Radiotherapy (RT) alone is the standard treatment for stage I (Category IB). Concurrent chemoradiotherapy (CRT) is the current standard of care for non-metastatic advanced stage (stages III, IVA, and IVB) nasopharyngeal carcinoma, with or without induction or adjuvant chemotherapy (Category IA). For intermediate-risk disease , stage II, it is recommended to give CRT instead of RT alone (Category 2B).

The MDACC series initially clarified the efficacy of RT alone for T1 category, while RT alone was capable of 5-year local control rates of 93, 79, 68, and 53 % for T1, T2, T3, and T4, respectively. Sanguinetti at al pointed out that advanced T category, squamous histology, and cranial nerve deficits were poor prognostic factors for local control [1].

The major data for combined CRT approach is derived from phase III trial of 230 stage II (T1–2N1M0 or T2N0M0 disease with parapharyngeal space involvement; 13 % is stage III based on AJCC 2010 TNM) nasopharyngeal cancer patients randomized into RT plus concurrent weekly cisplatin (30 mg/m²) versus RT alone [2]. The addition of concurrent cisplatin significantly improved overall survival from 85.8 % for RT alone to 94.5 % for CRT at 5 years; based on improvement in distant metastasis free survival (94.8 % vs. 83.9 %) without any difference in locoregional relapse-free survival (93.0 % vs. 91.1 %).

Addition of chemotherapy to definitive RT increases overall survival by 4–6 % at 5 years while decreases the risk of event by 10 % and the risk of death by 18 %. CRT demonstrated the most pronounced benefit in comparison to induction chemotherapy or adjuvant chemotherapy [3].

Intergroup 0099 (RTOG 8817) trial established a benefit from concurrent (cisplatin 100 mg/m² on days 1, 22, and 43) and adjuvant (cisplatin 80 mg/m² on day 1 and fluorouracil 1,000 mg/m²/day, days 1–4, every 4 weeks for three cycles) chemoradiotherapy (70 Gy, 35–39 fractions, 1.8–2.0 Gy/fraction/day) for stage III and IV nasopharyngeal cancer in comparison to RT alone (CRT vs. RT at 3 year, progression-free survival: 69 % vs. 24 %, overall survival: 78 % vs. 47 %; at 5 years in Table 6.1) [4]. Five-year OS and DFS favored CRT arms over RT alone in other Singapore [5], Taiwan [6], Hong Kong [7, 8], and China [9] randomized trials (Table 6.1).

Induction chemotherapy followed by RT alone approach has failed to show an overall survival benefit compared to RT alone (Table 6.2), but induction chemotherapy in addition to RT slightly improved relapse-free and disease-specific survival [17]. However, sequential therapy of induction chemotherapy followed by concurrent chemoradiotherapy started to be a popular alternative to concurrent chemoradiotherapy with adjuvant chemotherapy [18]. A recent phase II randomized trial comparing induction chemotherapy with docetaxel and cisplatin followed by weekly cisplatin concomitant with RT to weekly cisplatin concomitant with RT. Aside from similar quality of life scores, a trend toward improved 3-year progression-free survival with sequential therapy (88 % vs. 60 %, p = 0.12) and significant increase in overall survival with sequential therapy (94 % vs. 68 %) were evident [15].