Role of concurrent and adjuvant chemotherapy
The key evidence supporting the use of chemoradiation in nasopharyngeal carcinoma (NPC) is the Al-Sarraf et al. 1998 (Intergroup 0099 trial),r Lee et al. 2009 (RTOG 0225) trials,r the meta-analyses by Baujat et al. 2006,r Langendijk et al. 2004,r and more recently by Blanchard et al. 2015,r and Wang et al. 2015.r
The Intergroup 0099 RCT published by Al-Sarraf et al. in 1998, which randomly assigned patients to chemotherapy plus radiotherapy (CRT) versus radiotherapy (RT) alone was the first trial to show an improvement in survival outcomes with the addition of concurrent and adjuvant chemotherapy to RT.r This benefit was maintained with longer follow-up; 5 year overall survival was 37% vs 67% in favour of the CRT arm.r The addition of chemotherapy (Cxt) also decreased local, regional and distant recurrence rates. Meta-analysis confirmed this survival benefit.r
Chen et al. 2011 reported patients with stage II NPC (Chinese 1992 staging system) were randomly assigned to receive either RT alone (n = 114) or concurrent chemoradiotherapy (CCRT) (n = 116).r The CCRT patients were given concurrent cisplatin (30 mg/m2 on day 1) weekly during RT. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). With a median follow-up of 60 months, adding chemotherapy statistically significantly improved the 5-year OS rate (94.5% vs 85.8%; HR of death = 0.30, 95% CI = 0.12 to 0.76; P = .007), PFS (87.9% vs 77.8%; HR of progression = 0.45, 95% CI = 0.23 to 0.88; P= .017), and DMFS (94.8% vs 83.9%; HR of distant relapse = 0.27, 95% CI = 0.10 to 0.74; P = .007); however, there was no statistically significant difference in the 5-year LRFS rate (93.0% vs 91.1%; HR of locoregional relapse = 0.61, 95% CI = 0.25 to 1.51; P = .29). CCRT and RT is associated with a considerable survival benefit for patients with stage II NPC.
Individual patient data meta-analysis by Baujat et al. 2006 of 1753 patients comparing CRT with RT alone in 8 RCTs, reported an absolute benefit of 4% at 2 years (77-81%) and 6% at 5 years (56-62%).r The earlier meta-analysis by Langendijik et al. 2004 showed similar benefit with an overall survival benefit of 4% at 5 years.r The strongest evidence for the addition of chemotherapy to radiotherapy is in the concurrent setting. Both meta-analyses showed the largest benefit from chemotherapy is that which is administered concurrently with radiation (20% absolute survival benefit with concurrent chemotherapy at 3 years).
Figure 1: Kaplan-Meier overall survival curves in radiotherapy (RT) and radiotherapy plus chemotherapy (RT+CT) groups.r
© Int J Radiat Oncol Biol Physics 2006
Figure 2: Kaplan-Meier event-free survival curves in radiotherapy (RT) and radiotherapy plus chemotherapy (RT+CT) groups.r
© Int J Radiat Oncol Biol Physics 2006
The benefit of adjuvant chemotherapy is uncertain as the impact following CCRT on OS is less clear and what is known is that toxicity can be substantial.
The Intergroup 0099 study protocol included adjuvant chemotherapy (3 cycles of cisplatin 80 mg/m2 and 5FU 1g/m2/day for 96 hrs) in addition to concurrent treatment (cisplatin 100 mg/m2 every 3 weeks).r This trial reported a 30% overall survival benefit at 5 years; however it is not apparent what benefit the adjuvant component contributes. Note only 55% of patients planned for adjuvant chemotherapy completed all 3 cycles.
The meta-analyses did not show an improvement in OS for adjuvant chemotherapy added to RT alone when compared to RT alone.r A more recent meta-analysis by Zhang et al. 2010 stratified CRT vs RT alone trials by use of adjuvant chemotherapy.r In this indirect comparison, the hazard reduction for distant metastasis was identical, and was of similar magnitude for locoregional control between trials that did and did not add adjuvant chemotherapy to CRT. The hazard ratio for overall survival was 0.66 (95%, CI 0.48, 0.92) without adjuvant, and 0.83 (0.63, 1.09) with adjuvant.
An update on the previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group included data from 19 trials and 4806 patients and analysed separately the benefit of concomitant plus adjuvant chemotherapy.r The median follow-up was 7.7 years (IQR 6.2-11.9). This meta-analysis confirmed again that the addition of chemotherapy to RT significantly improved overall survival (hazard ratio [HR]0.79, 95% CI 0.73-0.86, p<0.0001; absolute benefit at 5 years 6.3%, 95% CI 3.5-9.1). The interaction between treatment effect (benefit of chemotherapy) on OS and the timing of chemotherapy was significant (P=0.01) in favour of concomitant plus adjuvant chemotherapy (HR 0.65, 0.56-0.76) and concomitant without adjuvant chemotherapy (0.80, 0.70-0.93) but not adjuvant chemotherapy alone (0.87, 0.68-1.12) or induction chemotherapy alone (0.96, 0.80-1.16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0.0001): progression-free survival (HR 0.75, 95% CI 0.69-0.81), locoregional control (0.73, 0.64-0.83), distant control (0.67, 0.59-0.75), and cancer mortality (0.76, 0.69-0.84).
Figure 3: Survival curves for overall survival in trials investigating (A) induction, (B) adjuvant, (C) concomitant, and (D) concomitant plus adjuvant chemotherapy.r
© Lancet Oncol 2015
Figure 4: Survival curves for progression-free survival in trials investigating (A) induction, (B) adjuvant, (C) concomitant, and (D) concomitant plus adjuvant chemotherapy.r
© Lancet Oncol 2015
In a Chinese phase III trial of 508 patients with nonmetastatic, advanced NPC, patients were randomly assigned to adjuvant chemotherapy (cisplatin plus fluorouracil) or observation following concurrent CRT with weekly cisplatin.r After a median follow-up of 68 months, there was no improvement in the five-year failure-free rate with adjuvant chemotherapy compared with concurrent CRT alone (five-year rate 75% vs 71%, HR 0.88, 95% CI 0.64-1.22).
However, in the MAC-NPC analysis, a consistent survival benefit was seen in six trials (n= 1267) in which concurrent CRT followed by adjuvant chemotherapy was compared with RT alone (given without concurrent or adjuvant chemotherapy).r OS was significantly improved compared with no chemotherapy (10-year OS 57% vs 43.1%, HR 0.65, 95% CI 0.56-0.76), and a similar benefit was seen in 10-year PFS (53.2% vs 38.5%).
Furthermore, in an individual patient data network meta-analysis that included 20 trials and 5,144 patients with locally advanced NPC, the combination of adjuvant chemotherapy plus concurrent CRT had the highest probability of benefit on OS (HR 0.65, 95% CI 0.56-0.75) when compared with RT alone.r
A significant benefit was also seen with concurrent CRT compared with RT alone (HR 0.77, 95% CI 0.64-0.92), but the difference was not statistically significant with induction chemotherapy followed by concurrent CRT versus RT alone (HR 0.81, 95% CI 0.63-1.04). In a comparison (two trials, 621 patients) of the combination of adjuvant chemotherapy plus concurrent CRT versus concurrent CRT alone, the benefit was also not statistically significant (HR 0.85, 95% CI 0.68-1.05).r
Concurrent CRT followed by adjuvant chemotherapy improves disease control compared with RT alone, although the benefit of intensive therapy may be partially offset by toxicities. In a trial comparing concurrent plus adjuvant chemotherapy versus RT alone, grade 3 or higher late toxicities were significantly more frequent at three years, but the difference between the treatment arms gradually decreased (10-year cumulative incidence 52% vs 47%, HR 1.25, 95% CI 0.89-1.76). Deaths attributable to disease progression were decreased with the addition of chemotherapy (26% vs 41%), and OS at 10 years was increased (62% vs 49%, HR 0.74, 95% CI 0.56-0.997).r
Although the results with and without adjuvant chemotherapy following concurrent CRT appear similar, substantial differences exist in patient populations and trial designs, which preclude a definitive conclusion; results from additional clinical trials will be required to identify the optimal approach.
Role of induction (neo-adjuvant) chemotherapy
Given the different biological behaviour of NPC compared to other head and neck small cell carcinomas, there is interest in the role of neo-adjuvant chemotherapy. No blanket statement can be made in this regards but to acknowledge that on a case by case basis it can be utilised to cyto-reduce disease in cases of extensive T4 or bulky nodal disease. The MAC-NPC meta-analysis has demonstrated a PFS benefit without OS benefit with the neo-adjuvant approach. Sun et al. 2016 compared neo-adjuvant chemotherapy and concurrent CRT versus concurrent CRT without adjuvant chemotherapy indicating an OS benefit of 92% vs 86% (HR 0.59, 95% CI 0.36-0.95) at 3 years.r Multiple phase 3 randomised control trials are underway to assess the role of neo-adjuvant chemotherapy.
Peters et al. 2010 reported on the impact of radiotherapy quality on patient outcomes in a large international phase III trial (TROG 02.02).r In patients with major deficiencies in their radiotherapy treatment plan there was a significantly inferior outcome; 2-year overall survival of 50% vs 70%; hazard ratio (HR), 1.99; P< .001; and 2-year freedom from locoregional failure, 54% v 78%; HR, 2.37; <P .001, respectively. These results show the critical importance of radiotherapy quality on outcome of chemoradiotherapy in locally advanced head and neck cancer.