Predictors for Tumor Recurrence After Primary Definitive Surgery for Oral Cancer

J Oral Maxillofac Surg 70:1724-1732, 2012

Predictors for Tumor Recurrence After Primary Definitive Surgery for Oral Cancer Inés Vázquez-Mahía, MD, PhD,* Juan Seoane, MD, DDS, MPDH, PhD,† Pablo Varela-Centelles, DDS, MMedSci, MPDH, PhD,‡ Inmaculada Tomás, DDS, PhD,§ Augusto Álvarez García, MD, PhD,储 and José Luis López Cedrún, MD, DDS, PhD¶ Purpose: The purpose of this study was to identify significant predictors for oral squamous cell

carcinoma recurrence. Patients and Methods:

This Ambispective cohort study was performed in consecutive metastasis-free patients treated for oral squamous cell carcinoma with curative intent from 1998 through 2003. Variables included gender, age, tumor site, macroscopic pattern of the lesion, coexisting disorders (diabetes, hepatic and heart disorders, other tumors/diseases), degree of differentiation, and pathologic TNM stage. Tumor recurrence was considered the dependent variable (outcome). The distribution of recurrences was assessed with ␹2 test. Survival times were estimated by Kaplan-Meier curves and differences were examined with log-rank test. Multiple Cox regression study was also performed. The significance level chosen for all tests was P ⬍ .05. Results: One hundred eighteen patients entered the study. Tumor recurrence was 44.9% during the follow-up period (10% local, 29.7% regional, and 5% distant). The mean period that had elapsed before recurrence was 15 months (1.5 to 81.8), with most recurrences (66%) during the first year after treatment (84.9% before 2 years). Multivariate Cox regression analysis indicated the presence of a coexisting disorder (P ⫽ .022) as the most relevant prognostic factor for relapse, because patients with associated diseases had a 2.43-fold risk of recurrence. Tumor stage (P ⫽ .037), degree of differentiation (P ⫽ .042), and macroscopic pattern of the lesion (P ⫽ .022) were also identified as prognostic factors for relapse. Conclusions: The risk profile for oral cancer recurrence includes patients younger than 60 years with coexisting diseases whose primary tumor occurred as an ulcerated lesion, and diagnosed at an advanced stage with a poorly differentiated tumor. © 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:1724-1732, 2012 Oral cancer is a serious and growing problem in many parts of the world; its estimated incidence is around 275,000 cases per year, with two-thirds of cases occurring in developing countries, with wide geographic variations (approximately 20-fold).1-3 Oral cancer remains a lethal disease for more than 50% of cases diagnosed annually.4 This out-

Received from A Coruña University Hospital, A Coruña, and the Stomatology Department, School of Medicine and Dentistry, Santiago de Compostela University, Santiago de Compostela, Spain. *Staff Physician, Service of Maxillofacial Surgery, A Coruña University Hospital. †Senior Lecturer and Head, Stomatology Department. ‡Lecturer, Stomatology Department. §Senior Lecturer, Stomatology Department. 储Staff Physician, Pathology Service, A Coruña University Hospital.

come is greatly influenced by the stage of the tumor (especially pathologic TNM staging)5 and recurrence of the disease after treatment.6 Screening for recurrences is an essential step in the first 5 years after treatment.2 Despite the progress made in early detection and therapy,7-10 early predictors of cancer recurrence at

¶Director, Service of Maxillofacial Surgery, A Coruña University Hospital. Address correspondence and reprint requests to Dr Seoane: Cantón Grande 5, Apt 1oE, 15003 A Coruña, Spain; e-mail: [email protected] © 2012 American Association of Oral and Maxillofacial Surgeons

0278-2391/12/7007-0$36.00/0 doi:10.1016/j.joms.2011.06.228

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the time of diagnosis or treatment are still missing for oral cancer. Pathologic features reflecting the tumorhost relation, such as the pattern of invasion, lymphocyte infiltration, perineural invasion, bone involvement, non-T4 muscular invasion, and the presence of abundant stromal myofibroblast, have been proved to predict local recurrence.5,6,11,12 Disease recurrence has also been linked to quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation,13 expression of RACK1 (receptor for activated C kinase-1),14 Ki-67,15 and a penetrating pattern of CD34, which have been used as predictive markers for early-stage oral carcinomas.16 These parameters may play a significant role in determining the therapeutic strategies for these patients, but very few studies have focused on clinical and pathologic prognostic factors that might predict the appearance of local recurrence from oral squamous cell carcinoma (OSCC).6 There is also a lack of consistent information on the clinical and pathologic features of those patients at risk of developing disease recurrence (local, regional, or distant), although a positive identification of recurrence predictors could assist in the surveillance for recurrent disease in this high-risk group.1,2 Thus, the purpose of this study was to identify significant predictors for OSCC recurrence under the hypothesis that some tumor features and/or patient characteristics favor tumor relapse after successful surgical treatment. The specific aims of this investigation were to disclose those tumor features related to recurrence and to assess whether concurrent disorders influence tumor relapse after successful surgical treatment for oral cancer.

Patients and Methods A retrospective cohort study was designed to analyze the presence of recurrences (survival study considering the date of treatment, ie, beginning of the study, and the date of diagnosis of the recurrence, ie, end of the study). This retrospective approach allowed the analysis of retrospective data (obtained from patients’ clinical records) and prospective observations recorded throughout the length of the study period. The study sample was composed of consecutive patients treated at the Service of Oral and Maxillofacial Surgery of A Coruña University Hospital from January 1998 through December 2003 who met the following inclusion criteria: a pathologic diagnosis of OSCC at any American Joint Committee on Cancer site,17 a tumor at any TNM stage,18 previous surgical treatment with curative intent, and an absence of distant metastases. Exclusion criteria were early re-

currence (ⱕ6 weeks after treatment) and incomplete clinical records. The variables considered were demographic (gender and age), clinical (tumor site and macroscopic pattern of the lesion [ulcerated, exophytic, or mixed]), coexisting disorders (ICD-10CM (International Classification of Diseases, 10th Revision, Clinical Modification): diabetes, hepatic and heart disorders, other tumors, and other diseases),19 and pathologic (degree of differentiation and pathologic TNM stage). The presence of tumor recurrence was considered the dependent variable (outcome), defined as reappearance of disease in a patient treated with curative intention,20 provided it occurred beyond 6 weeks after treatment.21 The study protocol was accepted by the University of Santiago de Compostela ethics committee and carried out according to European Union ethical protocols. STATISTICAL ANALYSIS

Data were analyzed with SPSS 12.0 (SPSS, Inc, Chicago, IL) and the sample was characterized by the variables of interest. The distribution of recurrences according to the different variables was assessed with ␹2 test (or Fisher exact test). Survival times were estimated by Kaplan-Meier curves and the differences between curves were examined with log-rank test. Multiple regression study was performed using Cox proportional hazard analysis. The statistical significance chosen for all tests was P ⬍ .05.

Results One hundred thirty-one patients were diagnosed during the study period, and 118 of them met the inclusion/exclusion criteria (mostly men, 2.27:1) and entered the study (Table 1). The mean age of the sample was 61.22 ⫾ 12.67 years (range, 36 to 88 years; median, 60 years). Tumor recurrence was 44.9% during the follow-up period (10% local, 29.7% regional, and 5% distant). The mean period that had elapsed until recurrence was 15 months (1.5 to 81.8), with most recurrences (66%) occurring during the first year after treatment (84.9% before 2 years). Patients with recurrent disease were about 5 years younger (57.87 vs 63) (P ⫽ .062), with significant differences among age groups. The macroscopic pattern of the lesion at diagnosis also influenced recurrence, being more common among ulcerated-type lesions (P ⫽ .029). Neck node status (P ⫽ .019), advanced stage at diagnosis (P ⫽ .024), and degree of differentiation of the tumor also showed an influence on disease recurrence.

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TUMOR RECURRENCE AFTER ORAL CANCER SURGERY

Table 1. CHARACTERIZATION OF SAMPLE (n ⴝ 118)

Variable

Patients

%

Cumulative (%)

Age (yrs), mean ⫾ standard deviation Gender Male Female Tobacco use Former smoker Nonsmoker Smoker Alcohol use Former drinker Nondrinker Drinker Precancerous lesions No Leukoplakia Erythroplakia Other Site Oral tongue Floor of mouth Gingiva (upper and lower) Oral mucosa Retromolar trigone Hard palate Macroscopic pattern Exophytic Ulcerated Mixed Coexisting disorders Yes No Surgical treatment Resection Resection ⫹ neck dissection Pathologic tumor size T0 Tis T1 T2 T3 T4 Neck node status Negative (N0) Positive (N1, 2, 3) Stage I II III IV Degree of differentiation Gx G1 G2 G3 Recurrence No Local Neck Distant

61.22 ⫾ 12.67 82 36

69.5 30.5

69.5 100

24 28 55

22.4 26.2 51.4

22.4 48.6 100

16 33 54

15.5 32 52.4

15.5 47.6 100

98 8 6 6

83.1 6.8 5.1 5.1

83.1 89.8 94.9 100

46 34 18 5 12 3

39 28.8 15.3 4.2 10.2 2.5

39 67.8 83.1 87.3 97.5 100

14 67 16

14.4 69.1 16.5

14.4 83.5 100

38 68

35.8 64.2

35.8 100

24 94

20.3 79.7

20.3 100

1 2 13 58 13 31

0.8 1.7 11 49.2 11 26.3

0.8 2.5 13.6 62.7 73.7 100

80 38

67.8 32.2

67.8 100

11 41 19 45

9.5 35.3 16.4 38.8

9.5 44.8 61.2 100

5 40 66 7

4.2 33.9 55.9 5.9

4.2 38.1 94.1 100

65 12 35 6

55.1 10.2 29.7 5

55.1 65.3 94.9 100

Abbreviations: Gx, undetermined; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated. Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

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VÁZQUEZ-MAHÍA ET AL

FIGURE 1. Recurrence-free patients in the present series (censored, lost to follow-up). Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

Survival analysis showed that 60.1% of survivors and 52.36% of all patients considered in the study were free of disease 5 years after treatment (Fig 1). Univariate survival analysis showed that patient age influenced tumor recurrence, which appeared

later in older patients (Fig 2); when the sample was divided into 2 groups by the median of the distribution (⬍60 and ⬎60 years), the differences were still significant (P ⫽ .029). The macroscopic pattern of the lesion (Fig 3) and the differentiation degree

FIGURE 2. Survival curves for the variable age (censored, lost to follow-up). Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

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FIGURE 3. Survival curves for the variable macroscopic pattern (censored, lost to follow-up). Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

FIGURE 4. Survival curves for the variable degree of differentiation (censored, lost to follow-up). Gx, undetermined; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated. Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

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Table 2. UNIVARIATE COX REGRESSION

Variable

n

Age (yrs) Gender Female* Male Tobacco habit Nonsmoker/former smoker* Smoker Alcohol intake Nondrinker/former drinker* Drinker Precancerous lesions No* Leukoplakia Erythroplakia Other Site Hard palate* Oral tongue Floor of mouth Gingiva (upper and lower) Oral mucosa Retromolar trigone Macroscopic pattern Exophytic and mixed* Ulcerated Coexisting disorders No* Yes Surgical treatment Resection* Resection ⫹ neck dissection Pathologic tumor size T1* T2 T3 T4* Other Neck node status Negative (N0)* Positive (N1, 2, 3) Disease stage I* II III IV Degree of differentiation G1* G2 G3

116

RR

95% CI

P

0.98

0.96-1.00

.11

82 34

1 0.54

0.28-1.03

.06

51 55

1 0.88

0.45-1.70

.70

48 54

1 1.07

0.59-2.02

.77

96 8 6 6

1 0.961 0.19 1.23

0.342-2.70 0.02-1.71 0.31-4.93

.94 .14 .77

3 44 34 18 5 12

1 2.40 1.76 1.96 2.11 1.60

0.32-17.87 0.23-13.53 0.24-15.74 0.19-23.33 0.19-13.77

.39 .59 .53 .54 .67

33 66

1 0.41

0.19-0.80

.02

67 37

1 0.63

0.33-1.20

.16

24 92

1 0.48

0.21-1.07

.07

12 58 12 31 3

1 6,110.05 8,218.50 14,223.42 9,302.58

0.00 0.00 0.00 0.00

.90 .90 .89 .90

78 38

1 0.62

0.36-1.08

.09

10 41 18 45

1 0.32 0.69 0.98

0.07-1.36 0.37-1.30 0.47-2.04

.12 .25 .95

38 66 7

1 0.36 0.46

0.13-0.99 0.18-1.19

.05 .11

Abbreviations: CI, confidence interval; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; RR: relative risk. *Reference. Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

(Fig 4) were also recognized as significant by survival analysis (Table 2). Although patient gender did not influence disease relapse, the recurrence-free time after treatment was noticeably shorter for men. The same situation occurred when the pres-

ence of additional disorders was explored (the trend toward recurrence was lower for those patients whose cancer was a single disease) and when tumor stage or neck node status was considered in univariate analysis.

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Table 3. MULTIVARIATE COX REGRESSION MODEL FOR TUMOR RECURRENCE

Variable Degree of differentiation Well differentiated* Moderately differentiated Poorly differentiated Age Coexisting disorders No* Yes Disease stage I, II, III* IV Macroscopic pattern Exophytic or mixed* Ulcerated

RR

95% CI

P

1 2.01 5.63 0.55

0.90-4.50 1.39-22.8 0.27-1.12

.90 .02 .098

1 2.44

1.13-5.24

.02

1 2.08

1.04-4.13

.04

1 2.44

1.13-5.24

.02

NOTE. Model was adjusted by gender, type of surgical treatment, and neck node status. Abbreviations: CI, confidence interval; RR, relative risk. *Reference. Vázquez-Mahía et al. Tumor Recurrence After Oral Cancer Surgery. J Oral Maxillofac Surg 2012.

Multivariate Cox regression analysis resulted in a model (Table 3) in which the most relevant variable for predicting disease recurrence was the presence of a coexisting disorder (P ⫽ .022), because patients with associated diseases had a 2.43-fold risk of recurrence. Tumor stage also predicted relapse of the disease (P ⫽ .037), because stage IV indicated a 2.07-fold risk of recurrence. Poorly differentiated tumors had a 5.6-fold risk of recurrence compared with well-differentiated tumors. Ulcerated macroscopic patterns showed a recurrence risk 2.4 times higher than exophytic and mixed presentations (P ⫽ .022). The resulting model showed that patient age (beyond 60 years) was a protective factor against relapse, but it did not reach statistical signification.

Discussion Although some reports have focused on unveiling the determining factors for locoregional tumor recurrence,6 the present study defined recurrence as local relapse, neck metastases, and distant metastases20,22 to identify those variables with predictive value for disease recurrence at any site. No standard criteria are universally available concerning the definition of recurrence. In this study, an interval beyond 6 weeks after treatment was chosen as an inclusion criterion for analysis. In any case, a very early recurrence could be explained only by the existence of positive surgical margins or the presence of genetically altered tissue adjacent to the original tumor.23

The interval from treatment to recurrence is an independent prognostic factor for patients with OSCC, and different cutoff points have been established (12 vs 18 months)24,25 beyond which a significant improvement of survival rates occur. The interval of recurrence for the present series showed an average of 15 months, which is consistent with previous reports.26 Tumor relapse at the site of primary lesions occurs in 7.9%27 to 18.71%28 of patients, with recurrences in the neck occurring in 13.86%27 to 40%26 of cases. The present results are consistent with these intervals for locoregional recurrences. Distant metastasis has been reported to occur in 5% to 25% of patients with OSCC, most commonly in uncontrolled locoregional and N-stage diseases, especially N2/N3. Extracapsular spread is a very strong predictor for systemic spread.22,29,30 Recurrence for OSCC within the first 36 months after treatment has been reported to occur in more than 85% of cases,31 whereas the present results showed that 57.7% of patients in this series were free of recurrence 3 years after treatment. Tumor recurrence implies a poor prognosis for patients with oral cancer, with a mortality rate close to 90%.32 The present series showed a mortality rate of 79.2% in patients with recurrence. Other investigations have reported a 5-year survival rate of 30.5% for those patients with neck recurrence.33 Several reports have disagreed on the association among age, gender or tumor site, and oral cancer recurrence.6,11 Regarding demographic variables, only age at diagnosis was found to be a prognostic factor as identified by Kaplan-Meier curves and log-rank test, because patients older than 60 years showed significantly longer recurrence-free times.12 The same results have been reported for patients older than 40 years.34 Although the site of the primary tumor, in particular the lateral border of the tongue and the floor of the mouth, can predict prognosis, probably because of the lymphatic drainage of these locations,22 the present results showed that no intraoral subsite influenced disease relapse. This finding agrees with previous reports, chiefly at early stages (I to II);11 but not for advanced stages, where the oral subsite may influence recurrence,35 probably because of a compromise at the surgical margins of the tumor. The predictive value for survival of the clinical appearance of the lesion is controversial, although it is accepted that ulcerated lesions imply poorer survival rates.36,37 The present study showed that ulcerated lesions predict shorter recurrence-free times. The existence of precancerous lesions associated with the tumor does not seem to modify the recurrence-free intervals, although proliferative verrucous leukoplakia11 or the presence of mild or moderate

VÁZQUEZ-MAHÍA ET AL

epithelial dysplasia at the margins of a surgically removed OSCC carries a significant risk of development of local recurrence.38 The presence of a simultaneous disorder can independently predict survival from oral cancer, and previous reports have proved a link between coexisting diseases and tumor recurrence,39 although it remains unclear how this association varies when adjustment for other covariates is performed. In the present study, the presence of additional disorders had an important weight in the multivariate model, because patients with coexisting pathologies showed shorter recurrence-free intervals. Advanced disease stages (pathologic TNM stages III and IV) at diagnosis also recur more frequently,6 as confirmed by the present results when recurrence at any site of the body is considered. The influence of histologic grading as a prognostic factor in OSCC has been found to be a predictor of regional failure and tumor recurrence (significantly better node control in well- and moderately differentiated tumors than that in poorly differentiated tumors).5 In the present series, poorly differentiated OSCC independently indicated a higher risk for tumor recurrence and shorter interval to relapse. Tumor heterogeneity and assessment of the degree of differentiation from oral biopsies and not from the surgical specimen may explain the dissimilarities in the results obtained for this variable by different research groups considering locoregional recurrence as the outcome.5,11 Although some reports have reported little benefit from the early recognition of relapses in SCC of the tongue,40 a prompt diagnosis of oral cancer recurrence seems to be significantly important to offer the patient a realistic second treatment. In this sense and taking into account the limitations inherent to this type of investigation, it is concluded that the risk profile for oral cancer recurrence includes a patient age younger than 60 years, presence of coexisting disease, and a primary tumor that occurred as an ulcerated lesion and was diagnosed at an advanced stage with a poorly differentiated tumor. The adequate identification of this kind of patient would allow for the development of adjusted follow-up programs and earlier diagnosis in the event of disease relapse.

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TUMOR RECURRENCE AFTER ORAL CANCER SURGERY 35. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al: Oral squamous cell carcinoma: Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 29:167, 2005 36. Jaulerry C, Bataini JP, Brunin F, et al: Facteurs pronostiques et résultants de l’irradiation externe des cancers de la base de langue. Ann Otolaryngol Chir Cervicofac 102:519, 1985 37. Wood NK, Goaz PW: Solitary oral ulcers and fissures, in Differential Diagnosis of Oral Lesions. Wood NK, Goaz PW (eds.). St Louis, Mosby, 1997, pp 162-181 38. Thomson PJ, Hamadah O: Cancerisation within the oral cavity: The use of. Oral Oncol 43:20, 2007 39. Alho OP, Hannula K, Luokkala A, et al: Differential prognostic impact of comorbidity in head and neck cancer. Head Neck 29:913, 2007 40. González-García R, Naval-Gías L, Sastre-Pérez J, et al: Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: A retrospective analytic study of 203 patients. Int J Oral Maxillofac Surg 36:507, 2007