Outcomes of Induction Chemotherapy Plus Intensity-Modulated Radiotherapy (IMRT) Versus IMRT Plus Concurrent Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma: A Propensity Matched Study.

PURPOSE: It deserves investigation whether induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) is inferior to the current standard of IMRT plus concurrent chemotherapy (CC) in locoregionally advanced nasopharyngeal carcinoma.
METHODS: Patients who received IC (94 patients) or CC (302 patients) plus IMRT at our center between March 2003 and November 2012 were retrospectively analyzed. Propensity-score matching method was used to match patients in both arms at equal ratio. Failure-free survival (FFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS) were assessed with Kaplan-Meier method, log-rank test, and Cox regression.
RESULTS: In the original cohort of 396 patients, IC plus IMRT resulted in similar FFS (P = .565), OS (P = .334), DMFS (P = .854), and LRFS (P = .999) to IMRT plus CC. In the propensity-matched cohort of 188 patients, no significant survival differences were observed between the two treatment approaches (3-year FFS 80.3% vs 81.0%, P = .590; OS 93.4% vs 92.1%, P = .808; DMFS 85.9% vs 87.7%, P = .275; and LRFS 93.1% vs 92.0%, P = .763). Adjusting for the known prognostic factors in multivariate analysis, IC plus IMRT did not cause higher risk of treatment failure, death, distant metastasis, or locoregional relapse.
CONCLUSIONS: IC plus IMRT appeared to achieve comparable survival to IMRT plus CC in locoregionally advanced nasopharyngeal carcinoma. Further investigations were warranted.

Introduction

Nasopharyngeal carcinoma (NPC) is a malignancy relatively rare in Europe and the United States [1] but highly endemic in Southern China [2] and Hong Kong [3]. Radiotherapy is the cornerstone of initial treatment. Since the publication of INT-0099 trial [4], several subsequent trials [5], [6], [7], [8], [9] have substantiated the survival benefits of concurrent chemoradiotherapy, which was consequently recommended as the standard of care in the subgroup of locoregionally advanced disease.

Interestingly, induction chemotherapy (IC) followed by two-dimensional conventional radiotherapy (2DCRT) alone was once reported to obtain encouraging response rates and improvement in disease-free survival (DFS) [10], [11], [12], [13]. It is expected to regress tumor extension, avoid irradiation of organs at risk, prevent tumor progression due to the long waiting time before radiotherapy, and finally improve local and distant control. Actually, benefit has been seen in reduction of both local and distant failures [14]. Even in the era of concurrent chemotherapy (CC) plus intensity-modulated radiotherapy (IMRT), IC appeared to achieve benefit in distant metastasis–free survival (DMFS) [15] and even overall survival (OS) [16]. Therefore, the combination of IC with concurrent chemoradiotherapy is a popular option for cases of locoregionally advanced disease with extensive involvement.

But unfortunately, a small number of patients fail to receive CC after finishing IC in clinical reality. The main reasons include, but are not restricted to, treatment costs, toxicities, and refusal for no reason. Nothing is known about IC followed by IMRT, as it has barely been compared head-to-head with the standard of care. Because more recent randomized trials [17], [18], [19] comparing IMRT plus CC with or without IC indicated no improvement of survival, IC followed by IMRT might be a promising approach with inferior survival outcomes but reduced toxicities. We thus retrospectively analyzed data of 396 patients receiving IC or CC plus IMRT, especially using propensity score matching method to mimic randomized trials [20]. This shall provide valuable effect assessment and pivotal reference for the future randomized controlled trials.

Materials and Methods

Patients

We enrolled 396 NPC patients who received treatment at our center between March 2003 and November 2012. All patients were diagnosed by history and physical examination, hematology and biochemistry profiles, fiberoptic nasopharyngoscopy with biopsy, magnetic resonance imaging (MRI) of nasopharynx and neck, chest radiography or computed tomography (CT), abdominal sonography or CT, and technetium-99m-methylene diphosphonate whole-body bone scan or CT/MRI of bones, and/or [18F]fluorodeoxyglucose positron emission tomography and CT. Patients were restaged based on the 2010 International Union Against Cancer/American Joint Committee on Cancer staging system for NPC.

Treatment

All patients were treated by IC or CC plus definitive IMRT. The target volumes of IMRT were defined in accordance with the International Commission on Radiation Units and Measurements reports 50 and 62. The primary nasopharyngeal gross tumor volume together with enlarged retropharyngeal nodes (GTVnx) and the involved cervical lymph nodes (GTVnd) were determined from the imaging, clinical, and endoscopic findings. Patients in the IC cohort were examined by MRI 2 weeks after the final cycle of chemotherapy to determine GTVnx and GTVnd. The first clinical tumor volume (CTV1) was defined as the GTVnx plus a margin of 5 to 10 mm for potential microscopic spread, including the entire nasopharynx mucosa plus a 5-mm submucosal volume. The second CTV (CTV2) was defined by adding a margin of 5 to 10 mm to CTV1 (when CTV2 was adjacent to critical organs such as brain stem and spinal cord, the margin was reduced to 3 to 5 mm) and included the retropharyngeal lymphnodal regions, clivus, skull base, pterygoid fossae, parapharyngeal space, inferior sphenoid sinus, posterior edge of the nasal cavity and maxillary sinuses, and bilateral cervical lymphatic area. Prescribed radiation doses were 68 Gy or greater to the planning tumor volume (PTV) of GTVnx, 60 to 68 Gy to PTV of GTVnd, 60 Gy or greater to PTV of CTV1, and 50 Gy or greater to PTV of CTV2 in 30 to 33 fractions. Further details of IMRT have been described previously [21]. IC regimen consisted of docetaxel/paclitaxel plus cisplatin/nedaplatin, cisplatin/nedaplatin plus fluorouracil, or docetaxel/paclitaxel plus cisplatin/nedaplatin plus fluorouracil given every 3 weeks for 2 to 3 cycles before radiotherapy. CC regimen consisted of 80 to 100 mg/m2 cisplatin given every 3 weeks for 2 to 3 cycles, or 30 to 40 mg/m2 cisplatin given weekly for up to 7 cycles.

Follow-Up

Patients underwent conventional examination every 3 to 6 months during the first 3 years and every 6 to 12 months thereafter until death to detect possible locoregional relapse or distant metastasis. Actually, the examination during this period was in line with that before treatment. Confirmed locoregional relapse, distant metastasis, or consistent disease received reirradiation, surgery, and/or chemotherapy. Patients without recent examination tests in the medical records were followed up by telephone.

Statistical Analysis

To reduce possible biases to a minimum in this retrospective analysis, we used propensity score matching method [22] to match IC plus IMRT cohort (case) with IMRT plus CC cohort (control). Propensity scores were computed by logistic regression, taking into account age, sex, histology (WHO II, differentiated nonkeratinizing carcinoma; WHO III, undifferentiated nonkeratinizing carcinoma [23]), T stage, N stage, and clinical stage. Propensity-matched cohorts were thus established following matching without replacement at equal ratio on those scores.

Characteristics of patients were compared using t test (continuous variable), χ2 test (categorical variable), and standardized difference [24]. Failure-free survival (FFS, time from treatment to evidence of treatment failure), OS (time from treatment to death from any cause), DMFS (time from treatment to the first distant metastasis), and locoregional relapse–free survival (LRFS, time from treatment to the first locoregional relapse) were estimated with Kaplan-Meier method [25], log-rank test, and Cox proportional hazards model [26]. In the propensity-matched cohort, survival outcomes were estimated using stratified log-rank test by matched pairs and Cox proportional hazards model with a robust variance estimator to account for the clustering within matched pairs [27].

All statistical analyses were performed using IBM SPSS Statistics version 23.0 and Stata version 12.0. Two-sided P values < .05 and standardized difference > 0.10 [28] were considered to be significant.

Results

Initially, 94 (23.7%) and 302 (76.3%) patients were treated with IC plus IMRT and IMRT plus CC, respectively. Of note, patients with advanced T stage, N stage, or overall clinical stage tended to receive IC plus IMRT, whereas such characteristics as age and sex scarcely affected treatment options. Following propensity score matching, 94 patients treated with IC plus IMRT and 94 patients treated with IMRT plus CC remained in the propensity-matched cohort. The matched patients in both arms had balanced characteristics (Table 1).

Table 1

Baseline Characteristics of Patients Who Underwent Induction or CC Plus IMRT

	The Original Unmatched Cohort				The Propensity-Matched Cohort
IC + IMRT (n = 94)	IMRT + CC (n = 302)	P	Standardized Difference	IC + IMRT (n = 94)	IMRT + CC (n = 94)	P	Standardized Difference
No. (%)	No. (%)	No. (%)	No. (%)
Age			.872	0.018			.548	0.087
Mean	44.99	45.19			44.99	44.01
SD	11.59	10.34			11.59	10.69
Median	44.50	45.00			44.50	43.50
Sex			.904	0.014			.866	0.025
Male	70 (74.5)	223 (73.8)			70 (74.5)	71 (75.5)
Female	24 (25.5)	79 (26.2)			24 (25.5)	23 (24.5)
Histology*			.461	0.091			1.000	0.000
II	4 (4.3)	19 (6.3)			4 (4.3)	4 (4.3)
III	90 (95.7)	283 (93.7)			90 (95.7)	90 (95.7)
T stage			.050				.978
T1	7 (7.4)	31 (10.3)		0.099	7 (7.4)	7 (7.4)		0.000
T2	15 (16.0)	59 (19.5)		0.094	15 (16.0)	13 (13.8)		0.060
T3	34 (36.2)	135 (44.7)		0.175	34 (36.2)	36 (38.3)		0.044
T4	38 (40.4)	77 (25.5)		0.322	38 (40.4)	38 (40.4)		0.000
N stage			.124				.985
N0	14 (14.9)	43 (14.2)		0.019	14 (14.9)	13 (13.8)		0.030
N1	50 (53.2)	197 (65.2)		0.247	50 (53.2)	52 (55.3)		0.043
N2	23 (24.5)	46 (15.2)		0.233	23 (24.5)	23 (24.5)		0.000
N3	7 (7.4)	16 (5.3)		0.088	7 (7.4)	6 (6.4)		0.042
Clinical stage			.004				1.000	0.000
II	10 (10.6)	69 (22.8)		0.331	10 (10.6)	10 (10.6)
III	40 (42.6)	140 (46.4)		0.077	40 (42.6)	40 (42.6)
IV	44 (46.8)	93 (30.8)		0.333	44 (46.8)	44 (46.8)

Based on the criteria of WHO histological type (1991): II, differentiated nonkeratinizing carcinoma; III, undifferentiated nonkeratinizing carcinoma.

Survival Outcomes

In the original unmatched cohort of 396 patients, median follow-up time was 40.58 months (8.33-99.73 months) for the IC arm and 49.77 months (3.50-107.63 months) for the CC arm, respectively. Overall, 3-year FFS, OS, DMFS, and LRFS rates did not differ significantly between the two arms (FFS 80.3% vs 82.0%, P = .565; OS 93.4% vs 93.8%, P = .334; DMFS 85.9% vs 87.7%, P = .854; and LRFS 93.1% vs 93.3%, P = .999; Figure 1, A–D). Accounting for age (continuous), sex, T stage, and N stage in multivariate analysis, IC plus IMRT was not associated with higher risk of death, locoregional relapse, or distant metastasis than IMRT plus CC (Table 2).

Figure 1

Kaplan-Meier survival curves for the IC arm and the CC arm in the original cohort of 396 patients. (A) FFS; (B) OS; (C) DMFS; (D) LRFS.

Table 2

Summary of Important Prognostic Factors in Multivariate Analysis

	The Original Unmatched Cohort		The Propensity-Matched Cohort
Hazard Ratio (95% CI)	P*	Hazard Ratio (95% CI)	P†
FFS
IC + IMRT vs IMRT + CC	0.99 (0.61-1.61)	.963	0.82 (0.44-1.52)	.522
Age (continuous)	1.00 (0.98-1.02)	.940	1.01 (0.98-1.04)	.488
Sex	0.92 (0.56-1.49)	.730	1.04 (0.52-2.06)	.911
Histology	0.50 (0.23-1.11)	.089	1.69 (0.20-14.09)	.628
T stage	1.65 (1.27-2.14)	< .001	1.83 (1.24-2.69)	.002
N stage	1.49 (1.12-1.98)	.006	1.62 (0.94-2.79)	.081
OS
IC + IMRT versus IMRT + CC	0.90 (0.46-1.75)	.746	0.86 (0.39-1.89)	.700
Age (continuous)	1.03 (1.00-1.05)	.064	1.03 (0.99-1.07)	.113
Sex	0.82 (0.42-1.62)	.575	0.83 (0.34-1.99)	.671
Histology	0.58 (0.21-1.64)	.306	–	–
T stage	2.06 (1.40-3.03)	< .001	2.75 (1.59-4.76)	< .001
N stage	2.00 (1.37-2.90)	< .001	2.25 (1.22-4.16)	.009
DMFS
IC + IMRT versus IMRT + CC	1.09 (0.60-2.00)	.776	0.85 (0.40-1.82)	.672
Age (continuous)	1.00 (0.97-1.02)	.690	0.99 (0.96-1.03)	.741
Sex	0.81 (0.43-1.50)	.499	1.16 (0.52-2.60)	.724
Histology	0.48 (0.19-1.24)	.129	–	–
T stage	1.67 (1.21-2.31)	.002	2.22 (1.38-3.57)	.001
N stage	1.90 (1.36-2.64)	< .001	2.28 (1.21-4.31)	.011
LRFS
IC + IMRT versus IMRT + CC	1.06 (0.45-2.47)	.899	0.95 (0.30-3.00)	.936
Age (continuous)	0.99 (0.96-1.02)	.457	0.99 (0.94-1.04)	.684
Sex	0.99 (0.44-2.22)	.976	0.74 (0.19-2.96)	.671
Histology	0.51 (0.15-1.71)	.276	0.49 (0.06-3.67)	.486
T stage	1.29 (0.86-1.93)	.221	1.10 (0.64-1.89)	.727
N stage	1.31 (0.80-2.12)	.282	1.01 (0.37-2.77)	.981

Adjusted for age (continuous), sex, histology, T stage, and N stage.

Adjusted for the same covariates with a robust variance estimator to account for the clustering within matched pair.

In the propensity-matched cohort of 188 patients, median follow-up time was 40.58 months (8.33-99.73 months) for the IC arm and 53.57 months (4.00-92.60 months) for the CC arm, respectively. In univariate analysis, IC plus IMRT achieved similar survival to IMRT plus CC (3-year FFS 80.3% vs 81.0%, P = .590; OS 93.4% vs 92.1%, P = .808; DMFS 85.9% vs 87.7%, P = .275; and LRFS 93.1% vs 92.0%, P = .763; Figure 2, A–D). In multivariate analysis, IC plus IMRT was also highly comparable to IMRT plus CC in risk of treatment failure, death, locoregional relapse, and distant metastasis (Table 2).

Figure 2

Kaplan-Meier survival curves for the IC arm and the CC arm in the propensity-matched cohort of 188 patients. (A) FFS; (B) OS; (C) DMFS; (D) LRFS.

Grade 3 to 4 Hematological Toxicities

In the propensity-matched cohort, IC plus IMRT significantly increased the incidence of grade 3 to 4 neutropenia, whereas IMRT plus CC tended to result in more leucopenia. The rates of grade 3 to 4 anemia and thrombocytopenia were similar in both cohorts (Table 3).

Table 3

Grade 3 to 4 Hematological Toxicities in the Propensity-Matched Cohort

	IC + IMRT (n = 94)	IMRT + CC (n = 94)	P	Standardized Difference
Leucopenia	14 (14.89%)	24 (25.53%)	.069	0.267
Neutropenia	27 (40.91%)	10 (21.74%)	.034	0.467
Anemia	5 (5.32%)	6 (6.38%)	.756	0.045
Thrombocytopenia	6 (6.38%)	11 (11.70%)	.204	0.186

Discussion

Currently, no strong evidence from phase III randomized trials supports the addition of IC to radiotherapy in locoregionally advanced NPC, whereas CC plus radiotherapy is the standard recommended by National Comprehensive Cancer Network because of the confirmed survival benefits [29]. Thus, speculatively, IC followed by IMRT appears to be inferior to IMRT plus CC. However, head-to-head comparison of these two approaches in the present study showed no significant differences in survival in both unmatched and matched cohorts. Actually, prior studies had given some hints in favor of this insignificant difference.

A study from Japan [30] investigated IC regimen of cisplatin plus 5-fluorouracil plus methotrexate plus leucovorin (PFML) in 21 NPC patients versus CC regimen of PFML or docetaxel plus cisplatin plus 5-fluorouracil in 25 patients, and observed no difference in survival. Besides, a study from Taiwan [31] also found similar survival between 38 patients who underwent IC of MEPFL regimen (mitomycin, epirubicin, cisplatin fluorouracil, and leucovorin) or PFL regimen (cisplatin, fluorouracil, and leucovorin) and 90 patients receiving CC of cisplatin or cisplatin and fluorouracil. Certainly, the small sample size in both studies maybe had insufficient power to detect differences, if they existed. More importantly, a large phase III randomized trial from Shanghai [32] compared IC plus adjuvant chemotherapy (AC) with CC plus AC among 338 stage III to IVb (the 2002 International Union Against Cancer/American Joint Committee on Cancer staging system) patients who received 2 cycles of cisplatin and 5-fluorouracil before or during 2DCRT and the same regimen at equal dosage for 4 cycles after radiotherapy. The trial showed similar OS and DFS between IC and CC but more acute toxicities from CC. As IMRT can achieve better LRFS and OS than 2DCRT [33], it is less likely to observe significant differences between IC and CC in the IMRT era. This trial strongly supported the outcomes of our present study despite the differences in chemotherapy regimens and the addition of AC in both arms.

In addition, the outcomes of IMRT plus cisplatin-based CC in our study were not inferior [17], [34] but even superior [16], [19] to those from randomized trials, whereas the results of IC plus IMRT were quite similar to those in randomized trials [16], [17]. So it was not unusual regarding the insignificant survival differences between IC plus IMRT and IMRT plus CC in our study.

The major strength of this study was the head-to-head comparison of IC with CC in NPC patients in the IMRT era using propensity score matching and multivariate analysis. The presented data were derived from a single institution in an endemic area with expertise in diagnosing and treating this disease, which provided the utility in treatment, especially the IMRT technique. The major limitation was that the small number of patients in this study provided relative low power to compare these two treatment approaches. Especially the smaller sample size in the matched cohort may lead to skewed result. But this report was currently the largest-scale head-to-head comparison in contrast with prior publications such as the study by Li et al. [35]. Further investigations with sufficient power are definitely warranted. Data on DNA copy number of the Epstein-Barr virus were missing in most of the cases, and acute nonhematological and late toxicities were unavailable because of the retrospective design and the long time span between the first and the last included case. Owing to the low sensitivity rate of chest radiography compared with chest CT, some patients might be delayed in detecting lung metastasis and had falsely high DMFS rate as a consequence. But the intrinsic differences in DMFS might scarcely change, as the chance of delay was equal in patients in both arms. Another limitation caused by the retrospective design was the heterogeneity of IC regimen and doses. Besides, experienced locoregional relapse or distant metastasis was updated from telephone call for some patients who completed the examination tests out of our cancer center.

In conclusion, this study indicated no significant differences in survival between IC and CC for NPC patients who received IMRT.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Sun Yat-sen University Cancer Center and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed Consent

As a retrospective study, individual informed consent was waived given the anonymous analysis of routine data.

Conflict of Interest

None.