Accepted Manuscript Prognostic value of residual node involvement after induction chemotherapy in operable oral squamous cell carcinoma Jiong Lyu , M.S Yi Zhong , Ph.D Chaojun Li , Ph.D Hao Song , M.S Guoxin Ren , Ph.D Wei Guo , Ph.D PII:
S2212-4403(14)00477-5
DOI:
10.1016/j.oooo.2014.05.009
Reference:
OOOO 923
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 11 March 2014 Revised Date:
21 April 2014
Accepted Date: 7 May 2014
Please cite this article as: Lyu J, Zhong Y, Li C, Song H, Ren G, Guo W, Prognostic value of residual node involvement after induction chemotherapy in operable oral squamous cell carcinoma, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.05.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page Prognostic value of residual node involvement after induction chemotherapy in operable oral squamous cell carcinoma
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Authors 1. Jiong Lyu (first author) M.S Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 2. Yi Zhong Ph.D Institute of Stomatology，Department of Oral Pathology, Nanjing Medical University Nanjing, China 3. Chaojun Li Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 4. Hao Song M.S Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 5. Guoxin Ren Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 6. Wei Guo (corresponding author) Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China E-mail: [email protected] OR [email protected] Postal address: No. 639 Zhizaoju Rd, Shanghai 200011, China Telephone number: +8621 5039 8070 Fax number: +8621 5090 5789
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Acknowledgement This work was supported by the Project of Science and Technology Commission of Shanghai Municipality (grants 10410711200 , 08140902100 and 11495802000)
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Key words: induction chemotherapy; oral cancer; lymph node; prognosis
Word count for the abstract:
149
Manuscript word count: 1641 Number of reference: 16 Number of figures/tables: 2/3 Number of supplementary elements: None
ACCEPTED MANUSCRIPT Abstract Objective: The aim of this study was to assess the prognostic value of residual node involvement after induction chemotherapy (ICT) on HNSCC and to investigate
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post-ICT node status associated with tumor characteristics. Study design: We retrospectively analyzed a cohort of 109 patients with operable oral squamous cell carcinoma underwent ICT followed by surgery with neck
SC
dissection. Median follow-up was 45 months. The primary endpoints were OS and
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DFS.
Results: After ICT, 48(44.0%) patients had no positive node, 46(42.2%) patients had 1-3 residual nodes, 15(13.7%) patients had more than 3 residual nodes. The number of residual node was significantly associated with OS and DFS. On multivariate
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analysis, the number of residual node was an independent prognostic factor (p=0.011 for DFS and p=0.034 for OS).
Conclusion: Although constituting a different parameter from primary surgery data,
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the number of positive nodes after ICT could still remain a prognostic factor at
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secondary surgery.
ACCEPTED MANUSCRIPT Introduction Induction chemotherapy (ICT) is used prior to other modalities and has several potential advantages: by reducing tumor volume, it may permit organ conservation
RI PT
in selected patients; It also allows earlier treatment of micro metastatic diseases.1,2 Nevertheless, ICT in locoregionally advanced head and neck cancer (HNSCC) remains controversial. Several randomized studies (including a phase III randomized trial in
SC
our institute) failed to demonstrate a significant survival advantage with the use of
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ICT compared with locoregional treatment alone.3-5 However, ICT could decrease the rate of distant metastasis of HNSCC6 and it was reported that clinical complete tumor regression was associated with improved survival. So the potentially beneficial roles
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of ICT in specific patients subsets will warrant additional research and validation.7,8
Investigating prognostic factors to ICT may help to understand its role. In HNSCC, the lymph node status is an important prognostic factor in patients having surgery as
EP
initial treatment9, and higher number of positive nodes are associated with worse
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prognosis. While in ICT setting, the incidence of positive nodes may be reduced by chemotherapy. Consequently, it could possibly modify the prognostic value of this parameter. Whether the residual number of involved nodes kept a clear prognostic factor in HNSCC is unknown.
We hypothesized that in oral cancer, the number of positive nodes after chemotherapy could still remain a valuable prognostic factor. In this retrospective
ACCEPTED MANUSCRIPT study, our aim was to assess the prognostic value of the persistence of node metastasis relative to other clinical variables in 109 patients with oral cancer treated
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with ICT.
Patients and Methods Patients selection
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This retrospective study was approved by the Institutional Review Board, The
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Shanghai Ninth people's hospital. We reviewed the records of patients with oral SCC who received ICT and surgery between May 2008 and April 2011. The eligibility criteria of this retrospective study included: no prior specific treatment, no metastatic spread, surgery with neck dissection within 4 weeks after ICT. 109 patients
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were analyzed, the following clinical data were collected: age, sex, smoking history, tumor staging, histological grade, treatment information, pathological results,
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recurrence and survival.
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Treatment modalities
From May 2008 to April 2011, 109 patients with stage III or IV oral SCC were treated in our institute by one or two cycle of ICT. Each cycle consisted of docetaxel 75mg/m2 intravenous on day 1, cisplatin 75mg/m2 intravenous on day 1, followed by fluorouracil 750mg/m2 given as a 120-hour intravenous infusion, the second cycle was administered 3 weeks after the first one. After ICT, all patient underwent surgery with neck dissection (unilateral/bilateral, functional/radical neck dissection). 92.6%
ACCEPTED MANUSCRIPT patients received post-operation radiotherapy.
Pathological assessment
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Pathological response was assessed after resection of the remaining tumor and nodes. Microscopic examination comprised at least 20 slides per primary tumor and the whole neck dissection. A favorable pathologic response of primary tumor was
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defined as absence of any tumor cells or presence of scattered foci of a few tumor
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cells.5,10 Lymph nodes that is present of viable tumor cells were considered as positive nodes, and those nodes that is absent of tumor cells or show histological changes include fibrosis, chronic inflammatory cell infiltration were considered as
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negative nodes.11
Statistical analyze
Descriptive statistics were used to describe patients' pathological and clinical
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characteristics. Chi-square test were used to compare various characteristics
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between subgroups. Overall survival (OS) was measured from the date of initial diagnosis to death due to any cause. Disease free survival (DFS) was measured from the completion of surgery to recurrence/metastasize. The OS and DFS were analyzed by Kaplan-Meier method. The log-rank test was performed to test difference in survival between subgroups. Multivariate analysis was performed using the Cox regression model. All tests were two-sided, and p=0.05 was set as the level of statistical significance. All statistical analyses were done by SPSS program (version
ACCEPTED MANUSCRIPT 13). Results There were 76 men and 33 women with ages ranging from 32 to 75 (median 55
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years). The anatomical sub-sites included palate (9 patients), buccal mucosa(20 patients), floor of mouth (17 patients), Retromolar trigone (6 patients), tongue (43 patients), gingival (14 patients). 61 patients had a positive history of cigarette
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SC
smoking. The tumor characteristics were shown in Table 1.
After pathological assessment of surgery specimen, favorable pathological responses of primary tumor were observed in 32 patients. 48 patients had no positive nodes, 46 patients had 1-3 residual nodes, 13 patients had 3-9 residual nodes, 2 patients
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had more than 10 nodes. Table 2 assessed tumor characteristics associated with post-chemotherapy nodes involvement. The number of involved nodes were significantly associated with clinical node stage at diagnosis and histological
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differentiation. ICT downstage the neck disease in 25.3% of patients with positive
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clinical nodes at diagnosis (N1 and N2). Conversely, 78.9% of initially N0 patients remained pN0 after chemotherapy. In patients with positive nodes at diagnosis, those patients with favorable primary tumor response were more likely to have pN0 than those with unfavorable response (41.6% versus 17.0%, p=0.024). The incidence of distant recurrence for patients with pN0, 1-3 residual nodes, more than 3 residual nodes were 0/48, 4/46, 2/15 (p=0.065).
ACCEPTED MANUSCRIPT The median follow up for all patients was 45 months. The 3-year DFS and OS rates of 109 patients were 69.6% (95% CI, 65.2-74.0%) and 70.6% (95% CI, 66.1-75.1%). In uni-variate analysis, pathological lymph node status was associated with DFS
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(p=0.000) and OS (p=0.000).(Fig.1, Fig.2) The 3-year DFS rates for patients with pN0, 1-3 residual nodes, more than 3 residual nodes were 89.3%, 60.9%, 33.3%. The 3-year OS rates for patients with pN0, 1-3 residual nodes, more than 3 residual nodes
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were 86.8%, 66.1%, 33.3%. Uni-variate analysis also showed that initial N stage was a
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prognostic factor for DFS (p=0.011) and OS (p=0.034). Pathological response of primary tumor was also a prognostic factor for DFS (p=0.031) but not OS. All other variables as gender, age, tobacco history, histological differentiation, T stage, N stage,
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adverse pathological feature were not statistically significant.
Multivariate analysis was performed to investigate the predictive value of gender, age, tobacco history, histological differentiation, T stage, N stage, adverse
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pathological feature, pathological response of primary tumor and post ICT node
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status on DFS and OS. The result showed that only the residual node number after ICT was a significant prognostic factor (p=0.002 for DFS and p=0.005 for OS, Table 3). Other variables did not correlate with survival.
Discussion The strategy of induction chemotherapy prior to planned definitive local therapy for head and neck cancer had been studied for over 30 years with the purpose to
ACCEPTED MANUSCRIPT improve outcome.2 Though up to now ICT failed to showed a survival advantage in unselected HNSCC, it may have a role in select clinical situations, for example the patients at high risk of distant metastasis or those who are very sensitive to ICT7. It is
RI PT
admitted that ICT leads to down-staging of tumor and nodes, so our goal was to determine if the residual number of involved nodes kept a clear prognosis factor for these people. Our result showed that residual number of nodes was the most
SC
significant prognostic factor which was independent of initial clinical node stage at
M AN U
diagnosis and pathologic response of primary tumor. After induction chemotherapy patients with pN0 had better survival while patients with residual nodes (especially those with more than 3 positive nodes) were associated with poor outcomes.
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Previous studies showed that in head and neck cancer persistent neck nodes after ICT was associated with poor prognosis.12 Our result was consistent with their conclusion but more definitive and accurate because our result was based on
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pathological evaluation. Our result suggested that the difference in survival according
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to the number of residual node were highly significant with a decreased survival associated with the increasing number of nodes. Patients with 4 or more residual nodes have a 18-fold increased relative risk of relapse and 12-fold increased relative risk of death compared to patients without residual nodes.
In our study, the clinical N0 stage at diagnosis was 34.8% and after ICT pathological examination showed 44.0% patients were negative node stage. We note that 25.3%
ACCEPTED MANUSCRIPT of patients with clinical positive node were pathological pN0 at surgery, while 21.1% of patients with clinical negative node were pathological node positive even after chemotherapy. We also noted that in patients with clinical N+, the absence of
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residual nodes was significantly associated with favorable pathological response of primary tumor (p=0.024). This result was in accordance with previous reports evaluating ICT in operable breast cancer and indicated that the persistence of
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existence of persistent systemic micrometastasis.13,14
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involved nodes may reflect the tumor chemo-resistance and subsequently the
Our finding raised some questions of interest: is treatment de-escalation feasible in patients with pN0 after ICT? In PARADIGM trial the intensity of subsequent
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chemo-radiotherapy was determined by the pathological response at the primary site and clinical response in the neck.4 And we think number of residual node involvement may be more accurate, because patients with clinical negative node
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after ICT may still had pathologic residual nodes. We also think those patients with
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multiple residual nodes after ICT should merit treatment escalation because of worse outcomes and higher incidence of distant metastasis. Since these patients may benefit little from chemotherapy, the addition of some other modalities (for example, targeted therapy et. al) may help to improve outcomes. Nevertheless there is a problem that in non-surgical approach, the pathological node status is hard to evaluate. We think osition emission tomography/computed tomography (PET/CT) may help to defined the possible status of lymph nodes.15,16
ACCEPTED MANUSCRIPT
In conclusion, we demonstrated that although constituting a different parameter from primary surgery data, the number of residual node involvement after
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chemotherapy could still remain a significant prognostic factor at secondary surgery. Further efforts is to identify which subgroup of patients will benefit from ICT and to investigate whether adjuvant treatment improves survival of patients with residual
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SC
node after primary chemotherapy.
References
1. Pointreau Y, Atean I, Fayette J, Calais G, Lefebvre JL. Induction chemotherapy in head and neck cancer: a new paradigm. Anticancer Drugs. 2011;22:613-620
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2. Fury MG, Shah JP. Induction chemotherapy in the management of head and neck cancer. J Surg Oncol. 2010;101:292-298 3. Cohen EEW, Karrison T, Kocherginsky M, Huang CH, Agulnik M, Mittal BB, et
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al. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F)
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(TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). Journal of Clinical Oncology. 2012;30:
4. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncology.
ACCEPTED MANUSCRIPT 2013;14:257-264 5. Zhong LP, Zhang CP, Ren GX, Guo W, William WN, Jr., Sun J, et al. Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil
Squamous Cell Carcinoma. J Clin Oncol. 2013;31:744-751
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Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral
6. Ma J, Liu Y, Huang XL, Zhang ZY, Myers JN, Neskey DM, et al. Induction
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chemotherapy decreases the rate of distant metastasis in patients with head and
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neck squamous cell carcinoma but does not improve survival or locoregional control: A meta-analysis. Oral Oncology. 2012;48:1076-1084
7. Loo SW, Geropantas K, Roques TW. DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma? Clin
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Transl Oncol. 2013;15:248-251
8. Haigentz M, Jr., Cohen EE, Wolf GT, Strojan P, Eisbruch A, Ferlito A. The future of induction chemotherapy for head and neck squamous cell carcinoma. Oral
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Oncol. 2012;48:1065-1067
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9. Olsen KD, Caruso M, Foote RL, Stanley RJ, Lewis JE, Buskirk SJ, et al. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg. 1994;120:1370-1374
10. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol. 2003;21:327-333
ACCEPTED MANUSCRIPT 11. Mertens LS, Fioole-Bruining A, van Rhijn BW, Kerst JM, Bergman AM, Vogel WV, et al. FDG-positron emission tomography/computerized tomography for monitoring the response of pelvic lymph node metastasis to neoadjuvant
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chemotherapy for bladder cancer. J Urol. 2013;189:1687-1691 12. Wolf GT, Fisher SG. Effectiveness of salvage neck dissection for advanced
preservation. Laryngoscope. 1992;102:934-939
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regional metastases when induction chemotherapy and radiation are used for organ
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13. Cure H, Amat S, Penault-Llorca F, le Bouedec G, Ferriere JP, Mouret-Reynier MA, et al. Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy. Breast Cancer Res Treat. 2002;76:37-45 14. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al.
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Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. Journal of Clinical Oncology. 1999;17:460-469
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15. Yoon DH, Cho Y, Kim SY, Nam SY, Choi SH, Roh JL, et al. Usefulness of interim
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FDG-PET after induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck receiving sequential induction chemotherapy followed by concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:118-125
16. Abgral R, Le Roux PY, Keromnes N, Rousset J, Valette G, Gouders D, et al. Early prediction of survival following induction chemotherapy with DCF (docetaxel, cisplatin, 5-fluorouracil) using FDG PET/CT imaging in patients with locally advanced
ACCEPTED MANUSCRIPT head and neck squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2012;39:1839-1847
Fig. 1 Disease free survival analyzed by Kaplan-Meier method
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Fig. 2 Overall survival analyzed by Kaplan-Meier method
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Figure
ACCEPTED MANUSCRIPT Table.1 Patients' initial clinical characteristics Characteristics
No.
%
Male
76
69.7
Female
33
30.3
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Sex
32-75 (55)
3 residual nodes vs. pN0)
0.000
18.390 (3.621-93.396)
0.001
12.275 (2.724-55.318)
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SC
Abbreviation: DFS=disease free survival; OS=overall survival; CI=confidence interval
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Lymph node status
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SC
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
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SC
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Number of residual node after chemotherapy could still remain a significant prognostic factor at secondary surgery. Further efforts is to identify which patients will benefit from ICT and to investigate whether adjuvant treatment improves survival of patients with residual node.
S2212-4403(14)00477-5
DOI:
10.1016/j.oooo.2014.05.009
Reference:
OOOO 923
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 11 March 2014 Revised Date:
21 April 2014
Accepted Date: 7 May 2014
Please cite this article as: Lyu J, Zhong Y, Li C, Song H, Ren G, Guo W, Prognostic value of residual node involvement after induction chemotherapy in operable oral squamous cell carcinoma, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2014), doi: 10.1016/j.oooo.2014.05.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page Prognostic value of residual node involvement after induction chemotherapy in operable oral squamous cell carcinoma
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SC
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Authors 1. Jiong Lyu (first author) M.S Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 2. Yi Zhong Ph.D Institute of Stomatology，Department of Oral Pathology, Nanjing Medical University Nanjing, China 3. Chaojun Li Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 4. Hao Song M.S Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 5. Guoxin Ren Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China 6. Wei Guo (corresponding author) Ph.D Department of oral and maxillofacial-head and neck oncology, Ninth people's hospital, Shanghai Jiaotong university school of medicine Shanghai, China E-mail: [email protected] OR [email protected] Postal address: No. 639 Zhizaoju Rd, Shanghai 200011, China Telephone number: +8621 5039 8070 Fax number: +8621 5090 5789
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Acknowledgement This work was supported by the Project of Science and Technology Commission of Shanghai Municipality (grants 10410711200 , 08140902100 and 11495802000)
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Key words: induction chemotherapy; oral cancer; lymph node; prognosis
Word count for the abstract:
149
Manuscript word count: 1641 Number of reference: 16 Number of figures/tables: 2/3 Number of supplementary elements: None
ACCEPTED MANUSCRIPT Abstract Objective: The aim of this study was to assess the prognostic value of residual node involvement after induction chemotherapy (ICT) on HNSCC and to investigate
RI PT
post-ICT node status associated with tumor characteristics. Study design: We retrospectively analyzed a cohort of 109 patients with operable oral squamous cell carcinoma underwent ICT followed by surgery with neck
SC
dissection. Median follow-up was 45 months. The primary endpoints were OS and
M AN U
DFS.
Results: After ICT, 48(44.0%) patients had no positive node, 46(42.2%) patients had 1-3 residual nodes, 15(13.7%) patients had more than 3 residual nodes. The number of residual node was significantly associated with OS and DFS. On multivariate
TE D
analysis, the number of residual node was an independent prognostic factor (p=0.011 for DFS and p=0.034 for OS).
Conclusion: Although constituting a different parameter from primary surgery data,
EP
the number of positive nodes after ICT could still remain a prognostic factor at
AC C
secondary surgery.
ACCEPTED MANUSCRIPT Introduction Induction chemotherapy (ICT) is used prior to other modalities and has several potential advantages: by reducing tumor volume, it may permit organ conservation
RI PT
in selected patients; It also allows earlier treatment of micro metastatic diseases.1,2 Nevertheless, ICT in locoregionally advanced head and neck cancer (HNSCC) remains controversial. Several randomized studies (including a phase III randomized trial in
SC
our institute) failed to demonstrate a significant survival advantage with the use of
M AN U
ICT compared with locoregional treatment alone.3-5 However, ICT could decrease the rate of distant metastasis of HNSCC6 and it was reported that clinical complete tumor regression was associated with improved survival. So the potentially beneficial roles
TE D
of ICT in specific patients subsets will warrant additional research and validation.7,8
Investigating prognostic factors to ICT may help to understand its role. In HNSCC, the lymph node status is an important prognostic factor in patients having surgery as
EP
initial treatment9, and higher number of positive nodes are associated with worse
AC C
prognosis. While in ICT setting, the incidence of positive nodes may be reduced by chemotherapy. Consequently, it could possibly modify the prognostic value of this parameter. Whether the residual number of involved nodes kept a clear prognostic factor in HNSCC is unknown.
We hypothesized that in oral cancer, the number of positive nodes after chemotherapy could still remain a valuable prognostic factor. In this retrospective
ACCEPTED MANUSCRIPT study, our aim was to assess the prognostic value of the persistence of node metastasis relative to other clinical variables in 109 patients with oral cancer treated
RI PT
with ICT.
Patients and Methods Patients selection
SC
This retrospective study was approved by the Institutional Review Board, The
M AN U
Shanghai Ninth people's hospital. We reviewed the records of patients with oral SCC who received ICT and surgery between May 2008 and April 2011. The eligibility criteria of this retrospective study included: no prior specific treatment, no metastatic spread, surgery with neck dissection within 4 weeks after ICT. 109 patients
TE D
were analyzed, the following clinical data were collected: age, sex, smoking history, tumor staging, histological grade, treatment information, pathological results,
EP
recurrence and survival.
AC C
Treatment modalities
From May 2008 to April 2011, 109 patients with stage III or IV oral SCC were treated in our institute by one or two cycle of ICT. Each cycle consisted of docetaxel 75mg/m2 intravenous on day 1, cisplatin 75mg/m2 intravenous on day 1, followed by fluorouracil 750mg/m2 given as a 120-hour intravenous infusion, the second cycle was administered 3 weeks after the first one. After ICT, all patient underwent surgery with neck dissection (unilateral/bilateral, functional/radical neck dissection). 92.6%
ACCEPTED MANUSCRIPT patients received post-operation radiotherapy.
Pathological assessment
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Pathological response was assessed after resection of the remaining tumor and nodes. Microscopic examination comprised at least 20 slides per primary tumor and the whole neck dissection. A favorable pathologic response of primary tumor was
SC
defined as absence of any tumor cells or presence of scattered foci of a few tumor
M AN U
cells.5,10 Lymph nodes that is present of viable tumor cells were considered as positive nodes, and those nodes that is absent of tumor cells or show histological changes include fibrosis, chronic inflammatory cell infiltration were considered as
TE D
negative nodes.11
Statistical analyze
Descriptive statistics were used to describe patients' pathological and clinical
EP
characteristics. Chi-square test were used to compare various characteristics
AC C
between subgroups. Overall survival (OS) was measured from the date of initial diagnosis to death due to any cause. Disease free survival (DFS) was measured from the completion of surgery to recurrence/metastasize. The OS and DFS were analyzed by Kaplan-Meier method. The log-rank test was performed to test difference in survival between subgroups. Multivariate analysis was performed using the Cox regression model. All tests were two-sided, and p=0.05 was set as the level of statistical significance. All statistical analyses were done by SPSS program (version
ACCEPTED MANUSCRIPT 13). Results There were 76 men and 33 women with ages ranging from 32 to 75 (median 55
RI PT
years). The anatomical sub-sites included palate (9 patients), buccal mucosa(20 patients), floor of mouth (17 patients), Retromolar trigone (6 patients), tongue (43 patients), gingival (14 patients). 61 patients had a positive history of cigarette
M AN U
SC
smoking. The tumor characteristics were shown in Table 1.
After pathological assessment of surgery specimen, favorable pathological responses of primary tumor were observed in 32 patients. 48 patients had no positive nodes, 46 patients had 1-3 residual nodes, 13 patients had 3-9 residual nodes, 2 patients
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had more than 10 nodes. Table 2 assessed tumor characteristics associated with post-chemotherapy nodes involvement. The number of involved nodes were significantly associated with clinical node stage at diagnosis and histological
EP
differentiation. ICT downstage the neck disease in 25.3% of patients with positive
AC C
clinical nodes at diagnosis (N1 and N2). Conversely, 78.9% of initially N0 patients remained pN0 after chemotherapy. In patients with positive nodes at diagnosis, those patients with favorable primary tumor response were more likely to have pN0 than those with unfavorable response (41.6% versus 17.0%, p=0.024). The incidence of distant recurrence for patients with pN0, 1-3 residual nodes, more than 3 residual nodes were 0/48, 4/46, 2/15 (p=0.065).
ACCEPTED MANUSCRIPT The median follow up for all patients was 45 months. The 3-year DFS and OS rates of 109 patients were 69.6% (95% CI, 65.2-74.0%) and 70.6% (95% CI, 66.1-75.1%). In uni-variate analysis, pathological lymph node status was associated with DFS
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(p=0.000) and OS (p=0.000).(Fig.1, Fig.2) The 3-year DFS rates for patients with pN0, 1-3 residual nodes, more than 3 residual nodes were 89.3%, 60.9%, 33.3%. The 3-year OS rates for patients with pN0, 1-3 residual nodes, more than 3 residual nodes
SC
were 86.8%, 66.1%, 33.3%. Uni-variate analysis also showed that initial N stage was a
M AN U
prognostic factor for DFS (p=0.011) and OS (p=0.034). Pathological response of primary tumor was also a prognostic factor for DFS (p=0.031) but not OS. All other variables as gender, age, tobacco history, histological differentiation, T stage, N stage,
TE D
adverse pathological feature were not statistically significant.
Multivariate analysis was performed to investigate the predictive value of gender, age, tobacco history, histological differentiation, T stage, N stage, adverse
EP
pathological feature, pathological response of primary tumor and post ICT node
AC C
status on DFS and OS. The result showed that only the residual node number after ICT was a significant prognostic factor (p=0.002 for DFS and p=0.005 for OS, Table 3). Other variables did not correlate with survival.
Discussion The strategy of induction chemotherapy prior to planned definitive local therapy for head and neck cancer had been studied for over 30 years with the purpose to
ACCEPTED MANUSCRIPT improve outcome.2 Though up to now ICT failed to showed a survival advantage in unselected HNSCC, it may have a role in select clinical situations, for example the patients at high risk of distant metastasis or those who are very sensitive to ICT7. It is
RI PT
admitted that ICT leads to down-staging of tumor and nodes, so our goal was to determine if the residual number of involved nodes kept a clear prognosis factor for these people. Our result showed that residual number of nodes was the most
SC
significant prognostic factor which was independent of initial clinical node stage at
M AN U
diagnosis and pathologic response of primary tumor. After induction chemotherapy patients with pN0 had better survival while patients with residual nodes (especially those with more than 3 positive nodes) were associated with poor outcomes.
TE D
Previous studies showed that in head and neck cancer persistent neck nodes after ICT was associated with poor prognosis.12 Our result was consistent with their conclusion but more definitive and accurate because our result was based on
EP
pathological evaluation. Our result suggested that the difference in survival according
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to the number of residual node were highly significant with a decreased survival associated with the increasing number of nodes. Patients with 4 or more residual nodes have a 18-fold increased relative risk of relapse and 12-fold increased relative risk of death compared to patients without residual nodes.
In our study, the clinical N0 stage at diagnosis was 34.8% and after ICT pathological examination showed 44.0% patients were negative node stage. We note that 25.3%
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residual nodes was significantly associated with favorable pathological response of primary tumor (p=0.024). This result was in accordance with previous reports evaluating ICT in operable breast cancer and indicated that the persistence of
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existence of persistent systemic micrometastasis.13,14
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involved nodes may reflect the tumor chemo-resistance and subsequently the
Our finding raised some questions of interest: is treatment de-escalation feasible in patients with pN0 after ICT? In PARADIGM trial the intensity of subsequent
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chemo-radiotherapy was determined by the pathological response at the primary site and clinical response in the neck.4 And we think number of residual node involvement may be more accurate, because patients with clinical negative node
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after ICT may still had pathologic residual nodes. We also think those patients with
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multiple residual nodes after ICT should merit treatment escalation because of worse outcomes and higher incidence of distant metastasis. Since these patients may benefit little from chemotherapy, the addition of some other modalities (for example, targeted therapy et. al) may help to improve outcomes. Nevertheless there is a problem that in non-surgical approach, the pathological node status is hard to evaluate. We think osition emission tomography/computed tomography (PET/CT) may help to defined the possible status of lymph nodes.15,16
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In conclusion, we demonstrated that although constituting a different parameter from primary surgery data, the number of residual node involvement after
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chemotherapy could still remain a significant prognostic factor at secondary surgery. Further efforts is to identify which subgroup of patients will benefit from ICT and to investigate whether adjuvant treatment improves survival of patients with residual
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node after primary chemotherapy.
References
1. Pointreau Y, Atean I, Fayette J, Calais G, Lefebvre JL. Induction chemotherapy in head and neck cancer: a new paradigm. Anticancer Drugs. 2011;22:613-620
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2. Fury MG, Shah JP. Induction chemotherapy in the management of head and neck cancer. J Surg Oncol. 2010;101:292-298 3. Cohen EEW, Karrison T, Kocherginsky M, Huang CH, Agulnik M, Mittal BB, et
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al. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F)
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(TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). Journal of Clinical Oncology. 2012;30:
4. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncology.
ACCEPTED MANUSCRIPT 2013;14:257-264 5. Zhong LP, Zhang CP, Ren GX, Guo W, William WN, Jr., Sun J, et al. Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil
Squamous Cell Carcinoma. J Clin Oncol. 2013;31:744-751
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Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral
6. Ma J, Liu Y, Huang XL, Zhang ZY, Myers JN, Neskey DM, et al. Induction
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chemotherapy decreases the rate of distant metastasis in patients with head and
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neck squamous cell carcinoma but does not improve survival or locoregional control: A meta-analysis. Oral Oncology. 2012;48:1076-1084
7. Loo SW, Geropantas K, Roques TW. DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma? Clin
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Transl Oncol. 2013;15:248-251
8. Haigentz M, Jr., Cohen EE, Wolf GT, Strojan P, Eisbruch A, Ferlito A. The future of induction chemotherapy for head and neck squamous cell carcinoma. Oral
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Oncol. 2012;48:1065-1067
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9. Olsen KD, Caruso M, Foote RL, Stanley RJ, Lewis JE, Buskirk SJ, et al. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg. 1994;120:1370-1374
10. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol. 2003;21:327-333
ACCEPTED MANUSCRIPT 11. Mertens LS, Fioole-Bruining A, van Rhijn BW, Kerst JM, Bergman AM, Vogel WV, et al. FDG-positron emission tomography/computerized tomography for monitoring the response of pelvic lymph node metastasis to neoadjuvant
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chemotherapy for bladder cancer. J Urol. 2013;189:1687-1691 12. Wolf GT, Fisher SG. Effectiveness of salvage neck dissection for advanced
preservation. Laryngoscope. 1992;102:934-939
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regional metastases when induction chemotherapy and radiation are used for organ
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13. Cure H, Amat S, Penault-Llorca F, le Bouedec G, Ferriere JP, Mouret-Reynier MA, et al. Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy. Breast Cancer Res Treat. 2002;76:37-45 14. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al.
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Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. Journal of Clinical Oncology. 1999;17:460-469
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15. Yoon DH, Cho Y, Kim SY, Nam SY, Choi SH, Roh JL, et al. Usefulness of interim
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FDG-PET after induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck receiving sequential induction chemotherapy followed by concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:118-125
16. Abgral R, Le Roux PY, Keromnes N, Rousset J, Valette G, Gouders D, et al. Early prediction of survival following induction chemotherapy with DCF (docetaxel, cisplatin, 5-fluorouracil) using FDG PET/CT imaging in patients with locally advanced
ACCEPTED MANUSCRIPT head and neck squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2012;39:1839-1847
Fig. 1 Disease free survival analyzed by Kaplan-Meier method
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Fig. 2 Overall survival analyzed by Kaplan-Meier method
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Figure
ACCEPTED MANUSCRIPT Table.1 Patients' initial clinical characteristics Characteristics
No.
%
Male
76
69.7
Female
33
30.3
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Sex
32-75 (55)
3 residual nodes vs. pN0)
0.000
18.390 (3.621-93.396)
0.001
12.275 (2.724-55.318)
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Abbreviation: DFS=disease free survival; OS=overall survival; CI=confidence interval
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Lymph node status
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Number of residual node after chemotherapy could still remain a significant prognostic factor at secondary surgery. Further efforts is to identify which patients will benefit from ICT and to investigate whether adjuvant treatment improves survival of patients with residual node.
