Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two
http://www.100md.com
▲還散笫雖悝◎
the Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
Department of Radiation Oncology & Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, Guangzhou, China
ABSTRACT
PATIENTS AND METHODS: The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat.
RESULTS: The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms.
CONCLUSION: The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.
INTRODUCTION
Of the three previously reported randomized phase III studies comparing induction chemotherapy followed by RT (CRT) with RT alone in NPC, two studies were conducted in Asia using a similar study design. The first study,9 reported in 1998, was a multicenter trial conducted by Asian Oceania Clinical Oncology Association (the AOCOA trial). The second study,10 reported in 2001, was a single-center trial conducted by investigators in Guangzhou, China (the Guangzhou trial). Both studies used two to three cycles of cisplatin-based induction chemotherapy in the study arm, with a similar radiation technique and treatment dose. The AOCOA trial reported a 7% improvement in survival at 3 years favoring the chemotherapy arm, but the difference did not achieve statistical significance. A similar 7% of absolute improvement in survival at 5 years was also reported by the Guangzhou trial; the difference also was not statistically significant. Both the AOCOA and Guangzhou trials were designed to detect a 15% improvement of survival with the addition of chemotherapy, and hence did not have sufficient power to detect a smaller improvement in survival. To better define the role of induction chemotherapy in NPC, the investigators of these two trials conducted a pooled data analysis to look for any significant improvement in treatment outcome with CRT compared with RT alone.
PATIENTS AND METHODS
There were equal numbers of patients allocated to the CRT and RT arms. Patients in the CRT arm received two to three cycles of chemotherapy followed by RT. The induction chemotherapy consisted of cisplatin 100 mg/m2 day 1, bleomycin 10 mg/m2 days 1 and 5, and fluorouracil 800 mg/m2 days 1 to 5, or cisplatin 60 mg/m2 day 1 and epirubicin 110 mg/m2 day 1, repeated every 21 days. Patients received two to three cycles of chemotherapy depending on the response and tolerance. RT was given to the nasopharynx and neck using megavoltage radiation, and the median dose to nasopharynx was 70 Gy. Treatment compliance was 92.6% in the CRT arm and 98% in the RT arm. Table 2 summarizes the patient and disease characteristics, and no significant difference in the distribution of pretreatment characteristics was observed in the two arms (Table 2).
Updated individual patient data of the two trials were collected and merged together for analysis. The median follow-up time for all patients was 51 months (range, 1 to 157 months), and for surviving patients it was 67 months. The end points examined were disease-specific survival, overall survival, relapse-free survival, locoregional relapse-free survival, and distant metastasis每free survival. The survival end points were analyzed and estimated using the product-limit method of Kaplan and Meier. The significance of differences between survival curves was estimated by log-rank test. Hazard ratios and CIs were estimated for various end points. Disease-specific survival was measured from the date of random assignment to the date of patient death or to the last date the patient was known to be alive.
In determining disease-specific survival, deaths as a result of uncontrolled disease or treatment-related complications were both counted as events, whereas deaths as a result of intercurrent disease were regarded as censored observations. In determining overall survival, deaths as a result of all causes were counted as events. Relapse-free survival was measured from the date of random assignment to the date of first documented relapse in any site, or to date of recent follow-up if no relapse had occurred. Patients who were given salvage therapy successfully for relapse were still considered to have experienced treatment failure at the time of event occurrence. In patients with residual disease after RT, relapse-free survival was counted as zero. Other end points were similarly measured from the date of random assignment to the time of event occurrence, or to date of recent follow-up if no event had occurred. Analysis was performed on the basis of intention to treat.
RESULTS
The combined results also showed a significant reduction in cancer-related deaths associated with the use of chemotherapy (P = .029; Fig 4), with a hazard ratio of 0.78 (95% CI, 0.62 to 0.98). The 20.5% relative reduction in the overall risk of cancer-related deaths is equivalent to an absolute improvement of disease-specific survival of 5.4% at 5 years and 10.4% at 7 years. The 5-year disease-specific survival rates in the CRT and RT arm were 63.5% and 58.1%, respectively, and the corresponding 7-year rates were 59.6% and 49.2%, respectively. Examination of the disease-specific survival curves of the two arms (Fig 4) indicates that the curves started to separate from approximately 12 months onward; the separation continued to increase and is more marked after 72 months.
When deaths as a result of all causes were counted, a similar trend in survival favoring the CRT arm was observed, but the difference was smaller and did not achieve statistical significance. The 5-year overall survival rates in the CRT and RT arms were 61.9% and 58.1%, respectively, and the corresponding 7-year rates were 57.2% and 48% (P = .092; Fig 5), respectively, with a hazard ratio of 0.83 (95% CI, 0.66 to 1.03). The discrepancy in observed difference between overall and disease-specific survival was related to the more frequent intercurrent deaths in the CRT arm compared with the RT arm (2.6% v 0.5%). In the CRT arm, four deaths were the result of late infection, two deaths were the result of a cerebrovascular accident, one death was the result of lung cancer, and three deaths were the result of other medical illness. In the RT arm, one death was the result of cerebrovascular accident and one death was the result of late infection. Most of the intercurrent deaths occurred at 5 years or later after treatment, and none of these patients had documented relapse at the time of death.
DISCUSSION
The improvement in disease-specific survival in the CRT arm was due to reduced risks of both locoregional relapse and distant metastases. The improvement in locoregional control after induction chemotherapy is not surprising given the high response rate to induction chemotherapy obtained before RT. The reduced risk of distant metastases in the CRT arm can be attributed not only to early eradication of micrometastases but also to enhanced locoregional control,16 as shown by the reduced number of patients with isolated distant metastases and those with locoregional relapse followed by distant failure. The latter failure pattern is reflected in the late occurrence of distant metastases in the RT arm, with 19% of distant metastases occurring beyond 3 years compared with 11% in the CRT arm.
The addition of induction chemotherapy to RT has not been shown to improve survival in head and neck squamous cell carcinoma. One explanation for the lack of survival benefit is the effectiveness of salvage surgery for locoregional treatment failures after chemoradiotherapy for head and neck cancers. Local failures of NPC, conversely, are less amenable to surgical salvage, and reirradiation is more commonly used instead. With the exception of small-volume and early-stage recurrence, results after reirradiation generally are poor.17每19 Given that advanced local failure of NPC carries a poor prognosis and locoregional failure itself predisposes to distant metastases, maximizing the chance of local control during primary treatment is important and crucial to patient survival. With the observed high response rate to induction chemotherapy, it is not unexpected to see improved locoregional control because of enhanced cytotoxicity of radiation and the substantial regression of tumor bulk before RT. Randomized trials have indeed reported improved locoregional control with induction chemotherapy,8每10 although earlier studies failed to observe any impact on survival. Our pooled data analysis showed that induction chemotherapy improved locoregional control, which was in turn translated to long-term disease-specific survival benefits in advanced-stage NPC.
Three large randomized phase III studies comparing CRT versus RT alone in NPC have been reported.8每10 Of these, two9,10 were included in the current pooled data analysis. The third study,8 conducted by the International Nasopharynx Cancer Group, compared three cycles of cisplatin, epirubicin, and bleomycin followed by RT with RT alone in 339 patients with N2-3 NPC. In a recent updated report of that study,20 no significant difference in overall survival was observed in the two arms after a median follow-up of 74 months, although disease-free survival was better in the CRT arm (41% v 30% at 6 years). Patients in the CRT arm had a high percentage of treatment-related death (8%) and aggressive chemotherapy was commonly given to patients in the RT arm after treatment failure; both of these factors may offset the survival benefit observed in the study arm. Compared with the International Nasopharynx Cancer Group trial, the chemotherapy regimens used in the AOCOA and Guangzhou trials were better tolerated, with only one chemotherapy-related death, although only 72% of patients in CRT arm in the former trial and 32% in the latter completed all three cycles of induction chemotherapy.
In the recent years, concurrent chemoradiotherapy has emerged as the treatment of choice for locoregionally advanced NPC, largely due to the positive findings of the Intergroup 0099 trial, which was the first randomized trial to demonstrate survival benefit with the use of chemotherapy in NPC.12 The Intergroup trial used three cycles of cisplatin concurrent with RT, followed by three cycles of adjuvant chemotherapy using cisplatin and fluorouracil in advanced-stage NPC. That study reported an absolute improvement of survival of 31% at 3 years with the addition of chemotherapy, and the estimated hazard ratio was 2.5. In a recent updated report,21 the 5-year survival rate was 67% in the concurrent chemoradiotherapy arm and 37% in the RT arm. There are, however, major concerns in extrapolating the findings of the Intergroup study to patient groups in the Asia context where NPC is endemic. Such cautions are quite legitimate in view of the high proportion of patients with WHO type I histology (24%) in the Intergroup study compared with predominant WHO type II to III histology in endemic areas, a high proportion of ineligible patients, and the inferior treatment outcomes in the control arm of the Intergroup study when compared with treatment results reported in the endemic areas. In addition, the relative contributions of concurrent and adjuvant chemotherapy cannot be determined from the Intergroup study and remain unclear.
After the publication of the results of the Intergroup study, three randomized trials conducted in Asia comparing concurrent chemoradiotherapy with or without adjuvant chemotherapy with RT alone in advanced-stage NPC have been reported.13,14,22 One trial used weekly cisplatin during RT in patients with advanced nodal disease and reported no significant difference in progression-free survival after a median follow-up of 2.7 years; the impact on survival was not analyzed because of the lack of events.22 Another randomized trial used two cycles of cisplatin and fluorouracil concurrent with RT showed improved survival compared with RT alone, with an absolute improvement of survival of 20% at 5 years.13 These two trials tested the role of concurrent chemotherapy only and did not include any adjuvant treatment. A third trial designed to evaluate the relative importance of concurrent chemotherapy using tegafur plus uracil and adjuvant chemotherapy using cisplatin plus fluorouracil alternating with vincristine plus bleomycin plus methotrexate was reported recently.14 That study used a 2 x 2 factorial design with patients randomly assigned to concurrent chemoradiotherapy versus RT alone, followed by adjuvant chemotherapy versus no treatment. The results showed that concurrent chemotherapy significantly improved failure-free and overall survival, whereas adjuvant chemotherapy did not improve outcome. These results suggest that concurrent chemoradiotherapy plays a major role in contributing toward improved outcome in advanced-stage NPC, although the optimal scheduling and regimens remain to be defined. The role of adjuvant chemotherapy is difficult to evaluate because of the low compliance rate observed in many trials, especially after concurrent chemoradiotherapy. Conversely, it may be easier to administer additional chemotherapy cycles as induction rather than adjuvant treatment when combining them with concurrent chemoradiotherapy, with the added benefit of rapid tumor shrinkage before RT.23
Contrary to the initial observation of lack of survival benefit, this pooled data analysis showed long-term benefits in terms of relapse-free and disease-specific survival associated with induction chemotherapy in advanced-stage NPC. On the basis of our study and the published results, there is strong evidence that the addition of chemotherapy to RT is associated with a significantly improved outcome in NPC. A recent literature-based meta-analysis of 1,528 patients from six randomized trials has demonstrated a significant improvement in disease-free survival with the use of chemotherapy even if the results of Intergroup trial were excluded.24 Although no formal studies comparing induction chemotherapy and concurrent chemoradiotherapy have been reported, the improvement in survival appears to be less with induction chemotherapy than that with concurrent chemoradiotherapy, and hence our findings should not change the current recommendation of using concurrent chemoradiotherapy in advanced-stage NPC. Induction chemotherapy using one of the study regimens from the current analysis followed by RT may be considered as an alternative option in patients who refused concurrent chemoradiotherapy because of its associated toxicities. Induction chemotherapy may also be combined with concurrent chemoradiotherapy to improve the treatment outcome in advanced-stage NPC and should be studied in future trials.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank the following investigators for their contributions to this study: Tahir Azhar (Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia); Vircharn Lorvidhaya, Yupa Sumitsawan, Sumityra Thongprasert (Department of Radiology, Chaingmai University, Chiangmai, Thailand); Visoot Vootiprux, Supatra Sangruchi (Department of Radiation Oncology, Siriraj Hospital, Bangkok, Thailand); Arkom Cheirsilpa (National Cancer Institute, Bangkok Thailand); Ary Reksodiputro, Averdin Roezin, Abidin Widjanarko (Cipto General Hospital, Jakarta, Indonesia).
NOTES
Both D.T.T.C. and J.M. contributed equally to this manuscript.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Bachouchi M, Cvitkovic E, Azli N, et al: High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin, and cisplatin before radiotherapy. J Natl Cancer Inst 82:616每620, 1990
2. Dimery IW, Peters LJ, Goepfert H, et al: Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 11:1919每1928, 1993
3. Garden AS, Lippman SM, Morrison WH, et al: Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma Results of treatment in the era of computerized tomography. Int J Radiat Oncol Biol Phys 36:1005每1012, 1996
4. Hong RL, Ting LL, Ko JY, et al: Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:4305每4313, 2001
5. Prasa U, Wahid MI, Jalaludin MA, et al: Long-term survival of nasopharyngeal carcinoma patients treated with adjuvant chemotherapy subsequent to conventional radical radiotherapy. Int J Radiat Oncol Biol Phys 53:648每655, 2002
6. Rossi A, Molinari R, Boracchi P, et al: Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: Results of a 4-year multicenter randomized study. J Clin Oncol 6:1401每1410, 1988
7. Chan ATC, Teo PML, Leung TWT, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569每577, 1995
8. International Nasopharynx Cancer Study Group: VUMCA I Trial: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV (≡N2, M0) undifferentiated nasopharyngeal carcinoma〞A positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 35:463每469, 1996
9. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83:2270每2283, 1998
10. Ma J, Mai H, Hong M, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:1350每1357, 2001
11. Chi KH, Chang YC, Guo WY, et al: A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 52:1238每1244, 2002
12. Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310每1317, 1998
13. Lin JC, Jan JS, Hsu CY, et al: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: Positive effect on overall and progression-free survival. J Clin Oncol 21:631每637, 2003
14. Kwong DL, Sham JS, Au GK, et al: Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: A factorial study. J Clin Oncol 22:2643每2653, 2004
15. American Joint Committee on Cancer: Manual for Staging of Cancer (5th ed). Philadelphia, PA, JB Lippincott, 1997
16. Kwong D, Sham J, Choy D, et al: The effect of loco-regional control on distant metastatic dissemination in carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 30:1029每1036, 1994
17. Pryzant RM, Wendt CD, Delclos L, et al: Re-treatment of nasopharyngeal carcinoma in 53 patients. Int J Radiat Oncol Biol Phys 22:941每947, 1992
18. Lee AW, Law SC, Foo W, et al: Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976每1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 26:773每782, 1993
19. Chua DT, Sham JS, Kwong DL, et al: Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379每386, 1998
20. El Gueddari B: Final results of the VUMCA I randomized trial comparing neo-adjuvant chemotherapy (CT) (BEC) plus radiotherapy (RT) to RT alone in undifferentiated nasopharyngeal carcinoma (UCNT). Proc Am Soc Clin Oncol 17:385a, 1998 (abstr 1482)
21. Al-Sarraf M, LeBlanc M, Giri PG, et al: Superiority of 5-year survival with chemoradiotherapy vs. radiotherapy in patients with locally advanced nasopharyngeal cancer: Intergroup 0099 phase III study〞Final report. Proc Am Soc Clin Oncol 20:227a, 2001 (abstr 905)
22. Chan AT, Teo PM, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in loco-regionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20:2038每2044, 2002
23. Rischin D, Corry J, Smith J, et al: Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 20:1845每1852, 2002
24. Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: Results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25:219每223, 2002(Daniel T.T. Chua, Jun Ma,)
Department of Radiation Oncology & Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, Guangzhou, China
ABSTRACT
PATIENTS AND METHODS: The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat.
RESULTS: The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms.
CONCLUSION: The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.
INTRODUCTION
Of the three previously reported randomized phase III studies comparing induction chemotherapy followed by RT (CRT) with RT alone in NPC, two studies were conducted in Asia using a similar study design. The first study,9 reported in 1998, was a multicenter trial conducted by Asian Oceania Clinical Oncology Association (the AOCOA trial). The second study,10 reported in 2001, was a single-center trial conducted by investigators in Guangzhou, China (the Guangzhou trial). Both studies used two to three cycles of cisplatin-based induction chemotherapy in the study arm, with a similar radiation technique and treatment dose. The AOCOA trial reported a 7% improvement in survival at 3 years favoring the chemotherapy arm, but the difference did not achieve statistical significance. A similar 7% of absolute improvement in survival at 5 years was also reported by the Guangzhou trial; the difference also was not statistically significant. Both the AOCOA and Guangzhou trials were designed to detect a 15% improvement of survival with the addition of chemotherapy, and hence did not have sufficient power to detect a smaller improvement in survival. To better define the role of induction chemotherapy in NPC, the investigators of these two trials conducted a pooled data analysis to look for any significant improvement in treatment outcome with CRT compared with RT alone.
PATIENTS AND METHODS
There were equal numbers of patients allocated to the CRT and RT arms. Patients in the CRT arm received two to three cycles of chemotherapy followed by RT. The induction chemotherapy consisted of cisplatin 100 mg/m2 day 1, bleomycin 10 mg/m2 days 1 and 5, and fluorouracil 800 mg/m2 days 1 to 5, or cisplatin 60 mg/m2 day 1 and epirubicin 110 mg/m2 day 1, repeated every 21 days. Patients received two to three cycles of chemotherapy depending on the response and tolerance. RT was given to the nasopharynx and neck using megavoltage radiation, and the median dose to nasopharynx was 70 Gy. Treatment compliance was 92.6% in the CRT arm and 98% in the RT arm. Table 2 summarizes the patient and disease characteristics, and no significant difference in the distribution of pretreatment characteristics was observed in the two arms (Table 2).
Updated individual patient data of the two trials were collected and merged together for analysis. The median follow-up time for all patients was 51 months (range, 1 to 157 months), and for surviving patients it was 67 months. The end points examined were disease-specific survival, overall survival, relapse-free survival, locoregional relapse-free survival, and distant metastasis每free survival. The survival end points were analyzed and estimated using the product-limit method of Kaplan and Meier. The significance of differences between survival curves was estimated by log-rank test. Hazard ratios and CIs were estimated for various end points. Disease-specific survival was measured from the date of random assignment to the date of patient death or to the last date the patient was known to be alive.
In determining disease-specific survival, deaths as a result of uncontrolled disease or treatment-related complications were both counted as events, whereas deaths as a result of intercurrent disease were regarded as censored observations. In determining overall survival, deaths as a result of all causes were counted as events. Relapse-free survival was measured from the date of random assignment to the date of first documented relapse in any site, or to date of recent follow-up if no relapse had occurred. Patients who were given salvage therapy successfully for relapse were still considered to have experienced treatment failure at the time of event occurrence. In patients with residual disease after RT, relapse-free survival was counted as zero. Other end points were similarly measured from the date of random assignment to the time of event occurrence, or to date of recent follow-up if no event had occurred. Analysis was performed on the basis of intention to treat.
RESULTS
The combined results also showed a significant reduction in cancer-related deaths associated with the use of chemotherapy (P = .029; Fig 4), with a hazard ratio of 0.78 (95% CI, 0.62 to 0.98). The 20.5% relative reduction in the overall risk of cancer-related deaths is equivalent to an absolute improvement of disease-specific survival of 5.4% at 5 years and 10.4% at 7 years. The 5-year disease-specific survival rates in the CRT and RT arm were 63.5% and 58.1%, respectively, and the corresponding 7-year rates were 59.6% and 49.2%, respectively. Examination of the disease-specific survival curves of the two arms (Fig 4) indicates that the curves started to separate from approximately 12 months onward; the separation continued to increase and is more marked after 72 months.
When deaths as a result of all causes were counted, a similar trend in survival favoring the CRT arm was observed, but the difference was smaller and did not achieve statistical significance. The 5-year overall survival rates in the CRT and RT arms were 61.9% and 58.1%, respectively, and the corresponding 7-year rates were 57.2% and 48% (P = .092; Fig 5), respectively, with a hazard ratio of 0.83 (95% CI, 0.66 to 1.03). The discrepancy in observed difference between overall and disease-specific survival was related to the more frequent intercurrent deaths in the CRT arm compared with the RT arm (2.6% v 0.5%). In the CRT arm, four deaths were the result of late infection, two deaths were the result of a cerebrovascular accident, one death was the result of lung cancer, and three deaths were the result of other medical illness. In the RT arm, one death was the result of cerebrovascular accident and one death was the result of late infection. Most of the intercurrent deaths occurred at 5 years or later after treatment, and none of these patients had documented relapse at the time of death.
DISCUSSION
The improvement in disease-specific survival in the CRT arm was due to reduced risks of both locoregional relapse and distant metastases. The improvement in locoregional control after induction chemotherapy is not surprising given the high response rate to induction chemotherapy obtained before RT. The reduced risk of distant metastases in the CRT arm can be attributed not only to early eradication of micrometastases but also to enhanced locoregional control,16 as shown by the reduced number of patients with isolated distant metastases and those with locoregional relapse followed by distant failure. The latter failure pattern is reflected in the late occurrence of distant metastases in the RT arm, with 19% of distant metastases occurring beyond 3 years compared with 11% in the CRT arm.
The addition of induction chemotherapy to RT has not been shown to improve survival in head and neck squamous cell carcinoma. One explanation for the lack of survival benefit is the effectiveness of salvage surgery for locoregional treatment failures after chemoradiotherapy for head and neck cancers. Local failures of NPC, conversely, are less amenable to surgical salvage, and reirradiation is more commonly used instead. With the exception of small-volume and early-stage recurrence, results after reirradiation generally are poor.17每19 Given that advanced local failure of NPC carries a poor prognosis and locoregional failure itself predisposes to distant metastases, maximizing the chance of local control during primary treatment is important and crucial to patient survival. With the observed high response rate to induction chemotherapy, it is not unexpected to see improved locoregional control because of enhanced cytotoxicity of radiation and the substantial regression of tumor bulk before RT. Randomized trials have indeed reported improved locoregional control with induction chemotherapy,8每10 although earlier studies failed to observe any impact on survival. Our pooled data analysis showed that induction chemotherapy improved locoregional control, which was in turn translated to long-term disease-specific survival benefits in advanced-stage NPC.
Three large randomized phase III studies comparing CRT versus RT alone in NPC have been reported.8每10 Of these, two9,10 were included in the current pooled data analysis. The third study,8 conducted by the International Nasopharynx Cancer Group, compared three cycles of cisplatin, epirubicin, and bleomycin followed by RT with RT alone in 339 patients with N2-3 NPC. In a recent updated report of that study,20 no significant difference in overall survival was observed in the two arms after a median follow-up of 74 months, although disease-free survival was better in the CRT arm (41% v 30% at 6 years). Patients in the CRT arm had a high percentage of treatment-related death (8%) and aggressive chemotherapy was commonly given to patients in the RT arm after treatment failure; both of these factors may offset the survival benefit observed in the study arm. Compared with the International Nasopharynx Cancer Group trial, the chemotherapy regimens used in the AOCOA and Guangzhou trials were better tolerated, with only one chemotherapy-related death, although only 72% of patients in CRT arm in the former trial and 32% in the latter completed all three cycles of induction chemotherapy.
In the recent years, concurrent chemoradiotherapy has emerged as the treatment of choice for locoregionally advanced NPC, largely due to the positive findings of the Intergroup 0099 trial, which was the first randomized trial to demonstrate survival benefit with the use of chemotherapy in NPC.12 The Intergroup trial used three cycles of cisplatin concurrent with RT, followed by three cycles of adjuvant chemotherapy using cisplatin and fluorouracil in advanced-stage NPC. That study reported an absolute improvement of survival of 31% at 3 years with the addition of chemotherapy, and the estimated hazard ratio was 2.5. In a recent updated report,21 the 5-year survival rate was 67% in the concurrent chemoradiotherapy arm and 37% in the RT arm. There are, however, major concerns in extrapolating the findings of the Intergroup study to patient groups in the Asia context where NPC is endemic. Such cautions are quite legitimate in view of the high proportion of patients with WHO type I histology (24%) in the Intergroup study compared with predominant WHO type II to III histology in endemic areas, a high proportion of ineligible patients, and the inferior treatment outcomes in the control arm of the Intergroup study when compared with treatment results reported in the endemic areas. In addition, the relative contributions of concurrent and adjuvant chemotherapy cannot be determined from the Intergroup study and remain unclear.
After the publication of the results of the Intergroup study, three randomized trials conducted in Asia comparing concurrent chemoradiotherapy with or without adjuvant chemotherapy with RT alone in advanced-stage NPC have been reported.13,14,22 One trial used weekly cisplatin during RT in patients with advanced nodal disease and reported no significant difference in progression-free survival after a median follow-up of 2.7 years; the impact on survival was not analyzed because of the lack of events.22 Another randomized trial used two cycles of cisplatin and fluorouracil concurrent with RT showed improved survival compared with RT alone, with an absolute improvement of survival of 20% at 5 years.13 These two trials tested the role of concurrent chemotherapy only and did not include any adjuvant treatment. A third trial designed to evaluate the relative importance of concurrent chemotherapy using tegafur plus uracil and adjuvant chemotherapy using cisplatin plus fluorouracil alternating with vincristine plus bleomycin plus methotrexate was reported recently.14 That study used a 2 x 2 factorial design with patients randomly assigned to concurrent chemoradiotherapy versus RT alone, followed by adjuvant chemotherapy versus no treatment. The results showed that concurrent chemotherapy significantly improved failure-free and overall survival, whereas adjuvant chemotherapy did not improve outcome. These results suggest that concurrent chemoradiotherapy plays a major role in contributing toward improved outcome in advanced-stage NPC, although the optimal scheduling and regimens remain to be defined. The role of adjuvant chemotherapy is difficult to evaluate because of the low compliance rate observed in many trials, especially after concurrent chemoradiotherapy. Conversely, it may be easier to administer additional chemotherapy cycles as induction rather than adjuvant treatment when combining them with concurrent chemoradiotherapy, with the added benefit of rapid tumor shrinkage before RT.23
Contrary to the initial observation of lack of survival benefit, this pooled data analysis showed long-term benefits in terms of relapse-free and disease-specific survival associated with induction chemotherapy in advanced-stage NPC. On the basis of our study and the published results, there is strong evidence that the addition of chemotherapy to RT is associated with a significantly improved outcome in NPC. A recent literature-based meta-analysis of 1,528 patients from six randomized trials has demonstrated a significant improvement in disease-free survival with the use of chemotherapy even if the results of Intergroup trial were excluded.24 Although no formal studies comparing induction chemotherapy and concurrent chemoradiotherapy have been reported, the improvement in survival appears to be less with induction chemotherapy than that with concurrent chemoradiotherapy, and hence our findings should not change the current recommendation of using concurrent chemoradiotherapy in advanced-stage NPC. Induction chemotherapy using one of the study regimens from the current analysis followed by RT may be considered as an alternative option in patients who refused concurrent chemoradiotherapy because of its associated toxicities. Induction chemotherapy may also be combined with concurrent chemoradiotherapy to improve the treatment outcome in advanced-stage NPC and should be studied in future trials.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank the following investigators for their contributions to this study: Tahir Azhar (Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia); Vircharn Lorvidhaya, Yupa Sumitsawan, Sumityra Thongprasert (Department of Radiology, Chaingmai University, Chiangmai, Thailand); Visoot Vootiprux, Supatra Sangruchi (Department of Radiation Oncology, Siriraj Hospital, Bangkok, Thailand); Arkom Cheirsilpa (National Cancer Institute, Bangkok Thailand); Ary Reksodiputro, Averdin Roezin, Abidin Widjanarko (Cipto General Hospital, Jakarta, Indonesia).
NOTES
Both D.T.T.C. and J.M. contributed equally to this manuscript.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Bachouchi M, Cvitkovic E, Azli N, et al: High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin, and cisplatin before radiotherapy. J Natl Cancer Inst 82:616每620, 1990
2. Dimery IW, Peters LJ, Goepfert H, et al: Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 11:1919每1928, 1993
3. Garden AS, Lippman SM, Morrison WH, et al: Does induction chemotherapy have a role in the management of nasopharyngeal carcinoma Results of treatment in the era of computerized tomography. Int J Radiat Oncol Biol Phys 36:1005每1012, 1996
4. Hong RL, Ting LL, Ko JY, et al: Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:4305每4313, 2001
5. Prasa U, Wahid MI, Jalaludin MA, et al: Long-term survival of nasopharyngeal carcinoma patients treated with adjuvant chemotherapy subsequent to conventional radical radiotherapy. Int J Radiat Oncol Biol Phys 53:648每655, 2002
6. Rossi A, Molinari R, Boracchi P, et al: Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: Results of a 4-year multicenter randomized study. J Clin Oncol 6:1401每1410, 1988
7. Chan ATC, Teo PML, Leung TWT, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33:569每577, 1995
8. International Nasopharynx Cancer Study Group: VUMCA I Trial: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV (≡N2, M0) undifferentiated nasopharyngeal carcinoma〞A positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 35:463每469, 1996
9. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83:2270每2283, 1998
10. Ma J, Mai H, Hong M, et al: Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 19:1350每1357, 2001
11. Chi KH, Chang YC, Guo WY, et al: A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 52:1238每1244, 2002
12. Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310每1317, 1998
13. Lin JC, Jan JS, Hsu CY, et al: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: Positive effect on overall and progression-free survival. J Clin Oncol 21:631每637, 2003
14. Kwong DL, Sham JS, Au GK, et al: Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: A factorial study. J Clin Oncol 22:2643每2653, 2004
15. American Joint Committee on Cancer: Manual for Staging of Cancer (5th ed). Philadelphia, PA, JB Lippincott, 1997
16. Kwong D, Sham J, Choy D, et al: The effect of loco-regional control on distant metastatic dissemination in carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 30:1029每1036, 1994
17. Pryzant RM, Wendt CD, Delclos L, et al: Re-treatment of nasopharyngeal carcinoma in 53 patients. Int J Radiat Oncol Biol Phys 22:941每947, 1992
18. Lee AW, Law SC, Foo W, et al: Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976每1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 26:773每782, 1993
19. Chua DT, Sham JS, Kwong DL, et al: Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379每386, 1998
20. El Gueddari B: Final results of the VUMCA I randomized trial comparing neo-adjuvant chemotherapy (CT) (BEC) plus radiotherapy (RT) to RT alone in undifferentiated nasopharyngeal carcinoma (UCNT). Proc Am Soc Clin Oncol 17:385a, 1998 (abstr 1482)
21. Al-Sarraf M, LeBlanc M, Giri PG, et al: Superiority of 5-year survival with chemoradiotherapy vs. radiotherapy in patients with locally advanced nasopharyngeal cancer: Intergroup 0099 phase III study〞Final report. Proc Am Soc Clin Oncol 20:227a, 2001 (abstr 905)
22. Chan AT, Teo PM, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in loco-regionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20:2038每2044, 2002
23. Rischin D, Corry J, Smith J, et al: Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 20:1845每1852, 2002
24. Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: Results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25:219每223, 2002(Daniel T.T. Chua, Jun Ma,)