**2. Evolution of chemoradiation in NPC**

Stage I disease is treated by radical radiotherapy. Locally advanced disease (stage III and IVA) was treated by radiotherapy till the early '90s. Chemo-radiation was first studied in the landmark intergroup trial by Al Saraaf et al [5]. This trial compared chemoradiation followed by adjuvant chemotherapy versus radiotherapy (RT) alone in stage III and IV NPC (N = 147). The radiotherapy dose was 70Gy, delivered by conformal technique. There was a significant improvement in PFS and OS with the addition of chemotherapy. The 3-year PFS rate was 69% versus 24% (P < .001) and the 3-year OS was 78% versus 47% (P = .005) in the chemoradiation and radiotherapy arms respectively. But this trial was conducted in a non-endemic area and 22% of patients had keratinizing SCC. Hence the results could not be extrapolated to endemic areas.

Four randomized trials were conducted in a similar fashion in the endemic population, one each from Singapore and China and two from Hongkong. Wee et al randomized patients (N = 221) with stage T3-4NxM0 or TxN2-3 M0 NPC with WHO type II or III histology to radiotherapy alone or chemoradiotherapy followed by adjuvant chemotherapy [6]. Patients on chemoradiotherapy received concurrent cisplatin (25 mg/m2 on days 1 to 4) on weeks 1, 4, and 7 of RT and adjuvant cisplatin (20 mg/m2 on days 1 to 4) and fluorouracil (1,000 mg/m2 on days 1 to 4) every 4 weeks (weeks 11, 15, and 19) for three cycles after completion of RT. RT dose was 70Gy in 7 weeks by conventional technique. The 3-year survival rate was 65% and 80% for RT alone and CCRT, respectively (HR 0.51 (95% CI, 0.31 to 0.81; P = .0061). There was a 17% decrease in cumulative incidence of distant metastasis in the chemotherapy arm (p = 0029).

Two parallel RCTs from Hongkong namely NPC 9901 and NPC 9902 were done for advanced regional disease and advanced local disease respectively in the endemic population [7, 8]. In NPC 9901, patients with nonkeratinizing/undifferentiated NPC staged T1–4N2-3 M0 were randomized to chemo-RT followed by adjuvant chemotherapy or RT alone (N = 348). There was a significant improvement in LRC and failure free survival (FFS) but at the expense of significantly higher rates of acute and late toxicities. The update also showed significant improvement in 5 year FFS (67% vs 55%, P = .014) and PFS (62% vs 53%, P = .035) in favor of chemotherapy [9]. There was an increase in acute toxicities (CRT vs RT: 83% vs 53%; P < .001), but late toxicities were not different. OS did not show any benefit, probably due to the increased rates of noncancer death in the chemotherapy arm. NPC 9902 included Stage T3-4N0-1M0, nonkeratinizing or undifferentiated carcinoma of the nasopharynx (N = 189). There were 4 arms; RT with conventional fractionation alone, RT with accelerated fractionation alone, RT with conventional fractionation + concurrent /adjuvant chemotherapy (CF + C), and RT with accelerated fractionation + concurrent/ adjuvant chemotherapy (AF- + C). There was a significant improvement in FFS in the AF + C compared to the CF arm (94% vs. 70% at 3 years, p = 0.008), but the difference was not significant between the AF arm and the CF + C. There was no significant difference in OS between the 4 arms.

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

Acute toxicities were significantly more in both the chemo-RT arms. The late toxicity was more in the AF + C arm compared to the CF arm(p = 0.05).

Another prospective trial with a similar design was conducted in the endemic population of China by Chen et al [10]. RT dose was 70Gy in 7 weeks by conventional technique. The chemotherapy arm received concurrent cisplatin (40 mg/m2 on Day 1) weekly during RT, followed by cisplatin (80 mg/m2 on Day 1) and fluorouracil (800 mg/m2 on Days 1–5) every 4 weeks (Weeks 5, 9, and 13) for three cycles after completion of RT. The 2 year overall survival rate (89.8% vs. 79.7%, p = 0.003), failure-free survival rate (84.6% vs. 72.5%, p = 0.001), distant failure-free survival rate (86.5% vs. 78.7%, p = 0.024), and locoregional failure-free survival rate (98.0% vs. 91.9%, p = 0.007) was better in the chemotherapy arm. But acute toxicities were more in the chemotherapy arm (62.6% vs. 32%, p = 0.000).

Different trials used different concurrent cisplatin schedules. A randomized phase 3 trial was conducted by Liang et al to identify the ideal concurrent regimen. Weekly cisplatin 40 mg/m2 was shown to have efficacy similar to 3 weekly cisplatin 100 mg/m2 but at the expense of increased hematological toxicities [11].

The chemoradiation trials showed improvement in failure-free survival and distant metastasis-free survival with the addition of chemotherapy at the expense of increased acute toxicities. But overall survival benefit was not consistent among trials. A meta-analysis of 7 randomized trials done in endemic population by Zhang et al showed significantly better 5 years OS in favor of the CCRT treatment groups with a relative risk (RR) of 0.74 [0.62–0.89]. Locoregional recurrence (RR of 0.67,95% CI, 0.49 to 0.91) and distant metastasis (RR of 0.71;95% CI, 0.58 to 0.88) was significantly lower in the chemo-RT arm [12].

A meta-analysis with ten RCTs was done by Langendijk et al (4 neoadjuvant trials, 3 concurrent +/−adjuvant trials, and 2 adjuvant trials) to identify the additional benefit of chemotherapy when added to radiation [13]. There was an absolute survival benefit of 4% at 5 years with chemotherapy. Among the three chemotherapy timings, concomitant chemotherapy was associated with an absolute survival benefit of 20% at 5 years (HR of 0.48 (95% CI, 0.32 to 0.72). There was a significant reduction in locoregional recurrences with the addition of chemotherapy. The RR for locoregional recurrence was 0.47 (p < 0.0001) with concomitant chemotherapy and 0.74 (p = 0.005) with induction chemotherapy. But there was no benefit with adjuvant chemotherapy for locoregional control. The addition of chemotherapy demonstrated significant benefit in reducing distant metastasis also(p < 0.001).

The MAC NPC collaborative group meta-analysis included trials 8 trials that used chemotherapy in induction, concurrent or adjuvant setting [14]. There was an absolute survival benefit of 6% at 5 years with the addition of chemotherapy to RT which corresponds to an 18% reduction in the HR of death (HR 0.82; p = 0.006). The concomitant schedule showed more benefit (HR = 0.60) than induction (HR = 0.99) and adjuvant (HR = 0.97) regimens. There was an absolute EFS benefit of 10% at 5 years with the addition of chemotherapy. Chemotherapy decreased the risk of locoregional failure (p 0.003; HR, 0.76) and distant failure (p = 0.001; HR, 0.72) irrespective of the timing of chemotherapy. Chemotherapy was more efficient against WHO type 1 disease than against WHO type 2 or 3 diseases (p = 0.003 for OS and p = 0.0001 for EFS). The survival outcomes were favoring the chemotherapy arms even after excluding WHO type 1 patients (p = 0.03).

The updated MAC NPC meta-analysis included 19 trials and with a median follow-up of 7.7 years [15]. There was an absolute survival benefit of 6.3% at 5 years by the addition of chemotherapy to radiotherapy. The addition of chemotherapy resulted in significant improvement in PFS, LRC, distant control, and cancer mortality. The outcome was analyzed separately for concurrent chemotherapy with or without adjuvant chemotherapy. The benefit of chemotherapy was dependent

on the timing of chemotherapy. HR was 0·65 (0·56–0·76) for concomitant plus adjuvant chemotherapy, and 0·80 (0·70–0·93) for concomitant with out adjuvant chemotherapy. There was no significant benefit with induction chemotherapy alone or adjuvant chemotherapy alone.

A meta-analysis of 28 RCTs on the association of chemoradiotherapy regimens and survival done by Zhang et al showed that concurrent chemoradiotherapy (CCRT) was significantly associated with improved OS, PFS, DMFS, and LRFS compared with radiotherapy. The addition of induction chemotherapy resulted in improvement in OS ([HR 0.84; 95%CI 0.74–0.95), PFS (HR 0.73; 95% CI, 0.64–0.84), DMFS (HR, 0.67; 95% CI, 0.59–0.78), and LRFS (HR, 0.74; 95% CI, 0.64–0.85). The addition of adjuvant chemotherapy was not associated with survival benefits [16].
