regimens for recurrent/metastatic NPC

Authors Chemotherapy Response rate (%) Median progression-free survival Median survival 
Yeo et al. (3) Paclitaxel/carboplatin 59 6.0 months 13.9 months 
Tan et al. (7) Paclitaxel/carboplatin 75 7.0 months 12.0 months 
McCarthy et al. (9) Docetaxel/cisplatin 22 8.4 months not reported 
Chua et al. (8) Docetaxel/cisplatin 63 5.6 months 12.4 months 
Ngan et al. (5) Gemcitabine/cisplatin 73 10.6 months 15 months 
Chua et al. (10) Gemcitabine/cisplatin 75 not reported not reported 
Wang et al. (11) Gemcitabine/vinorelbine 36 5.6 months 11.9 months 
Foo et al. (15) Gemcitabine (chemotherapynaïve) 28 3.6 months 7.2 months 
Foo et al. (15) Gemcitabine (pretreated) 48 5.1 months 10.5 months 
Dugan et al. (14) Mitoxantrone 25 2.7 months 13.0 months 
Poon et al. (16) Irinotecan 17 3.9 months 11.4 months 
Current report Capecitabine 37 5 months 14 months 
Authors Chemotherapy Response rate (%) Median progression-free survival Median survival 
Yeo et al. (3) Paclitaxel/carboplatin 59 6.0 months 13.9 months 
Tan et al. (7) Paclitaxel/carboplatin 75 7.0 months 12.0 months 
McCarthy et al. (9) Docetaxel/cisplatin 22 8.4 months not reported 
Chua et al. (8) Docetaxel/cisplatin 63 5.6 months 12.4 months 
Ngan et al. (5) Gemcitabine/cisplatin 73 10.6 months 15 months 
Chua et al. (10) Gemcitabine/cisplatin 75 not reported not reported 
Wang et al. (11) Gemcitabine/vinorelbine 36 5.6 months 11.9 months 
Foo et al. (15) Gemcitabine (chemotherapynaïve) 28 3.6 months 7.2 months 
Foo et al. (15) Gemcitabine (pretreated) 48 5.1 months 10.5 months 
Dugan et al. (14) Mitoxantrone 25 2.7 months 13.0 months 
Poon et al. (16) Irinotecan 17 3.9 months 11.4 months 
Current report Capecitabine 37 5 months 14 months 

NPC, nasopharyngeal carcinoma.

In summary, this retrospective study confirmed the findings of our previous Phase II trial about the single agent activity of capecitabine in recurrent and metastatic NPC. Presence of severe hand-foot syndrome predicts good response and better survival after treatment. Combining capecitabine with other chemotherapeutic agents may further improve the efficacy and is worth investigating. Two multi-center Phase II studies testing the combination of capecitabine plus cisplatin and capecitabine plus oxaliplatin in recurrent and metastatic NPC are currently being conducted in Asian regions. Based on our experience, capecitabine monotherapy should be considered in patients with recurrent and/or metastatic NPC after prior treatment with other chemotherapy regimens.

Conflict of interest statement

None declared.

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