*Chemotherapy in Nasopharyngeal Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.98550*

to be a major problem and hence adjuvant chemotherapy was tried. But it failed to show benefit and the compliance to chemotherapy after chemoradiation was poor. Induction chemotherapy was tried to decrease the rates of distant metastasis, to increase survival, and to reduce radiotherapy toxicities by decreasing treatment volumes.

Six randomized trials on induction chemotherapy have been published; three from China, one each from Europe, Taiwan, and Singapore. These trials used different induction regimens, radiotherapy techniques, and dosage schedules. The three Chinese trials showed improvement in DFS, OS, and DMFS with the addition of induction chemotherapy [21–25]. But GORTEC, Taiwan, and Singapore trials did not show any advantage in terms of DMFS or OS [26–28]. All these trials reported significantly higher rates of acute toxicities with induction chemotherapy. Jin et al tested TPF against PF as induction therapy in locally advanced NPC and reported similar outcomes with better tolerance and compliance in the PF arm [29]. The details of induction chemotherapy trials are given in **Table 1**.

Three meta-analyses of induction chemotherapy have been published. Tan et al included 6 RCTs and five observational studies with 2802 patients. Induction chemotherapy was associated with significantly improved PFS (HR 0.69, P = 0.0003) and OS (HR 0.77, P = 0.03,) at the expense of increased toxicities. There was a statistically significant 37% reduction in the hazard for the development of distant metastases (HR 0.63, P = 0.001) in favor of induction chemotherapy [30]. Individual patient data pooled analysis of 4 randomized trials from endemic areas by Chen et al reported an absolute benefit of 9.3% in 5 year PFS with the addition of induction chemotherapy to CCRT (P = 0.0009). Induction chemotherapy also improved OS (HR = 0.75; p = 0.04) and reduced distant failure (HR0.68; P = 0.008) [31]. Meta-analysis of 8 randomized trials with 2384 patients by Mane et al reported a significant benefit in OS (HR 0.68, P = 0.001) and PFS (HR 0.657, P < 0.001) with the addition of induction chemotherapy to CCRT, but acute toxicities were more with induction chemotherapy [32].

Induction chemotherapy before chemoradiation is associated with improvement in PFS, OS, and DMFS. TPF did not show any advantage over PF and the optimal induction regimens are cisplatin-infusion 5FU and cisplatin-gemcitabine.

## **6. Chemotherapy in stage II NPC**

Radical radiotherapy is the treatment for stage I disease. Stage III and IVA are managed by induction chemotherapy followed by chemoradiation or chemoradiotherapy with or without adjuvant chemotherapy. But the treatment of stage II disease is controversial. Stage II is a heterogeneous group with T2N0M0, T1N1M0, and T2N1M0disease. A phase 3 trial done by Chen et al in the conventional RT era randomized stage II patients into RT or CCRT [33]. Chemo-RT resulted in better 5 year OS, PFS and Distant metastasis-free survival at the expense of increased acute toxicities. IMRT resulted in improvement in OS by reducing local and regional recurrence with decreased toxicities and better quality of life compared to 2D RT. The benefit of concurrent chemotherapy in the IMRT era is doubtful. Many comparative studies were done to study the effect of the addition of chemotherapy to IMRT. But most of the studies are retrospective in nature. A randomized phase 2 trial by Huang et al showed no significant difference in OS, LFFS, RFFS, DFS, and DMFS after a median follow-up of 75 months. There was a detrimental effect on bone marrow function with chemo-RT [34]. Two retrospective studies from endemic areas showed no improvement in survival with the addition of chemotherapy to IMRT [35, 36]. Propensity score matching analysis in intermediate-risk NPC

*Chemotherapy in Nasopharyngeal Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.98550*

by Zhang et al showed no survival benefit (OS, FFS) by adding concurrent chemotherapy to IMRT [37]. Two meta-analyses of stage 2 trials have been published. Xu et al included 2D and IMRT studies [38]. CRT had significantly higher OS (HR 0.67, P = 0.04) and LRRFS (HR = 0.61, P = 0.0003) compared to RT alone, but there was no difference in DMFS. Acute toxicities were more in the chemo-RT arm. Subgroup analysis showed that IMRT alone achieved equivalent OS(P = 0.14), LRRFS(P-0.06) and DMFS(P = 0.89) compared to CRT. Liu et al published a meta-analysis of seven trials that compared IMRT alone with IMRT plus concurrent chemotherapy [39]. There was no benefit with the addition of chemotherapy to IMRT in terms of OS, PFS, DMFS, or LRRFS. Moreover CCRT was associated with increased rates of grade 3–4 leukopenia.

The benefit of adding chemotherapy to intensity-modulated radiotherapy in stage II disease is doubtful and is still under investigation.
