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Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study

  • Sanghyuk Song1,
  • Hong-Gyun Wu2Email author,
  • Chang Geol Lee3,
  • Ki Chang Keum3,
  • Mi Sun Kim3,
  • Yong Chan Ahn4,
  • Dongryul Oh4,
  • Hyo Jung Park4,
  • Sang-Wook Lee5,
  • Geumju Park5,
  • Sung Ho Moon6,
  • Kwan Ho Cho6,
  • Yeon-Sil Kim7,
  • Yongkyun Won7,
  • Young-Taek Oh8,
  • Won-Taek Kim9 and
  • Jae-Uk Jeong10
BMC Cancer201717:598

https://doi.org/10.1186/s12885-017-3571-3

Received: 28 July 2016

Accepted: 21 August 2017

Published: 30 August 2017

Abstract

Background

Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches.

Methods

We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and clinicopathologic factors were analyzed.

Results

At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively).

Conclusions

In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes.

Keywords

Tonsil cancer Chemoradiotherapy Surgery Adjuvant radiotherapy Induction chemotherapy

Background

The tonsils, a subsite of the oropharynx, are the most common site of oropharyngeal neoplasm [1]. The incidence of tonsil cancer is increasing [2, 3]. Odynophagia, dysphagia, otalgia and asymptomatic mass is common presentations. Histologically, squamous cell carcinoma is most commonly observed in tonsil cancer. Regional nodal metastases are frequent in more than half of patients, while contralateral nodal diseases are found in more than one fifth of patients with tonsil cancer [4]. Management of tonsil cancer is limited to either surgery or radiotherapy, yet there is a scarcity of randomized prospective trials comparing these treatment options. However, several retrospective studies published similar oncologic outcomes with both modalities [57]. Therefore, current guidelines recommend both strategies based on such findings [8].

In recent decades, breakthroughs in the field have included the introduction of chemotherapy, resulting in improved survival rates after definitive radiotherapy and postoperative radiotherapy [9, 10]. Furthermore, randomized clinical trial data showed that more than half of oropharyngeal cancers were human papillomavirus (HPV) positive and responded well to definitive radiotherapy [11]. The incidence of HPV positive tumors is continuously increasing [12]. In the era of chemotherapy and endemic HPV, comparisons of the efficacy between treatment modalities is still controversial. In the present study, we conducted a large-scale retrospective multicenter study to evaluate the outcome of chemoradiotherapy and surgery followed by postoperative radiotherapy in tonsil cancer patients.

Methods

A total of 620 tonsil cancer patients who were treated with radiotherapy between 1998 and 2010 were identified in 16 institutions in Korea. Of these, we analyzed data from 586 patients who were treated with definitive radiotherapy with chemotherapy (CRT; 201 patients) or surgery followed by radiotherapy and/or chemotherapy (SRT; 385 patients). All institutional review boards of participating hospitals approved the collection of these data. The need for consent had been waived by the institutional review boards. Patient demographics, performance status, smoking history, imaging study, stage, pathology, type of surgery, radio- and chemotherapeutic information, and follow-up results were compiled.

The median age at diagnosis was 56 (range, 26–89) and patients were predominantly male (89%). The performance status of most patients was Eastern Cooperative Oncology Group (ECOG) grade 0–1 (94%). More than half of the patients (52%) had a history of smoking. Computed tomography (CT) scans of the neck were performed at diagnosis in 91% of individuals; positron emission tomography (PET) or CT scans were taken in 69% of patients, while magnetic resonance imaging of the oropharynx and neck was performed in 48%.

Patient characteristics according to the two treatment groups are summarized in Table 1. Younger patients and those with early T stage were more likely to receive surgery (p = 0.041 and 0.002, respectively). Unknown histologic differentiation was less frequent in the SRT group. Chemotherapy and intensity modulated radiotherapy (IMRT) were more commonly used in the CRT group (p < 0.001 and 0.014, respectively). Radiotherapy dose was also higher in the CRT group than in those receiving SRT (p < 0.001).
Table 1

Patient Characteristics

Characteristic

Number of patients (%)

All (n = 586)

CRT (n = 201)

SRT (n = 385)

p-value

Sex

0.913

 Male

523

(89)

179

(89)

344

(89)

 

 Female

63

(11)

22

(11)

41

(11)

 

Age (years)

0.041

 < 60

395

(67)

125

(62)

270

(70)

 

 ≥ 60

189

(32)

76

(38)

113

(29)

 

 Unknown

2

(0)

0

(0)

2

(1)

 

Smoker

0.673

 Never smoker

232

(40)

73

(36)

159

(41)

 

 Ex-smoker a

98

(17)

32

(16)

66

(17)

 

 Current smoker

206

(35)

73

(36)

133

(35)

 

 Unknown

50

(8)

23

(11)

27

(7)

 

Performance

0.351

 ECOG 0

197

(34)

74

(37)

123

(32)

 

 ECOG 1

351

(60)

117

(58)

234

(61)

 

 ECOG 2

21

(3)

5

(2)

16

(4)

 

 Unknown

17

(3)

5

(2)

12

(3)

 

PET/CT

0.072

 No

182

(31)

72

(36)

110

(29)

 

 Yes

404

(69)

129

(64)

275

(71)

 

Differentiation

<0.001

 WD

62

(11)

15

(7)

47

(12)

 

 MD

297

(51)

73

(36)

224

(58)

 

 PD

129

(22)

37

(18)

92

(24)

 

 UD

16

(3)

11

(5)

5

(1)

 

 Unknown

82

(14)

65

(32)

17

(4)

 

T stage

0.002

 T1

134

(23)

31

(15)

103

(27)

 

 T2

292

(50)

101

(50)

191

(50)

 

 T3

74

(13)

30

(15)

44

(11)

 

 T4a

73

(12)

30

(15)

43

(11)

 

 T4b

13

(2)

9

(4)

4

(1)

 

N stage

0.779

 N0

73

(12)

20

(10)

53

(14)

 

 N1

79

(13)

28

(14)

51

(13)

 

 N2a

45

(8)

16

(8)

29

(8)

 

 N2b

307

(52)

105

(52)

202

(52)

 

 N2c

60

(10)

23

(11)

37

(10)

 

 N3

22

(4)

9

(4)

13

(3)

 

Stage

0.092

 I

8

(1)

2

(1)

6

(2)

 

 II

42

(7)

23

(11)

37

(10)

 

 III

82

(14)

29

(14)

53

(14)

 

 IVA

419

(72)

143

(71)

276

(72)

 

 IVB

35

(6)

18

(9)

17

(4)

 

Chemotherapy

<0.001

 Induction

61

(10)

33

(16)

28

(7)

 

 Concurrent

244

(42)

167

(83)

77

(20)

 

 Adjuvant

13

(2)

1

(1)

12

(3)

 

 No

268

(46)

0

(0)

268

(70)

 

Radiotherapy technique

0.014

 3D–CRT

391

(67)

121

(60)

270

(70)

 

 IMRT

194

(33)

80

(40)

114

(30)

 

 Unknown

1

(0)

0

(0)

1

(0)

 

Total dose of radiotherapy

Median 66

Median 70

Median 63

<0.001

 (Gy)

(range, 25.2–76)

(range, 59.4–76)

(range, 25.2–72.6)

 

Abbreviations: CRT radiotherapy with chemotherapy, SRT surgery followed by radiotherapy, ECOG Eastern Cooperative Oncology Group, PET/CT positron emission tomography/computed tomography, WD well differentiated, MD moderate differentiation, PD poor differentiation, UD undifferentiated, 3D–CRT three-dimensional conformal radiotherapy, IMRT intensity modulated radiotherapy

aAn adult who has smoked at least 100 cigarettes in his or her lifetime but who had quit smoking at the time of diagnosis

Overall survival (OS) was defined as the time from the date of treatment initiation to either death or last follow-up. Disease-free survival (DFS) was defined as the time from treatment initiation to recurrence, death, or last follow-up. Locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) were defined as the time from treatment initiation to locoregional/distant recurrence or last follow-up, respectively. Univariate and multivariate analyses were performed using the log rank test and Cox-proportional hazard regression model, respectively.

Results

With a median follow-up duration of 54 months (range, 2–176 months), 67 (11%) patients demonstrated locoregional recurrence, while 50 (9%) patients failed with distant metastases. The 5-year OS, DFS, LRRFS, and DMFS rates of the cohort as a whole were 81, 75, 87, and 91%, respectively. When the data from the CRT and SRT groups were analyzed independently, no significant differences were observed between the two groups. The 5-year OS rates were 82 and 81% (p = 0.698) in the CRT and SRT groups, respectively; DFS, 78 and 73% (p = 0.612); LRRFS, 89 and 87% (p = 0.695); and DMFS, 94 and 89% (p = 0.157). The survival curves of each group are plotted in Fig. 1.
Fig. 1

Overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival according to treatment group

Older age, current smoking, advanced T and N stage, and induction chemotherapy treatment were associated with poor OS in the univariate analysis (Table 2). Furthermore, patients undergoing induction chemotherapy showed inferior survival in both treatment groups (Fig. 2); the 5-year OS rates of patients treated with and without induction chemotherapy were 71 and 83%, respectively (p < 0.001). This significant finding was also observed when the treatment groups were analyzed independently; in the CRT group, the 5-year OS rates of patients with or without induction chemotherapy were 70 and 84% (p = 0.001), respectively, and 72% vs 82% in the SRT group (p = 0.033).
Table 2

Univariate Analyses

Characteristic

OS

DFS

LRRFS

DMFS

No.

5Y (%)

p-value

No.

5Y (%)

p-value

No.

5Y (%)

p-value

No.

5Y (%)

p-value

Sex

 Male

523

80

0.082

521

73

0.037

525

86

0.025

522

91

0.787

 Female

63

90

 

63

88

 

63

94

 

63

91

 

Age (years)

 < 60

395

85

<0.001

393

80

<0.001

395

89

0.121

394

92

0.026

 ≥ 60

189

73

 

189

62

 

189

83

 

189

86

 

Smoking history

 Never/ex-smoker

330

85

0.001

329

79

0.001

330

90

0.005

330

92

0.306

 Current smoker

206

76

 

205

67

 

206

82

 

205

89

 

Performance status

 ECOG 0

197

85

0.094

197

80

0.027

197

93

0.008

197

92

0.45

 ECOG 1–2

372

79

 

370

72

 

372

85

 

371

90

 

PET/CT

 No

182

79

0.226

181

74

0.847

182

88

0.669

182

93

0.311

 Yes

404

83

 

403

74

 

404

87

 

403

89

 

T stage

 T1–T2

426

87

<0.001

425

81

<0.001

426

90

0.003

425

94

<0.001

 T3–T4

160

67

 

159

58

 

160

81

 

160

82

 

N stage

 N0–N2b

504

84

0.005

503

78

<0.001

504

88

0.055

504

83

<0.001

 N2c–N3

82

67

 

81

55

 

82

81

 

81

79

 

Stage

 I–III

132

90

0.066

132

85

0.016

132

93

0.06

132

97

0.004

 IVA–IVB

454

79

 

452

72

 

454

86

 

453

89

 

Chemotherapy

 Concurrent/no

525

83

<0.001

523

76

0.006

525

88

0.263

524

90

0.762

 Induction

61

71

 

61

64

 

61

83

 

61

93

 

Radiotherapy technique

 3D–CRT

391

80

0.420

389

74

0.36

391

87

0.754

390

90

0.235

 IMRT

194

84

 

194

76

 

194

88

 

194

92

 

Treatment modality

 CRT

201

82

0.698

201

78

0.612

201

89

0.695

201

94

0.157

 SRT

385

81

 

383

73

 

385

87

 

384

89

 

Abbreviations: OS overall survival, DFS disease-free survival, LRRFS locoregional recurrence-free survival, DMFS distant metastasis-free survival, ECOG Eastern Cooperative Oncology Group, PET/CT positron emission tomography–computed tomography, 3D–CRT three-dimensional conformal radiotherapy, IMRT intensity modulated radiotherapy, CRT radiotherapy with chemotherapy, SRT surgery followed by radiotherapy

Fig. 2

Overall survival according to presence or absence of induction chemotherapy in each treatment group

The multivariate analysis (Table 3) also indicated that induction chemotherapy was a risk factor for poor OS and DFS, but not for LRRFS or DMFS. Other prognostic factors such as old age, current smoking, poor initial performance status and advanced T stage were associated with inferior OS. For DFS, advanced N stage was an additional significant prognostic factor. However, in terms of LRRFS, patient age and use of induction chemotherapy were not included in the Cox model. Age, and T and N stage were also identified as independent prognostic factors for DMFS.
Table 3

Multivariate Analyses

 

OS

DFS

LRRFS

DMFS

Characteristics

p-value

HR

95% CI

p-value

HR

95% CI

p-value

HR

95% CI

p-value

HR

95% CI

Age (years)

 ≥ 60

<0.001

3.000

2.001–4.497

<0.001

2.516

1.779–3.560

   

0.009

2.227

1.217–4.077

Smoking history

 Current smoker

0.012

1.663

1.116–2.478

0.015

1.54

1.089–2.176

0.014

1.919

1.141–3.226

   

Performance status

 ECOG 1–2

0.045

1.566

1.010–2.426

0.017

1.587

1.087–2.315

0.019

2.094

1.130–3.879

   

T stage

 T3–T4

<0.001

2.913

1.943–4.366

<0.001

2.572

1.808–3.659

0.021

1.852

1.097–3.127

<0.001

3.312

1.804–6.082

N stage

 N2c–N3

0.069

1.542

0.966–2.462

0.008

1.735

1.155–2.607

0.075

1.747

0.946–3.226

0.007

2.435

1.271–4.664

Chemotherapy

 Induction

0.003

2.224

1.313–3.768

0.033

1.712

1.044–2.806

      

Abbreviations: OS overall survival, DFS disease-free survival, LRRFS locoregional recurrence-free survival, DMFS distant metastasis-free survival, HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group

Discussion

Controversy surrounds the treatment of tonsil cancer. Both definitive surgery and radiotherapy resulted in favorable outcomes in retrospective studies [57]. With the use of chemotherapy, improved survival rates were reported with both treatment modalities [9, 10]. However, no well-designed prospective study comparing radiotherapy and surgery has been completed in the era of widely used chemotherapy. The only prospective randomized trial comparing chemoradiotherapy and surgery followed by radiotherapy was stopped prematurely due to slow accrual and therefore failed to detect any significant difference in DFS between treatment groups [13].

In the present study, we report the outcome of 586 patients from 16 hospitals. To the best of our knowledge, this is one of the largest tonsil cancer cohorts in the literature. We found that old age and advanced T stage which were associated with inferior survival in a multivariate analysis are more found in the CRT group. Despite these discrepancies in patient demographic and disease stage, there was no significant difference between the two treatment modalities under investigation in terms of survival, recurrence, or failure pattern. Our findings suggest that the CRT approach is more effective than SRT; however, further studies are required to confirm this hypothesis.

If the outcome is comparable between two treatment options, morbidity associated with the treatment becomes important when choosing the treatment modality. Unfortunately, we were unable to collect extensive information regarding treatment-related toxicities. Future trials should address not only the outcomes of treatment, but also any associated complications.

The outcomes of our multicenter study are comparable with those of previously published series. Canis et al. reported the outcome of 102 tonsil cancer patients who were treated with transoral laser microsurgery [14]. The 5-year locoregional control rates of T1–T2 and T3–T4 stage tumors were 78 and 75%, respectively. In the current study, the corresponding rates were 90 and 81%, respectively. Similarly, researchers from MD Anderson Cancer Center reported 5-year locoregional control and OS rates of 97 and 86%, respectively, in 120 patients who were treated with tonsillectomy followed by postoperative radiotherapy [15]. Poulsen et al. studied the outcomes of 148 patients who received surgery followed by radiotherapy or definitive radiotherapy [16], yielding 5-year locoregional control and OS rates of 84 and 57%, respectively. Other studies performed before the early 2000s reported lower 5-year locoregional control rates of 63–77% and OS rates of 53–60% [7, 1719], possibly because these studies included a large proportion of patients who were treated in the pre-chemotherapy era. Although direct comparisons are not possible, our treatment outcomes are acceptable when compared with the literature.

In the present study, the induction chemotherapy approach negatively influenced both OS and DFS, but had little effect on LRRFS or DMFS in the multivariate analysis. These findings suggest that induction chemotherapy may cause non-cancer related death. Recently, randomized trials reported increased toxicities and no survival gain with induction chemotherapy [20, 21]. Despite the limitations of retrospective studies (e.g., patient selection), our findings support the proposal that the toxicity associated with routine use of induction chemotherapy might be potentially harmful to tonsil cancer patients who are highly curable without such treatment. This is further indicated by our finding that patients with tonsil cancer showed favorable prognosis and a low rate of distant metastasis, despite 86% demonstrating stage III–IVA disease.

Tobacco smoking is a well-known risk factor for head and neck cancer [22]. Indian researchers reported that prior tobacco abuse was an independent poor prognostic factor for DFS and locoregional control in oropharyngeal cancer [23]. Less than half of tumors in that study were located in the tonsils. In our study, current smokers showed significantly worse OS, DFS, and LRRFS than non- or ex-smokers in the multivariate analysis. Differing tumor biology in smokers may affect disease outcome [24]. It is well known that persistent smoking during radiation therapy adversely affects the response and survival rate of head and neck cancer patients [25]. Smoking cessation may be beneficial and should be encouraged in patients with tonsil cancer.

Age of >60 years was associated with a significant risk of death, disease recurrence, and distant metastasis in the multivariate analysis. HPV infection, which correlated with favorable prognosis, was more frequently observed in younger patients than in the elderly; [12] therefore, smoking history and old age could be secondary surrogates of poor tumor biology which is unrelated to HPV infection. Unfortunately, because the HPV status of patients in the present study was unknown, this hypothesis could not be tested. Regarding that many recent studies for altering therapy based on HPV status are in progress, the lack of details of HPV status in this study has significant limitations [26].

Conclusion

Our large, multicenter, retrospective review of tonsil cancer patients showed favorable survival and disease control. Despite more high-risk patients being treated with definitive chemoradiotherapy than surgery followed by radiotherapy, demonstrated comparable outcomes. Furthermore, our study indicated that induction chemotherapy is correlated with significant risk of death and should not be routinely given to tonsil cancer patients.

Abbreviations

CRT: 

Chemoradiotherapy

CT: 

Computed tomography

DFS: 

Disease-free survival

DMFS: 

Distant metastasis-free survival

ECOG: 

Eastern Cooperative Oncology Group

HPV: 

Human papillomavirus

IMRT: 

Intensity modulated radiotherapy

KROG: 

Korean Radiation Oncology Group

LRRFS: 

Locoregional recurrence-free survival

OS: 

Overall survival

PET: 

Positron emission tomography

SRT: 

Surgery followed by postoperative radiotherapy

Declarations

Acknowledgements

None.

Funding

This research was supported by a grant from the National Research Foundation of Korea (NRF), which is funded by the Korean government (MEST, grant no.2015M2A2A7055063); a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (H14C3459); and the National R&D Program through the Dong-nam Institute of Radiological and Medical Sciences (DIRAMS) funded by the Ministry of Education, Science, and Technology (50595–2016). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on request.

Authors’ contributions

SS, HGW, LCG, KCK, YCA, DO, SWL, KHC, YSK, YTO and WTK were involved in the study concept and design. Data acquisition was undertaken by CGL, KCK, MSK, DO, HJP, SWL, GP, SHM, YW, YTO, WTK and JUJ. Analysis and interpretation of data were performed by SS, HGW, YCA, YSK and KHC. SS, HGW, HJP, GP, MSK, SHM, YW and JUJ drafted the manuscript. All of the authors have read and approved the final manuscript.

Ethics approval and consent to participate

The study protocol was reviewed and approved by the Institutional Review Boards of all participating hospitals, and adhered to the tenets of the Declaration of Helsinki. Owing to retrospective approach of this study, the need for informed consent was waived by the ethics committees. Additional information about the ethics committees and waiver of informed consent is provided in Additional file 1.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Radiation Oncology, Kangwon National University Hospital
(2)
Department of Radiation Oncology, Seoul National University College of Medicine
(3)
Department of Radiation Oncology, Yonsei Cancer Center
(4)
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine
(5)
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine
(6)
Research Institute and Hospital, National Cancer Center
(7)
Department of Radiation Oncology, Seoul St. Mary’s Hospital, The Catholic University of Korea
(8)
Department of Radiation Oncology, Ajou University School of Medicine
(9)
Department of Radiation Oncology, Pusan National University Hospital and Pusan National University School of Medicine
(10)
Department of Radiation Oncology, Chonnam National University Medical School

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