Phase III randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety

Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 8, 2004

Presenter: Joseph Wee
Presenter's Affiliation: National Cancer Center, Singapore
Type of Session: Scientific


  • Nasopharyngeal cancer (NPC) is most prevalent in Asia and in these endemic areas, the types of NPC differ from those seen in other parts of the world.  In Asia, non-keratinized WHO grade II/III NPC represents >90% of NPC
  • Previously, Intergroup Trial 0099 showed a 25% overall survival (OS) benefit for chemoradiotherapy (CRT) compared to radiotherapy (RT) alone for NPC; howver, 30% of patients had WHO grade I NPC in this study
  • In addition, RT techniques differ in Asia compared to other parts of the world, and the RT only arm of Intergroup Trail 0099 appeared to be lower than is usually seen Asia
  • This study was undertaken to repeat the treatment regimen in Intergroup Trial 0099 to see if similar results can be achieved in NPC of the endemic variety

Materials and Methods

  • From September 1997 to November 2002, patients with Stage III/IV (T3-4Nany and TanyN3) WHO grade II/III NPC with ECOG performance status 0-1 were enrolled
  • Patients were randomized to receive either
    • Arm 1: RT 70Gy total dose in 35 fractions using conventional RT techniques
    • Arm 2: The same RT given concurrently with cisplatin (25 mg/m2 d1-4 on wks 1,4,7 of RT) followed by cisplatin (20 mg/m2 d1-4) + 5-FU (1000mg/m2 d1-4) on wks 11, 15, 19
  • The study was designed to detect a 35% 2-year OS difference with a power of 90%.  The study accrual goal was 200 patients to achieve this power


  • 221 patients were enrolled, 3 of these patient were excluded
  • Median follow-up = 37.8 mo
  • Treatment arms were well-matched for age, gender, race, N stage, and performance status
  • Arm 1 had a higher rate of T2 tumors while Arm 2 had a higher rate of T1 and T4 tumors, although these were not statistically significant
  • In Arm 2, 71% of patients received all 3 cycles of concurrent chemotherapy and 50% completed all 3 cycles of adjuvant therapy.  37 patients on this arm did not receive any adjuvant therapy
  • 90% of all patients received at least 70 Gy of RT
  • Overall, a higher rate of mucositis, anorexia, neutropenia, and thrombocytopenia was seen on the CRT arm (Arm 2)
  • The most common toxicity seen in patients during the adjuvant chemotherapy was neutropenia
  • 2-year disease-free survival (DFS) for Arm 1 vs. Arm 2: 59% vs. 76% (HR=0.60, p=0.027)
  • 2-year distant metastatic rate (DM): 30% vs. 13% (p=0.0007)
  • 2-year OS: 77% vs. 84% (HR = 0.50, p=0.006)
  • Patients differed in their site of initial relapse with 30.9% of patients receiving RT only presenting with distant relapse compared to 10% in the CRT arm
  • Improvement in local-regional control was seen in the CRT arm only for patients with T4 tumors

Author's Conclusions

  • CRT improves local control for T4 tumors in patients with endemic NPC
  • CRT improves DFS, DM, and OS compared to RT alone in these patients
  • These results confirmed to findings of Intergroup 0099 and show that they are applicable to patients with WHO grade II/III NPC

Clinical/Scientific Implications

The results of this study are similar to those found in the large Intergroup trial of NPC that has previously been mentioned.  Although patients with WHO grade II/III NPC have an improved prognosis compared to those with WHO grade I NPC, this study finds that patients with endemic-type NPC also benefit in all survival endpoints compared to RT alone.  It should be noted, however, that only patients with T4 tumors have an improvement in local control.  Currently, combined CRT should be considered the standard of care for all patients who have stage III/IV NPC regardless of WHO grade.  Despite these encouraging findings, almost a quarter of patients treated with CRT have recurred or died two years after treatment.  Future studies should focus on improving this rate, particularly with respect to the distant metastatic rate, as well as decreasing toxicity from treatment.

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