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Clinical Cancer Research Vol. 5, 801-806, April 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic Significance of Clinical Parameters and Biological Markers in Patients with Squamous Cell Carcinoma of the Head and Neck Treated with Concurrent Chemoradiotherapy1

Akihiro Homma2, Yasushi Furuta, Nobuhiko Oridate, Yuko Nakano, Gen Kohashi, Katsunori Yagi, Tatsumi Nagahashi, Satoshi Fukuda, Kazuaki Inoue and Yukio Inuyama

Departments of Otolaryngology [A. H., Y. F., N. O., Y. N., K. Y., T. N., S. F., Y. I.] and Public Health [G. K.], Hokkaido University School of Medicine, and Department of Pathology, Hokkaido University Hospital [K. I.], Sapporo 060-8648, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Concurrent chemoradiotherapy is reported to have a fair clinical outcome with organ preservation for patients with squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to determine whether biological markers are related to proliferative activity or apoptosis of tumor cells and whether clinical factors are associated with a clinical outcome in SCCHN patients treated with concurrent chemoradiotherapy.

Immunostaining with antibodies specific for p53, bcl-2, bax, and MIB-1 was performed to evaluate expression of these proteins in formalin-fixed, paraffin-embedded specimens of 111 SCCHN patients treated with concurrent chemoradiotherapy (carboplatin, 100 mg/m2, four to six times every week; total radiation therapy dose of 40–65 Gy over 4–6.5 weeks).

Multivariate analysis indicated that nodal status was a significant indicator of overall survival (OS; P = 0.001) and locoregional control (LRC; P = 0.002). In a univariate analysis, patients with a low MIB-1-positive index (< 40%) had better OS than those with a high MIB-1-positive index (>=40%; P = 0.013), although the difference was not statistically significant in a multivariate analysis (P = 0.060). Patients with bcl-2-positive tumors had better LRC than those with bcl-2-negative tumors, based on a multivariate analysis (P = 0.017). No statistically significant association was found between p53 or bax expression and clinical outcome.

These results indicate that nodal status is the major prognostic factor in SCCHN patients treated with concurrent chemoradiotherapy. In addition, our findings suggest that bcl-2 positivity is associated with better LRC and that the proliferative activity of tumor cells might be prognostic for OS.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chemoradiotherapy has been investigated in SCCHN3 as a treatment for patients with locally advanced disease. Despite the high response rate achieved, an enhancement of long-term tumor control or increased survival is still controversial (1, 2, 3, 4) . Although patients with nonrecurrent tumor have a good quality of life with organ preservation, salvage surgery is required for patients with residual or recurrent diseases. Such patients require a prolonged treatment course and suffer a decreased quality of life. Therefore, there is interest in finding a predictive factor to indicate which patients will have a poor outcome.

Several biological markers have been analyzed for clinical significance as predictive factors. Tumor cell kinetics is one of the most useful parameters for understanding tumor behavior (5) . Proliferative activity of the tumor cells has been investigated using immunohistochemical staining with antibodies against proliferation-associated markers, such as Ki-67 and proliferating cell nuclear antigens. Although several studies have demonstrated that proliferative activity is valuable as a prognostic marker (6, 7, 8) , no investigation to date has analyzed its significance in patients with SCCHN treated with concurrent chemoradiotherapy.

In addition, recent studies suggest that induction of apoptosis in tumor cells has an important role in radiation and chemotherapy (9) . One of the functions of the tumor suppressor gene p53 is the induction of apoptosis. Bcl-2 protein and its family members, including bax, bcl-X, and mcl-1, regulate programmed cell death after an apoptotic stimulus (10) . An important feature of bcl-2 is its ability to inhibit apoptosis induced by radiation and chemotherapeutic agents (11) . In contrast, bax protein promotes cell death (12) . Several groups have attempted to clarify the significance of expression of these proteins in clinicopathological behavior of tumor cells. Thus far, controversial results have been reported on the prognostic values of these factors (8 , 13, 14, 15, 16, 17, 18) . Here, we examined the expression of p53, bcl-2, bax, and MIB-1 in patients with SCCHN treated with concurrent chemoradiotherapy and sought to determine whether these biological markers in addition to clinical factors predict a clinical outcome.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Patients with SCCHN (n = 147) underwent concurrent chemoradiotherapy at Hokkaido University Hospital from November 1990 to November 1994. Radiotherapy was administered at a daily dose of 2.5 Gy, four times a week. Carboplatin (100 mg/m2) was administered i.v. in 250 ml of 5% glucose, once a week, 1 h before radiotherapy. After a dose of 40 Gy was administered, the response of primary and nodal tumors was evaluated by both radiation oncologists and otolaryngologists. If the percentage of tumor shrinkage was <50% in at least one dimension by endoscopic examination and/or on computed tomography or magnetic resonance imaging examination, chemoradiotherapy was terminated, and radical surgery was indicated. Otherwise, a total dose of 65 Gy was indicated using a field shrinkage technique. After completion of chemoradiotherapy, salvage surgery was performed, if possible, for residual or recurrent locoregional diseases. Patients were staged according to Union Internationale Contre le Cancer tumor-node-metastasis clinical classification (19) . All H&E-stained specimens were reviewed to confirm original diagnosis and to determine the histological grading according to a modification of the Broders method (20 , 21) by one of the authors (K. I.) who had no knowledge of the clinical outcome.

Immunohistochemical Staining.
Paraffin-embedded tumor specimens from the primary site were available from 111 of the 147 patients. These specimens were cut into 4-µm-thick sections. The specimens were then deparaffinized in xylene, dehydrated through graded alcohols and placed in 0.1% hydrogen peroxide to quench endogenous peroxidase activity. Following microwave pretreatment in citrate buffer (pH 6.0) three times for 5 min at 750 W, these sections were treated with 10% normal rabbit or goat serum for 30 min to prevent nonspecific binding of the antibody. The slides were then incubated with four different antibodies overnight at 4°C. We used an anti-p53 antibody (DO7, 1:100 dilution; Novacastra Laboratories, Newcastle, United Kingdom), an anti-bcl-2 antibody (NCL-bcl-2, 1:80 dilution; Novacastra Laboratories, Newcastle, United Kingdom), an anti-bax antibody (4F11, 1:3000 dilution; Phar-Mingen, San Diego, CA), and an anti-Ki-67 antibody (MIB-1, 1:100 dilution; Immunotech SA, Marseille, France). Tissues were incubated with a biotin-labeled rabbit antimouse or goat antirabbit secondary antibody [Histofine SAB-PO(M) kit; Nichirei, Tokyo, Japan] for 30 min at 37°C followed by reaction with streptavidin-biotin horseradish peroxidase complex [Histofine SAB-PO(M) kit]. The reaction products were visualized by immersing the slides in freshly prepared diaminobenzidine solution for 10 min and counterstained with hematoxylin before dehydration and mounting.

The percentage of p53 or MIB-1-positive tumor cells was determined by counting the number of brown-stained tumor nuclei in the most highly stained area on each slide. We used an image analysis system (Video Micro Meter Model VM-30; Olympus, Tokyo, Japan) linked to a light microscope at high magnification. In each specimen, we examined 117-1196 tumor cells (mean, 1003) in different selected fields containing tumor tissue. A p53 or MIB-1-positive index was calculated from the ratio of the number of positively stained tumor cells to the total number of tumor cells counted per section. This procedure was performed in all cases by one investigator (Y. N.) who had no knowledge of the clinical outcome. p53 expression was categorized as positive when >10% of the tumor nuclei were stained according to previous reports (13 , 14) .

Bcl-2 or bax immunoreactivity was localized in the cytoplasm of neoplastic cells. The expression of these proteins was categorized according to previous reports (18 , 22) as follows: negative, <30% of tumor cells were stained; positive, >30% of tumor cells were stained.

Statistical Analysis.
All patients were closely observed during follow-up. The longest follow-up period was 70 months, and the shortest was 24 months (the median and mean follow-up periods were 46.9 and 45.9 months, respectively).

The nonparametric Mann-Whitney U test was used to compare the percentage of p53- and MIB-1-positive cells with age, sex, T stage, nodal status, clinical stage, and histological grading. The nonparametric Kruskal-Wallis test was used for comparisons of p53- and MIB-1-positive cells with primary sites. Contingency table analyses based on {chi}2 statistics were used to determine statistical significance of associations between categorical variables. Patients who received surgery after 40 Gy of chemoradiotherapy and or patients with persistent or recurrent locoregional disease after 65 Gy were considered locoregional failures. The probability of OS and LRC was calculated using the Kaplan-Meier method and was compared using the log-rank test. The Ps less than 0.05 were considered significant. For determination of factors related to OS and LRC, a Cox proportional hazards model was used. Statistical significance was defined as a two-tailed P less than 0.05. Statistical calculations were performed using the Statview software package (Version 4.5; Abacus Concepts, Inc., Berkeley, CA).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathological Parameters and Outcome.
The clinicopathological characteristics of the 111 patients with SCCHN are shown in Table 1Citation . Of the 111 patients, 102 patients (91.9%) underwent 65 Gy of radiotherapy with four to six doses of carboplatin, whereas 9 patients received surgery after 40 Gy of chemoradiotherapy because of poor responses. The 5-year OS and LRC rate were 63.8% and 51.3%, respectively, for this study group.


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  		Table 1 Clinicopathological characteristics of 111 SCCHN patients

 
In the univariate analysis (Table 2)Citation , patients with T stages 3 and 4 (P = 0.010), node-positive tumors (P = 0.004), and stage III and IV tumors (P = 0.004) had statistically worse LRC. Patients with carcinomas in the hypopharynx had worse LRC than those with laryngeal cancers (P < 0.001).


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  		Table 2 Univariate Cox proportional hazards analysis of 111 SCCHN patients according to clinicopathological parameters

 
In the univariate analysis, patients with node-positive tumors (P < 0.001), stage III and IV tumors (P < 0.001), and histologically grade 3 tumors (P = 0.006) had statistically worse OS. Patients with carcinoma of the oropharynx (P < 0.001), hypopharynx (P < 0.001), and nasal cavity and paranasal sinuses (P = 0.040) had worse prognosis than those with laryngeal cancers. In addition, multivariate analysis indicated that nodal status was a statistically significant indicator of OS (P = 0.001) and LRC (P = 0.002; Table 5Citation ).


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  		Table 5 Multivariate Cox proportional hazards analysis in 111 SCCHN patients

 
Immunohistochemical Staining and Clinicopathological Parameters.
The results of immunostaining of four biological markers are shown in Table 3Citation . The range of the MIB-1-positive index was 0–96%, and the mean MIB-1-positive index was 50.1%. The mean p53 positive index was 37.1%. No positive staining with the p53 antibody was observed in 47 cases, and <10% of tumor cells were stained in three cases. Therefore, 61 of 111 (55%) specimens were determined to be positive for the p53 antibody. Bcl-2 protein was expressed in 14 of 111 cases (12.6%), and bax immunostaining was positive in 73 of 111 cases (65.8%).


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  		Table 3 Clinicopathological parameters and immunoreactivity

 
MIB-1-positive index was significantly higher in the lymph node-positive group (P = 0.044), stage III and IV group (P = 0.006), and histologically grade 3 group (P = 0.008). The p53-positive index was correlated with histological grading (P = 0.031). The percentage of bcl-2-positive tumors was significantly higher in patients with carcinoma in nasal cavity and paranasal sinuses (P = 0.032) and in a histologically grade 3 group (P = 0.021). No such correlation was observed between bax immunostaining and clinicopathological parameters.

Immunohistochemical Staining and Outcome.
Patients with bcl-2-positive tumors had better LRC than those with bcl-2-negative tumors in both univariate (P = 0.023) and multivariate analyses (P = 0.017; Tables 4Citation and 5Citation ; Fig. 1aCitation ). No statistically significant association was found between expression of p53, bax, or MIB-1 proteins and LRC (Table 4)Citation .


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  		Table 4 Univariate Cox proportional hazards analysis of 111 SCCHN patients according to immunoreactivity

 


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  		Fig. 1. a, LRC in 111 SCCHN patients treated with concurrent chemoradiotherapy according to bcl-2 expression status. b, OS according to MIB-1 status (Kaplan-Meier method).

 
A significant difference in 5-year OS was found between the patients with a low MIB-1-positive index (<40%), and those with a high MIB-1-positive index (>=40%; P = 0.008; Fig. 1bCitation ). In the multivariate analysis, a considerable difference in OS was observed between patients with a low MIB-1-positive index and those with a high index, but the difference was not statistically significant (P = 0.060; Table 5Citation ). No statistically significant association was found between expression of p53, bcl-2, or bax proteins and OS (Table 4)Citation .


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Several reports indicate that lymph node status is the most important prognostic factor in SCCHN (23) . Consistent with these reports, in this study, both univariate and multivariate analyses indicate that nodal status is the most statistically significant predictor of OS and LRC in patients with SCCHN treated with concurrent chemoradiotherapy. Our results suggest that clinical stage and histological grading are additional candidates for parameters that predict prognosis. It is still difficult to predict the efficacy of treatments in patients with SCCHN using the conventional clinicopathological criteria (24) .

In addition to clinical parameters, this study indicates that bcl-2 expression is a useful biological marker for predicting LRC in patients with SCCHN treated with concurrent chemoradiotherapy. Members of the bcl-2 protein family are involved in an apoptotic process of both normal and malignant cells (10 , 12) . Because bcl-2 protein is an inhibitor of apoptosis, tumor cells that express bcl-2 protein might avoid apoptosis. In hematological tumor cell lines or in leukemic cells from patients, a poor response to radiotherapy or chemotherapy was observed when bcl-2 protein was expressed (11 , 25) . Gallo et al. (18) reported that bcl-2 expression is closely associated with a high risk of recurrence and poor survival in stage I and II SCCHN patients. In contrast, our data indicate that bcl-2 positivity predicts better LRC. Gasparini et al. (16) also reported that the bcl-2-positive head and neck tumors were highly responsive to concurrent chemoradiotherapy, which was determined using univariate analysis. In non-small cell lung cancer, patients with bcl-2-positive tumors have better clinical outcome (26 , 27) . These findings suggest that bcl-2 expression in solid cancers potentiates the therapeutic effect.

Bax is considered to be a proapoptotic protein, and its actions are neutralized when it is heterodimerized with bcl-2 and some other members of the bcl-2 protein family that function as suppressors of cell death (12) . Therefore, bax might be involved in the apoptotic elimination of tumor cells after exposure to DNA-damaging drugs or radiation. No report, however, has been published on bax expression in SCCHN. This study indicates that bax expression does not predict OS or LRC. Because bcl-2 and bax proteins coordinately interact to control apoptotic cell death, we analyzed the relationship between the expression pattern of these proteins and a clinical outcome. There was no statistical significance, due possibly to the small number of patients (data not shown).

Our results indicate that overexpression of p53 detected by immunostaining is not related to OS and LRC. Overexpression of p53 is reported to be a useful prognostic marker in colorectal and breast cancers (28 , 29) . In SCCHN, the prognostic value of p53 overexpression is still controversial (14, 15, 16) . Bradford et al. (17) reported that the presence of a p53 mutation is associated with decreased survival in patients with advanced laryngeal carcinomas enrolled in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study, although the presence of p53 overexpression as detected with immunohistochemistry did not predict survival in their previous study (15) . Because numerous studies reported discrepancies between p53 mutation and protein overexpression, further analysis of p53 abnormalities at the genetic level is needed to evaluate the role of this protein as a predictive marker in patients with SCCHN.

In addition to biological markers correlating with apoptotic pathways, this study indicates that the proliferative activity of tumor cells, determined by the MIB-1-positive index, is a useful biological marker for predicting OS. Proliferative activity of tumor cells is an important prognostic indicator in several types of cancers, particularly breast cancer (5) . Although several studies have analyzed the clinical significance of cell kinetics in patients with SCCHN, there is a controversy as to the prognostic value of MIB-1 or Ki-67 immunohistochemistry. Tomasino et al. (6) reported on the prognostic significance of cell kinetics in laryngeal cancer. Our study also demonstrates that the MIB-1-positive index is a prognostic factor in OS but not in LRC. Roland et al. (7) and Spafford et al. (8) , however, found no relationship between Ki-67 scores and survival. The difference between these reports might be due to the study design because all of the patients in our study as well as in Tomasino’s study were treated with the same protocol, concurrent chemoradiotherapy and surgery. In contrast, various treatments were performed in the other studies. Further study of a large patient population is needed to determine whether MIB-1 is a useful biological marker for predicting a clinical outcome in patients with SCCHN treated with chemoradiotherapy.

In conclusion, this study indicates that nodal status is the major prognostic factor in SCCHN patients treated with chemoradiotherapy. In addition, our findings suggest that bcl-2 positivity is associated with better LRC and that the proliferative activity of tumor cells might be prognostic in OS. These results provide useful information for predicting prognosis in patients with SCCHN treated with concurrent chemoradiotherapy.


   ACKNOWLEDGMENTS
 
We wish to thank Mr. Mikio Shimizu and Miss Midori Nagaki for their technical assistance. We are grateful to Drs. Hiroki Shirato, Takeshi Nishioka, and Kenji Kagei of the Department of Radiology, Hokkaido University School of Medicine, for their help in providing the patients’ clinical and follow-up data.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Otolaryngology, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8648, Japan. Phone: 81-11-707-3387; Fax: 81-11-717-7566; E-mail: ak-homma{at}med.hokudai.ac.jp Back

3 The abbreviations used are: SCCHN, squamous cell carcinoma of the head and neck; OS, overall survival; LRC, locoregional control. Back

Received 5/ 1/98; revised 10/26/98; accepted 11/25/98.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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