Int J Clin Oncol (2014) 19:38–44 DOI 10.1007/s10147-013-0532-y
ORIGINAL ARTICLE
Is postoperative adjuvant chemoradiotherapy necessary for high-risk oropharyngeal squamous cell carcinoma? Tomoya Yokota • Tetsuro Onitsuka • Kimihide Kusafuka • Hirofumi Ogawa • Yusuke Onozawa • Masahiro Nakagawa • Yoshiyuki Iida • Tomoyuki Kamijo • Tetsuo Nishimura • Takashi Nakajima • Narikazu Boku • Hirofumi Yasui
Received: 7 November 2012 / Accepted: 24 January 2013 / Published online: 5 March 2013 Ó Japan Society of Clinical Oncology 2013
Abstract Background High-risk factors for recurrence of head and neck squamous cell carcinoma after surgical resection include involvement of C2 regional lymph nodes, extracapsular spread, and microscopic involvement of resected mucosal margins. Adjuvant chemoradiotherapy is thought to improve postoperative locoregional control and survival. In this paper, we evaluate the efficacy of adjuvant therapy for high-risk oropharyngeal squamous cell carcinoma (OPSCC) (i.e., with C2 lymph nodes, positive extracapsular spread, or positive margins). Methods This is a retrospective analysis of 45 high-risk OPSCC patients who underwent surgery without adjuvant
T. Yokota (&) N. Boku H. Yasui Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto-gun, Shizuoka 411-8777, Japan e-mail:
[email protected] T. Onitsuka Y. Iida T. Kamijo Division of Head and Neck Surgery, Shizuoka Cancer Center, Shizuoka, Japan K. Kusafuka T. Nakajima Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan H. Ogawa T. Nishimura Division of Radiation Oncology, Shizuoka Cancer Center, Shizuoka, Japan
therapy (n = 19), with radiotherapy (n = 17), or with chemoradiotherapy (n = 9). Results The median follow-up period was 41.0 months. Radiotherapy patients showed a trend toward longer overall survival than patients without adjuvant therapy [hazard ratio (HR) = 0.32, p = 0.176]. However, overall survival for the chemoradiotherapy group seemed to be the same as that for the no adjuvant therapy group (HR = 0.79, p = 0.779). Multivariate analysis found that the relative risk of recurrence for patients without adjuvant therapy compared with any adjuvant therapy was 3.02 (p = 0.101). The relative recurrence risk in radiotherapy patients was 0.95 compared with that in chemoradiotherapy patients (p = 0.971). However, pathological T-stage was significantly associated with disease-free survival for highrisk OPSCC. Conclusions Although the current study uses data from a small retrospective sample of patients, our results suggest that the addition of chemotherapy to radiotherapy may not be necessary as an adjuvant therapy for all high-risk OPSCC. A novel prognostic factor, such as pathological T-stage, should be considered for selecting those patients with high-risk OPSCC who would benefit from adjuvant therapy. Keywords Oropharyngeal cancer Adjuvant therapy High-risk patients Chemoradiotherapy Squamous cell carcinoma
Y. Onozawa Division of Medical Oncology, Shizuoka Cancer Center, Shizuoka, Japan
Introduction
M. Nakagawa Division of Plastic and Reconstructive Surgery, Shizuoka Cancer Center, Shizuoka, Japan
Head and neck cancers mostly involve the oral cavity, pharynx, and larynx, and [90 % of such cancers are histologically squamous cell carcinomas [1]. Most patients
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with head and neck squamous cell carcinoma (HNSCC) present with locally or regionally advanced disease [2]. Although the primary surgical approach is a standard treatment option for locally advanced HNSCC, surgery alone is often associated with a high risk of relapse, indicating the need for a better selection of postoperative treatments [3]. Traditionally, patients with locally advanced HNSCC who undergo resection are divided into 2 categories: high risk and low risk, depending on the probability of locoregional failure [4, 5]. High-risk features include: (1) involvement of C2 regional lymph nodes (LN), (2) extracapsular spread of the disease (ECS), and (3) microscopic mucosal resection margins found on histological examination of the surgical specimens [6]. On the basis of the Radiation Therapy Oncology Group 95-01 and European Organisation for Research and Treatment of Cancer 22931 trials, postoperative chemoradiotherapy (CRT) is widely considered superior to radiotherapy (RT) in high-risk patients for improved locoregional control and survival [7, 8]. However, postoperative CRT is associated with severe mucositis, xerostomia, and dysphagia, resulting in permanent gastrostomy-tube dependence, which has emerged as a serious long-term morbidity [9–11]. HNSCC is a heterogeneous disease and has received growing interest in the last few decades because of emerging data regarding tumor biology and from clinical trials. Recently, oropharyngeal squamous cell carcinoma (OPSCC) has been recognized as a distinct group of tumors with favorable clinical outcomes. In particular, patients with human papilloma virus (HPV)-positive OPSCC have a favorable prognosis even when treated with surgery alone [12]. Therefore, there remains a question regarding the necessity for intensive CRT after surgery for OPSCC. The aim of this retrospective study was to define factors influencing survival of OPSCC patients who underwent surgical treatment with and without postoperative RT or CRT by analyzing their clinical outcomes.
Patients and methods Patients OPSCC patients who underwent primary resection and/or neck dissection and meeting at least 1 of the following pathological features were selected: (1) microscopically involved mucosal resection margins (positive margin), (2) positive ECS, and (3) involvement of C2 regional LN. This study was approved by the institutional review committee of Shizuoka Cancer Center (Shizuoka, Japan) and meets the standards set out in the Declaration of Helsinki. Written informed consent was obtained from all patients.
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Adjuvant therapy The decision to choose the adjuvant therapy after primary resection and neck dissection for each patient, depending on the extent of LN disease, presence of ECS, positive margins, patient preference, performance status, and metabolic criteria, was made during a multidisciplinary tumor board discussion. Evaluation All clinical data were retrospectively obtained from medical records. Disease-free survival (DFS) was calculated from the date of primary resection or neck dissection to the earliest date of recurrence or death and censored on the last date of confirmed survival. Overall survival (OS) time was calculated from the date of primary resection or neck dissection to the date of death from any cause or to the last date of confirmed survival. Adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria version 3.0. The toxicities were surveyed until 2 months after surgery (no adjuvant therapy group) or 1 month after termination of RT or CRT. p16 immunohistochemistry p16 immunohistochemistry was performed on the surgical specimens using a monoclonal antibody included in the CINtecÒ Histology Kit (Roche MTM Laboratories AG, Westborough, MA, USA) on a Ventana BenchMark immunostainer (Ventana Inc., Tucson, AZ, USA) following standard protocols [13]. Statistical analysis The Fisher’s exact test was performed to find any significant relationship between the type of adjuvant therapy and patient characteristics. Survival rates were analyzed by the Kaplan–Meier method. Survival curves were compared using the log-rank test. Two-sided p values of \ 0.05 were considered statistically significant. First, we performed a univariate comparison of factors that could potentially affect the survival time using the log-rank test and then performed multivariate analyses using the Cox proportional hazards model.
Results Patient characteristics One hundred and seventeen OPSCC patients underwent surgery at Shizuoka Cancer Center between January 2003
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and October 2011. Of these 117 patients, 30 who underwent salvage surgery after CRT or tracheotomy were excluded from the study. Of the remaining 87 patients who underwent primary resection and/or neck dissection, 46 had at least 1 unfavorable pathological finding, such as C2 LN, positive ECS, or positive margins. One patient enrolled in a clinical trial of adjuvant chemotherapy with S-1 (an oral fluoropyrimidine) was excluded from the study. Thus, the subjects of our study comprised 45 patients (Fig. 1). Overall, 26 of the 45 patients (58 %) received adjuvant therapy, including 17 patients (38 %) who received RT alone and 9 patients (20 %) who received CRT. The baseline characteristics and surgical approaches in the 3 groups are shown in Table 1. Histological examination of the surgical specimens revealed that positive ECS was present in 89 % (8/9) of the CRT group, compared with 53 % of the RT group and 32 % of the no adjuvant therapy group (p = 0.0752). Regarding p16 expression status as a surrogate marker of human papilloma virus (HPV) infection, the RT group showed a trend towards a high frequency of p16-positive specimens, although this difference was not statistically significant (p = 0.0691). All patients with any adjuvant therapy received conventional RT. Of these, 25 patients were given single daily fractionated radiation (2 Gy/day on 5 days/week), and one patient received 1.8 Gy/day on 5 days/week. Between the RT and CRT groups, there were no differences in timing, dosage, field size, or technique of RT administration. The planned RT dose was delivered in all patients in the RT and CRT groups (Table 1). Of the 9 patients who received CRT, 1 received cisplatin plus 5-fluorouracil (FP) and 8 received cisplatin monotherapy (Table 1). The FP regimen consisted of intravenous cisplatin (20 mg/m2) and a
Fig. 1 Patient selection criteria. A flow chart illustrating the composition of the study cohort (n = 45). OPSCC oropharyngeal squamous cell carcinoma, CRT chemoradiotherapy
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continuous infusion of 5-FP (400 mg/m2/day) for 5 days, given every 4 weeks for two cycles. With regard to cisplatin monotherapy, 6 patients received cisplatin at 80 mg/ m2/day, one patient at 100 mg/m2/day, and one patient at 20 mg/m2/day for 4 days, given every 3 weeks. Of the 8 patients who received cisplatin monotherapy, 4 patients completed 3 cycles of cisplatin, 2 completed 2 cycles, and 2 tolerated only 1 cycle. Survival DFS and OS are shown in Figs. 2 and 3, respectively. The median follow-up period in patients surviving without recurrence was 41.0 months (range, 5.6–110.7 months). Kaplan–Meier analysis showed that the 17 patients in the RT group had a trend toward longer OS than that of patients without adjuvant therapy [hazard ratio (HR) = 0.32; 95 % confidence interval (CI) = 0.06–1.67; p = 0.176]. However, OS for the CRT group seemed to be the same as that for the no adjuvant therapy group (HR = 0.79; 95 % CI = 0.15–4.08; p = 0.779). Similarly, the RT group had a trend toward longer DFS than the no adjuvant therapy group (HR = 0.31; 95 % CI = 0.08–1.19; p = 0.087). However, DFS for the CRT group was not different from that for the no adjuvant therapy group (HR = 0.71; 95 % CI = 0.19–2.66; p = 0.606; Fig. 2). With regard to the prognostic factors, univariate analysis showed that pathological tumor (T)-stage was significantly associated with poor survival (p = 0.006). Nonlateral location of the primary site, C2 LN, and multiple levels of LN positivity all showed a trend towards poor DFS (p = 0.090, 0.082, and 0.07, respectively), but a positive ECS and positive margin were not statistically associated
Int J Clin Oncol (2014) 19:38–44
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Table 1 Patient characteristics
Table 1 continued
No adjuvant therapy (n = 19)
RT alone (n = 17)
CRT (n = 9)
p value**
Male
16
12
8
0.4985
Female
3
5
1
C65
10
7
2
\ 65
9
10
7
0, 1
19
17
9
C2
0
0
0
Ever
17
12
7
Never
2
4
2
Gender
Median dose (minimum– maximum), Gy
No adjuvant therapy (n = 19)
RT alone (n = 17)
CRT (n = 9)
p value**
–
60 (0–60)
60 (39.6–60#)
Combined chemotherapy
Age 0.3084
Cisplatin ? 5fluorouracil
–
–
1
Cisplatin
–
–
8
PS PS performance status, NE not evaluated, ECS extracapsular spread, RT radiation therapy, CRT chemoradiotherapy, LN lymph nodes
Smoking status 0.5247
* Pathological stage, ** Fisher’s exact test, *** free flap reconstruction, # one patient had received 39.6 Gy because of a history of irradiation against hypopharyngeal cancer
Surgical approach Pull-through
10 (4***)
10 (5***)
5 (2***)
Transoral
4
3
0
Mandibular swing approach
3 (2***)
4 (4***)
2 (2***)
Others/unknown
2
0
2
T1/T2
12
11
5
T3/T4
7
6
4
0.4964
T-stage* 0.9254
N-stage* N1
7
4
1
N2/N3
12
13
8
0.3834
Level of LN positivity Single
11
10
3
Multiple
5
6
6
NE
3
1
0
Negative
9
6
3
Positive
9
11
6
NE
1
0
0
0.3120
Surgical margins 0.7567
No. of lymph nodes 0, 1
5
7
2
C2
11
9
7
NE
3
1
0
Negative
10
7
1
Positive
6
9
8
NE
3
1
0
Keratinizing
4
4
5
Nonkeratinizing
15
13
4
0.6157
ECS 0.0752
Keratinization status 0.1795
p16 status Positive
6
12
4
Negative
13
5
5
60 (0–70)
60 (0–60)
Radiation to primary site Median dose (minimum– maximum), Gy Radiation to neck
–
0.0691
Fig. 2 A Kaplan–Meier plot showing disease-free survival (n = 45). RT radiation therapy, CRT chemoradiotherapy
with poor survival by univariate analysis (Table 2). To investigate significant prognostic factors, we performed multivariate analysis using the Cox proportional hazards model including the following variables: C2 LN, positive ECS, positive margin (which are high-risk pathological criteria), presence or absence of adjuvant therapy, location of primary site, pathological T-stage, and level of LN positivity, which univariate analysis suggested may potentially affect the survival time. Although the multivariate analysis demonstrated that none of the high-risk pathological criteria was an independent prognostic factor, pathological T-stage was confirmed as an idicator of poor prognosis (HR = 12.7; 95 % CI = 2.16–75.3; p = 0.005). The relative risk of recurrence for patients treated with surgery alone was 3.02 compared with patients treated with any adjuvant therapy although the difference was not statistically significant (p = 0.101; Table 2). To compare the
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and dysphagia were higher in the CRT group than in the RT group (44 vs. 24 % and 22 vs. 6 %, respectively). Furthermore, grade 2 dysgeusia occurred in 56 % of patients treated with CRT and 35 % of those treated with RT alone. Grade 3 infections occurred in 1 patient in each of the RT and CRT groups. None of the patients developed renal toxicity and there were no treatment-related deaths in either group.
Discussion
Fig. 3 A Kaplan–Meier plot showing overall survival (n = 45). RT radiation therapy, CRT chemoradiotherapy
relative risk of recurrence between patients treated with RT alone and those treated with CRT, we performed a multivariate analysis using the 26 patients who received adjuvant therapy. The relative risk of recurrence for patients treated with RT alone was 0.95 compared with patients treated with CRT (p = 0.971). Toxicity The worst toxicities (C grade 3) observed after surgery (no adjuvant therapy group) or during the adjuvant treatment periods are listed in Table 3. Grade 3/4 oral mucositis
The incidence of OPSCC has shown an annual increase of 2–3 % in the US population aged 20–44 years [14], and was found to be etiologically unrelated to excessive smoking or alcohol abuse [15, 16]. Recently, OPSCC has been characterized by a favorable prognosis compared with SCC of other primary sites. Indeed, Boscolo–Rizzo et al. [17] reported that the 3-year OS rate was estimated to be 73.6 % in patients with locoregionally advanced resectable OPSCC who had undergone surgery plus postoperative RT. Although CRT has been a recent mainstay of postoperative treatment in high-risk HNSCC after surgery, it shows significantly enhanced acute treatment-related toxicity and serious long-term morbidity [9–11]. In particular, several reports have suggested that management of toxicities such as mucositis is difficult in cancers of the oral cavity. Although oral cancers are treated with surgery and adjuvant RT, irradiation of the oral cavity is associated with significant mucositis, which results in treatment interruption and a subsequent decrease in treatment efficacy
Table 2 Factors associated with disease-free survival by univariate and multivariate analyses (all patients) Variable
Univariate analysis HR
95 % CI
Multivariate analysis p value
Gender: men versus women
3.52
0.46–27.0
0.226
Age [ 65
1.03
0.36–2.96
0.963
Smoker: ever versus never
1.41
0.32–6.31
0.653
Location: nonlateral versus lateral
2.51
0.87–7.29
0.090
No neck dissection
1.67
0.37–7.50
0.500
T-stage: T3–T4 versus T1–T2*
5.09
1.60–16.3
0.006
N-stage: N2–N3 versus N1*
2.33
0.52–10.4
0.269
No. of LN: C2
6.17
0.80–47.8
0.082
HR
1.70 12.0 8.39
95 % CI
p value
0.42–6.87
0.458
2.17–65.8
0.004
0.63–112.5
0.108
Level of LN positivity: multiple versus single
3.04
0.91–10.1
0.07
0.80
0.16–3.97
0.780
Positive ECS
1.80
0.54–5.99
0.336
2.39
0.52–11.0
0.261
0.85
0.20–3.63
0.828
3.02
0.80–11.3
0.101
Positive surgical margin
0.83
0.28–2.46
0.730
Keratinizing
0.94
0.30–3.01
0.922
Adjuvant therapy: none versus any
2.32
0.80–6.78
0.123
p16: negative versus positive
1.95
0.65–5.84
0.235
HR hazard ratio, CI confidence interval, ECS extracapsular spread, LN lymph nodes * Pathological stage
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Table 3 Summary of toxicity during adjuvant therapy (Cgrade 3) No adjuvant therapy (n = 19)
RT alone (n = 17)
CRT (n = 9)
%
%
% Hematological toxicity Neutrophils
0
0
0
0
1
11
Hemoglobin Platelets
4 0
21 0
0 0
0 0
1 0
11 0
Nonhematological toxicity Nausea/vomiting
0
0
0
0
1
11
Dysphagia
3
16
1
6
2
22
Mucositis
0
0
4
24
4
44
Anorexia
0
0
3
18
2
22
Dysgeusia (grade 2)
0
0
6
35
5
56
Creatinine
0
0
0
0
0
0
Infection
0
0
1
6
1
11
RT radiation therapy, CRT chemoradiotherapy
[18–21]. Our results also indicated that CRT for OPSCC leads to a higher incidence of nonhematological toxicities, such as oral mucositis, dysphagia, and dysgeusia, than RT alone. Clinically, it is unclear whether adjuvant CRT is essential for all high-risk OPSCC cases after surgery. To clarify this, we first compared the outcome for patients who had received adjuvant therapy (RT alone or CRT) with that for patients who received no adjuvant therapy (Table 2). Although the difference is not statistically significant, the univariate and multivariate analyses revealed that surgery alone may tend to have a higher risk of recurrence than surgery plus any adjuvant therapy, suggesting that some form of adjuvant therapy is necessary after surgery. However, the multivariate analysis using data from the 26 patients who had received adjuvant therapy demonstrated no improvement in terms of DFS from the addition of chemotherapy to radiation (HR 0.95, p = 0.971). These results suggest that CRT may not necessarily be required as an adjuvant therapy for high-risk OPSCC after surgery. Kao et al. [22] recently compared patients receiving postoperative RT with those receiving no adjuvant therapy. The magnitude of the reduction in risk of death due to use of adjuvant radiation was greater for cancers of the hypopharynx and larynx (HR = 0.66 and 0.66, respectively) compared with cancers of the oral cavity and oropharynx (HR = 0.84 and 0.72, respectively). These findings raise the possibility of a correlation between tumor primary sites and the need for intensive adjuvant therapy. Therefore, it may be necessary to individualize adjuvant treatment according to the primary tumor site. We further tried to define factors influencing DFS in OPSCC patients who underwent surgical treatment. Our study identified pathological T-stage as an independent
prognostic factor for high-risk OPSCC, and a higher T-stage was related to a shorter DFS. This result is consistent with other reports that T-stage is the most significant prognostic factor for locoregional control and OS in OPSCC patients treated with RT alone [23]. In this study, multivariate analysis showed that the HR of RT alone compared with CRT was 0.95 after adjusting for other potential prognostic factors. These findings suggest that the indication for intensive adjuvant therapy such as CRT could be limited to high-risk OPSCC with an advanced pathological T-stage. In other words, it is speculated that RT alone is the most appropriate treatment option as a postoperative therapy for high-risk OPSCC with low pathological T-stage. Recently, intensity-modulated radiation therapy (IMRT) has emerged as a promising treatment for HNSCC. The advantage of IMRT is its highly conformal dose distribution to the primary tumor and involved LN with sufficiently low exposure to organs at risk, such as the parotid gland, brain stem, spinal cord, optic pathway, and mandible. Sher et al. [24] reported that IMRT for OPSCC decreased the incidence of long-term radiation-induced xerostomia, dysphagia, and respiratory complications despite the intensive nature of this therapy. Although all patients in the RT and CRT groups of this study received conventional RT, additional optimized radiation such as IMRT might benefit adjuvant therapies for OPSCC in the future. Importantly, patients with HPV-positive tumors have better prognoses than those with HPV-negative tumors [12]. HPV-positive tumors also reportedly show characteristic microscopic features distinguished by a lack of keratinization with basaloid morphologies [16, 25] and have a tendency to be located on the lateral wall as the primary site [26]. Therefore, we examined p16 expression and keratinization status in the surgical specimens from all the patients we analyzed. However, a series of these factors were not prognostic in OPSCC patients treated with surgery. Cohen et al. [27] demonstrated that the survival outcome for HPV-negative OPSCC patients treated with the transoral robotic surgical technique were not statistically different from HPV-positive OPSCC cases. These findings suggest that HPV status may not be a significant prognostic factor for OPSCC patients who receive surgical treatment. In conclusion, although some adjuvant therapies may be necessary postoperatively, our results suggest that the addition of chemotherapy to RT may not necessarily be required as an adjuvant therapy for all high-risk OPSCC patients. We cannot deny the fact that the current study has some limitations, such as the use of limited retrospective data and the involvement of a single center. Therefore, even though there is no significant difference between any variables, this may be due to the statistical weakness of the
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small sample size in this study. However, our results have suggested novel prognostic factors for high-risk OPSCC, such as pathological T-stage. The exact prognostic factors available to stratify high- and low-risk OPSCC may be useful for identifying patients who need more intense adjuvant therapy after surgery. Therefore, our observations warrant further prospective investigations to compare treatment outcomes and the resultant morbidity of postoperative RT versus CRT for patients with high-risk OPSCC. Conflict of interest
None.
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