**6. Concomitant CT-RT**

The results of concurrent chemoradiotherapy (CCRT) Intergroup study 0099, made gradually this combined approach as a standard in the treatment of patients with stage III and IV NPC (Al Sarraf et al, 1998; Chan et al, 2010). Within the randomized other studies, several meta-analysis and a pooled data analysis reported a significant improvement of survival in NPC patients treated by CTRT versus RT alone (Baujat et al, 2006). The NPC meta-analysis had shown the superiority of concomitant scheme vs neoadjuvant chemotherapy. It concerned 1753 patients with N1> 2cm, N2> 3cm, N3, T4, PS 0- 1, WHO 2- 3 and a mean age of 46 years. The follow-up was < 5 years for 2 trials (299 pts), 5-9 years for 6 (1454 pts) and a median follow-up of 6 years for the whole population. Delivered radiotherapy were for tumor: 65-74 Gy, for N0 : 50-66 Gy and for N+ 60-76 Gy, by using a "classical" technique and a boost for residual N associated to concomitant cisplatin-based CT in all trials. Authors reported a benefit of concomitant scheme by increasing 5-year OS from 56% to 62% and EFS from 42% to 52% significantly better than neoadjuvant chemotherapy. Recently a meta-analysis focused on South East Asian phase III trials of CT-RT from the NPC endemic area. 1608 patients were collected from seven trials (Zhang L et al, 2010) and they reported Risk ratios (RRs) of 0.63 (95% CI, 0.50 to 0.80), 0.76 (95% CI, 0.61 to 0.93) and 0.74 (95% CI, 0.62 to 0.89) for 2, 3 and 5 years OS respectively in favor of the CCRT group. Concerning the 3-years absolute number of locoregional recurrence rate (LRR), a significant overall benefit in favor of the addition of chemotherapy was found with RR of 0.67 (95% CI, 0.49 to 0.91). A significant decrease of metastatic risk was also observed in term of 3-years absolute number of distant metastasis rate (DMR) with a RR of 0.71. The RRs were larger than that detected in the previously reported meta-analysis (including both endemic and non-endemic), and authors concluded that "the relative benefit of CCRT in endemic population might be less than that from previous meta-analyses".

#### **6.1 CT Protocols of concomitant CT-RT**

The schemes used for CTRT are mainly based on "Al Sarraf" schedule with Cisplatin 100mg/m2, every 3 weeks on D1,22,43 or weekly Cisplatin at 40mg/m2(Chan Scheme),

Update on Medical Therapies of Nasopharyngeal Carcinoma 183

Despite many technical advances in RT, late toxicities i.e mainly xerostomia, cervical subcutaneous fibrosis, trismus, hearing loss of less frequently second cancers are observed decreasing the Quality of Life of long-term survivors from NPC, specially those treated in

After the era of exclusive CT-RT, appeard the next generation protocols associating PCT followed by CT-RT (Fountzilas et al, 2011, Hui et al, 2009). PCT protocols included "classical" 5FU-cisplatin, anthracyclin-cisplatin or more recently taxanes-cisplatin associations (Table 2). Hui and al, reported their results on 65 patients treated cisplatindocetaxel (DC) protocol followed by CCRT vs CCRT alone. They observed a significant survival benefit at 2 years for the DC arm (93% vs 76%, *p* = .013). Others studies including also taxanes, showed a benefit for overall and disease-free survival of patients treated for NPC in MA are currently varying from 66 to 94% and 63 to 88.2% (table 3). Many of these studies have a short Follw-up, but OS and DFS rates seems to be promising probably better than those reported in exclusive CT-RT. In Tunisia, a prospective GORTEC French trial is ongoing, comparing 2 cycles of primary TPF followed by chemoradiotherapy vs CCRT with

Author/year Nb CT RT ORPCT ORCT-RT OS/DFS Zheng/2010 60 Ned/FU IMRT ----- 95.3% 3 yr 85.5/75%

Fountzilas 72 CPE-CRT 66-70/50-66 70% 83% 3 yr 66.6/64.5 2011 69 CRT -------- ----- 85% 3 yr 71.8/63.5 Hui 34 DC-CRT 70/50-60 76,5% 97.1% 3 yr 94.1/88.2% 2009 31 CRT 70/50-60 ---- 100% 3 yr 69.2/63% CPE :Cisplatin-Paclitaxel-Epirubicin, DC : Docetaxel-cisplatin, CRT : Concomitant chemo-radiotherapy,

Table 2. Therapeutics results of open or randomized studies of PCT followed by CT-RT.

Instead of the classical T,N,Age,Sex and histologic type, prognostic value of Primary Tumor Volume(PTV), measured by CT-scan have been explored for NPC in 112 patients with Stage I-IVB NPC treated by IMRT (Chen et al, 2011). The mean PTV was 33.9 ± 28.7 ml and classified from V1 to V4 (from 15.65 to 50,5ml). It impacted on 5-year overall survival who varies from 88.5, 83.3, 82.4 to 54.5% for V1 to V4 from, showing that V1-V4 are clearly separated from V4 (p = 0.014). Cox proportional hazards regression model analysis showed that a PTV >50 ml was an independent risk factor for radiotherapy (risk ratio = 3.485, P = 0.025). In 56 Turkish patients with locally advanced NPC, PTV have been calculated by measuring tumor diameters by CT and MR film hardcopies computed as an ellipsoid (V=4/3·π·d1·d2·d3) to obtain the diameter-based volume(Sarisahin et al, 2011). They reported in the monovariate analysis, that primary tumor volume have a significant predictive value on DFS and DMFS, if tumor volume < 20ml, DFS was 60% vs 0% if > 60ml(p=0.007). The residual tumor volume (RTV) at first control after treatment was also

childhood or adolescence (Boussen et al,2010; Xiao et al,2011).

weekly cisplatin (40mg/m2) in advanced(N2-3, T3-4).

Ned Conc 70/55-60

**7. Tumor volume in NPC: A new prognostic factor?** 

Ned : Nedaplatin.

**6.3 What next after concomitant CT-RT?** 

who's the most frequently used in MA and NA, while radiotherapy doses is usually ≥66Gy (1.8-2Gy/Fx/d, 5Fx/wk) for primary nasopharyngeal tumor and its extensions + additional boosts to the parapharyngeal space, the primary or nodal sites not exceeding 20Gy. Since 10 years, CCRT is now recognized and applied as the better therapeutic approach for locally advanced NPC (Al Sarraf,1998 ; Chan et al,2010 ).

#### **6.2 Acute and late toxicities of CT-RT**

CT-RT compared to PCT, however increased significantly acute grade 3-4 toxicity at the end of combined treatment i.e mucositis, radiodermitis, dysphagia and consequently severe weight loss (WL) in most of the open or randomized studies (Table 1). This acute toxicity reduced considerably the compliance of weekly concomitant cisplatin, that was administered during the 6 weeks of CT-Rt in 94%,88%,74%,35%,7% and 3% for weeks 1 to 6 in Hui study (Hui et al,2009). The frequency of severe WL > 5-10% is probably underestimated by many authors and requires sometimes nasal tube feeding or parenteral nutrition as well as delay in the planned protocol. In a Chinese study (Qiu et al, 2011), of patients treated by CT-RT for NPC, 56% had at baseline, a mean 5% WL evaluated at 6.9 Kg after CT-RT (range 2.1-12.6 kg). Xerostomia is one of the most frequent sequelae after salivary gland irradiation and Intensity-Modulated RT permits to reach a high tumor control rate, but also to reduce severity and frequency of xerostomia (Lee et al, 2009).


Table 1. Acute and late toxicities after CT-RT.

Despite many technical advances in RT, late toxicities i.e mainly xerostomia, cervical subcutaneous fibrosis, trismus, hearing loss of less frequently second cancers are observed decreasing the Quality of Life of long-term survivors from NPC, specially those treated in childhood or adolescence (Boussen et al,2010; Xiao et al,2011).

#### **6.3 What next after concomitant CT-RT?**

182 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

who's the most frequently used in MA and NA, while radiotherapy doses is usually ≥66Gy (1.8-2Gy/Fx/d, 5Fx/wk) for primary nasopharyngeal tumor and its extensions + additional boosts to the parapharyngeal space, the primary or nodal sites not exceeding 20Gy. Since 10 years, CCRT is now recognized and applied as the better therapeutic approach for locally

CT-RT compared to PCT, however increased significantly acute grade 3-4 toxicity at the end of combined treatment i.e mucositis, radiodermitis, dysphagia and consequently severe weight loss (WL) in most of the open or randomized studies (Table 1). This acute toxicity reduced considerably the compliance of weekly concomitant cisplatin, that was administered during the 6 weeks of CT-Rt in 94%,88%,74%,35%,7% and 3% for weeks 1 to 6 in Hui study (Hui et al,2009). The frequency of severe WL > 5-10% is probably underestimated by many authors and requires sometimes nasal tube feeding or parenteral nutrition as well as delay in the planned protocol. In a Chinese study (Qiu et al, 2011), of patients treated by CT-RT for NPC, 56% had at baseline, a mean 5% WL evaluated at 6.9 Kg after CT-RT (range 2.1-12.6 kg). Xerostomia is one of the most frequent sequelae after salivary gland irradiation and Intensity-Modulated RT permits to reach a high tumor control rate, but also to reduce severity and frequency of xerostomia (Lee et al,

 Author/year Hui/2010 Lee/2010 Zheng/2010 After PCT An --- -- 1.7% Neutr 97% -- 6.8% Thr -- -- -- N/V 8.8% -- 5.1%

 An 8.8 19.2 19 1 39% Neutr 26.4 15.3 32% 1% 35.6%

 Mucos 23.5 7.7 61% 48% --- N/V 8.8 7.7 18% 1% 47.1%

 Dys --- 3.8% 1% 0% 3.4% Xer 32.4 30.8% --- --- 91.5%

 HL 8.8 11.5% 6% --- 3.4% Otit 21 15% 3.5% Hypoth 8% 6% 6.8%

Thr 2% 0%

 WL 27% 27% Rad 20% 16%

Skin 11.8 19.2% 4% 5%

Subc 20.6 11.5%

SC 5.9 3.8%

Table 1. Acute and late toxicities after CT-RT.

advanced NPC (Al Sarraf,1998 ; Chan et al,2010 ).

**6.2 Acute and late toxicities of CT-RT** 

2009).

After CT-RT

Late toxicities

After the era of exclusive CT-RT, appeard the next generation protocols associating PCT followed by CT-RT (Fountzilas et al, 2011, Hui et al, 2009). PCT protocols included "classical" 5FU-cisplatin, anthracyclin-cisplatin or more recently taxanes-cisplatin associations (Table 2). Hui and al, reported their results on 65 patients treated cisplatindocetaxel (DC) protocol followed by CCRT vs CCRT alone. They observed a significant survival benefit at 2 years for the DC arm (93% vs 76%, *p* = .013). Others studies including also taxanes, showed a benefit for overall and disease-free survival of patients treated for NPC in MA are currently varying from 66 to 94% and 63 to 88.2% (table 3). Many of these studies have a short Follw-up, but OS and DFS rates seems to be promising probably better than those reported in exclusive CT-RT. In Tunisia, a prospective GORTEC French trial is ongoing, comparing 2 cycles of primary TPF followed by chemoradiotherapy vs CCRT with weekly cisplatin (40mg/m2) in advanced(N2-3, T3-4).


CPE :Cisplatin-Paclitaxel-Epirubicin, DC : Docetaxel-cisplatin, CRT : Concomitant chemo-radiotherapy, Ned : Nedaplatin.

Table 2. Therapeutics results of open or randomized studies of PCT followed by CT-RT.
