PROGNOSTIC INDICATORS FOR SURVIVAL IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS: ANALYSIS OF A SERIES OF 621 CASES

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1 PROGNOSTIC INDICATORS FOR SURVIVAL IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS: ANALYSIS OF A SERIES OF 621 CASES Christophe Le Tourneau, MD, 1 Michel Velten, MD, PhD, 1,2 Guy-Michel Jung, MD, 2 Guy Bronner, MD, 3 Henri Flesch, MD, 3 Christian Borel, MD 2 1 Service d épidémiologie et de biostatistique, Centre Paul Strauss, 3, rue de la porte de l hôpital, Strasbourg, France. clt1@tiscali.fr 2 Paul Strauss Comprehensive Cancer Center, Strasbourg, France 3 Sainte-Barbe Clinic, Strasbourg, France Accepted 24 March 2005 Published online 5 August 2005 in Wiley InterScience ( DOI: /hed Abstract: Background. We sought to study the influence of pt classification, pn status, tumor volume, and number of lymph nodes invaded on survival of patients with head and neck cancers to improve therapeutic indications. Methods. This was a retrospective study of 621 consecutive patients treated from 1990 to 1997 by a single team. Results. In univariate analysis, pt classification (p <.0001), pn status (p <.0001), capsule rupture (p <.0001), the number of lymph nodes invaded (0, 1 3, 4 9, z10) (p <.0001), and the tumor volume (p <.0001) were significantly associated with overall survival. A Cox model identified as independent prognostic indicators age (p <.0001), pt classification (p <.0001), and pn status (p <.0001). Conclusions. Not only pt classification and pn status but also the number of the lymph nodes invaded and the tumor volume should be considered as essential prognostic indicators, and any clinical trial developed should stratify accordingly. A 2005 Wiley Periodicals, Inc. Head Neck 27: , 2005 Keywords: head; neck; cancer; prognostic indicators Correspondence to: C. Le Tourneau B 2005 Wiley Periodicals, Inc. The well-established prognostic indicators for survival in cases of head and neck squamous cell carcinomas (HNSCC) are the presence of lymph node metastases, invasion of the resection margins, and poorly differentiated appearances with perineuronal or perivascular invasion. 1 The presence of any of these factors represents an indication for adjuvant radiotherapy. Several studies have shown that the number of cervical lymph nodes invaded in patients with HNSCC is a prognostic indicator for survival The 5-year overall survival (OS) rates, however, are relatively heterogeneous between the different studies. In addition, pt classification, pn status, and tumor volume have not been studied in much detail. 11,15 We, therefore, decided to conduct a retrospective study of prognostic indicators for survival in 621 patients operated on for HNSCC, in particular by considering the pt classification, pn status, number of lymph nodes invaded, and tumor volume. Prognostic Indicators in Head and Neck Cancer HEAD & NECK September

2 PATIENTS AND METHODS Patients. All patients undergoing surgery for HNSCC at the Sainte-Barbe Clinic in Strasbourg by the same surgical team between January 1, 1990, and December 31, 1997, were included. Patients who had a history of cancer, metastatic disease from the outset, coexistent cancer apart from other microinvasive sites or in situ cancer of the head and neck, or those who were given neoadjuvant therapy were excluded. Patients for which the number of lymph nodes removed was less than 10 were also excluded. Thus, 22 patients were excluded for this reason during the period mentioned. The primary malignant site was the oral cavity in 107 patients (17%), the oropharynx in 277 patients (45%), the larynx in 68 patients (11%), and the hypopharynx in 169 patients (27%). Fifty-three (8%) of the 621 patients were women. The median age of the study population at the time of initial surgery was 57 years (range, years). Treatment. The initial surgical treatment involved broad tumor excision associated with lymph node clearance, ipsilateral if the tumor was lateralized, and bilateral if it extended beyond the midline (56% of cases). The lymph node clearances and primary tumors were analyzed by the same pathology team. Three hundred ninetyseven patients with lymph node metastases, invaded resection margins, or large tumors underwent adjuvant radiotherapy (64%). In addition, 23 patients received adjuvant radiochemotherapy (4%). The primary tumors and the lymph node involvement were classified according to the Union Internationale Contre le Cancer (UICC) 16 classification, 5th edition, This classification is entirely consistent with the American Joint Committee on Cancer (AJCC) 17 classification of HNSCC. The classification was performed by a single investigator from the pathology report. The distribution by pt classification and pn status was as follows: pt1, n = 85 (14%); pt2, n = 281 (45%); pt3, n = 142 (23%); and pt4, n = 113 (18%); pn0, n = 217 (35%); pn1, n = 82 (13%); pn2a, n = 35 (6%); pn2b, n = 178 (28%); pn2c, n = 80 (13%); and pn3, n = 29 (5%). The median number of lymph nodes removed was 29 (range, ). Two hundred seventeen patients (35%) had no invaded lymph nodes, 301 patients (48%) had one to three invaded, 90 (15%) had four to nine invaded, and 13 (2%) had more than 10 invaded. The tumor volume was estimated from the product of the three dimensions of the tumor from the pathology report. Micrometastases were considered to have a volume of 1 mm 3. Two hundred nineteen patients had a tumor volume of 5 cm 3 or less, 191 between 5 and 15 cm 3, and 211 more than 15 cm 3. Forty-seven percent of the subjects with invaded lymph nodes had at least one lymph node with capsule rupture. The Broder classification was used to characterize cell differentiation. Three hundred thirty-eight primary tumors (55%) were well differentiated, 158 (25%) were moderately differentiated, 111 (18%) were poorly differentiated, and 12 (2%) were undifferentiated. Invasion of the sections was present in 14% of cases. The closing date was set on January 1, For all those patients whose date of death was not known, a systematic search was conducted at the council offices of the patient s place of birth to establish their status at the closing date. To determine the dates of locoregional and distant recurrence and the development of subsequent cancers, we used data from the medical records. A locoregional recurrence was defined as either a recurrence at the level of the surgical scar or as the development of metastatic cervical lymph nodes. Finally, we contacted the general practitioner when the same team no longer followed the patient. The rate of patients lost to follow-up was, as a result, 1.5%. Table 1. Five-year overall survival rates by pt and pn classification. Survival rate by pn classification, % pt classification Total 1 76 (n = 48) 83 (n =6) 60(n = 25) 17 (n =6) 68(n = 85) 2 65 (n = 108) 53 (n = 36) 39 (n = 124) 15 (n = 13) 50 (n = 281) 3 47 (n = 35) 43 (n = 22) 26 (n = 82) 33 (n =3) 34(n = 142) 4 49 (n = 26) 28 (n = 18) 8 (n = 62) 0 (n =7) 20(n = 113) Total 63 (n = 217) 47 (n = 82) 30 (n = 293) 13 (n = 29) 43 (n = 621) 802 Prognostic Indicators in Head and Neck Cancer HEAD & NECK September 2005

3 Table 2. Univariate analysis of clinical and pathologic prognostic indicators for overall survival, survival without distant metastases, and survival without locoregional recurrence. % patients by survival Variables No. of patients 5-y OS 2-y MFS 2-y RFS Clinical prognostic indicators Age, y V > p =.0002 p =.67 p =.45 Sex Female Male p =.25 p =.02 p =.53 Site of cancer Oral cavity Oropharynx Larynx Hypopharynx p =.0001 p =.0005 p =.05 Pathologic prognostic indicators Cell differentiation Well differentiated Moderately differentiated Poorly differentiated Undifferentiated p =.26 p =.03 p =.02 Invasion of sections No Yes p =.17 p =.12 p =.94 No. of nodes invaded z p <.0001 p <.0001 p =.04 Capsule rupture Yes No p <.0001 p <.0001 p =.08 Tumor volume (v) v V 5cm <vV 15 cm v > 15 cm p <.0001 p <.0001 p =.0001 pt classification pt pt pt pt p <.0001 p =.003 p <.0001 pn classification pn pn pn2a pn2b pn2c pn p <.0001 p <.0001 p =.02 Abbreviations: OS, overall survival; MFS, distant metastasis free survival; RFS, recurrence-free survival. Prognostic Indicators in Head and Neck Cancer HEAD & NECK September

4 FIGURE 1. Graph shows overall survival by pt classification. p value, log-rank test. FIGURE 2. Graph shows overall survival by pn status. p value, log-rank test. Statistical Analysis. The start date was set at the day of initial surgical operation. The prognostic indicators studied were age at the time of initial surgery, sex, site of the primary tumor, number of invaded lymph nodes (0, 1 3, 4 9, z10), tumor volume (V5 cm 3, 5 15 cm 3, >15 cm 3 ), pt classification, pn status, capsule rupture, invasion of sections, and cell differentiation. The three dimensions were known for all of the primary tumors. All of the variables were first analyzed independently of each other to estimate their effect on OS, distant metastasis free survival (MFS), and locoregional recurrence free survival (RFS). The 2- and 5-year survival rates were calculated by the Kaplan Meier method, 18 and the differences between the survival curves were analyzed by the log-rank test. All of the variables for which the p value was less than.20 in univariate analysis, as well as their interactions, were then integrated into a Cox model 19 to determine their independent effect on survival. A stepwise forward regression model was performed. The proportional hazards assumption underlying the Cox model was checked by means of a plot representing log(-log S(t)) as a function of time. The a level was set at 5%. All analyses were performed on SAS software, version 8.02 (SAS Institute, Cary, NC). RESULTS General Results. Thirty-two percent of patients were alive at the closing date; the median followup time was 99 months. The 5-year OS rate for the entire series was 43%, and the median survival was 47 months. Twenty-three percent of patients had a locoregional recurrence, 19% of patients had distant metastases develop because of their primary cancer, and 25% of patients had a second cancer develop. The 5-year OS rates by pt FIGURE 3. Graph shows overall survival by the number of lymph nodes invaded. n.i., nodes invaded; p value, log-rank test. FIGURE 4. Graph shows overall survival by the tumor volume. v, tumor volume in cm 3 ; p value, log-rank test. 804 Prognostic Indicators in Head and Neck Cancer HEAD & NECK September 2005

5 classification and pn status are shown in Table 1. The 5-year OS rate for a patient with pt1pn0 disease was 76% compared with 0% for a patient with pt4pn3 disease. Univariate Analysis. On univariate analysis, the prognostic indicators significantly associated with OS, MFS, and RFS were age, site of cancer, pt classification, pn status, capsule rupture, number of lymph nodes invaded, and tumor volume (Table 2). For instance, the 5-year OS rates for patients with pt1, pt2, pt3, and pt4 disease were 68%, 50%, 34%, and 20%, respectively ( p <.0001; Figure 1). The 5-year OS rate for a patient with pn0 disease was 63%, compared with 13% for a patient with pn3 disease (Figure 2). Patients with a pt4 tumor had a risk of locoregional recurrence of 41% but also a 2-year risk of metastases of 29%. The 5-year OS rates for patients with 0, 1 to 3, 4 to 9, and more than 10 lymph nodes invaded were 63%, 37%, 20%, and 8%, respectively ( p <.0001; Figure 3). The risk of metastases rose to 56% at 2 years when more than 10 lymph nodes were invaded. Finally, the 5-year OS rates for patients with a tumor volume of 5 cm 3 or less, between 5 and 15 cm 3 and more than 15 cm 3 were 55%, 48%, and 27%, respectively (Figure 4). Invasion of sections was not a statistically significant prognostic indicator of OS, MFS, or RFS Table 3. Multivariate analysis of prognostic indicators for overall survival, survival without distant metastases, and survival without locoregional recurrence. OS MFS RFS Variables RR 95% CI RR 95% CI RR 95% CI Age, y V > p <.0001 Site of cancer Oral cavity 1 1 Oropharynx Larynx Hypopharynx p =.05 p =.001 pt classification pt1 1 1 pt pt pt p <.0001 p <.0001 pn classification pn pn pn2a pn2b pn2c pn p <.0001 p <.0001 p =.04 Tumor volume (v) v V 5cm 3 1 5<vV 15 cm v > 15 cm p =.007 Cell differentiation Well differentiated 1 Moderately differentiated Poorly differentiated Undifferentiated p =.02 Abbreviations: OS, overall survival; MFS, distant metastasis free survival; RFS, recurrence-free survival; RR, relative risk; CI, confidence interval. Prognostic Indicators in Head and Neck Cancer HEAD & NECK September

6 (Table 2). Conversely, cell differentiation was a statistically significant prognostic indicator for MFS and RFS, but not for OS. Multivariate Analysis. All of the variables that had a significance level of.20 or less on univariate analysis were introduced into a multivariate model (Table 3). Age was an independent prognostic indicator for OS, whereas site of tumor was a statistically independent prognostic indicator for MFS and RFS. pt classification emerged as a statistically independent prognostic indicator for OS and RFS. Interactions did not reach statistical significance; in particular, there was no interaction between tumor site and pt classification or tumor volume. pn status emerged as an independent indicator for OS, MFS, and RFS. The number of lymph nodes invaded was not a significant prognostic indicator of survival. Tumor volume was significantly related to MFS. Finally, the study also showed cell differentiation to be a statistically independent indicator for RFS. The reason why the capsule rupture was not selected in the model is its close relationship with pn status and pt classification, as well as its relationship with the number of invaded lymph nodes and tumor volume. A separate analysis for cancers of the oropharynx and of the hypopharynx (accounting for 72% of the cases), although not formally necessary because there were no interactions with tumor site, led to the same results, with only slight departures of the values of the coefficients from the values found in the general analysis. DISCUSSION Our results show that the pt classification is an independent prognostic indicator, not only for survival but also for locoregional recurrence. The pn status is an independent prognostic indicator for survival, for locoregional recurrence, and for metastatic progression. The number of lymph nodes invaded is not an independent prognostic indicator for survival, whereas the tumor volume is an independent prognostic indicator for MFS. We based the study of the lymph nodes invaded on the criteria defined by the new edition of the TNM classification for breast cancers, 20 which took effect in 2003 and which takes into account the number of axillary lymph nodes invaded. We used the same cutpoints for the number of cervical lymph nodes invaded (0, 1 3, 4 9, z10). The method used to calculate tumor volume is based on the product of the three dimensions, which has the advantage of simplicity and ability to make comparisons with other studies performed using the same basis. Actual tumor volume is probably slightly inferior, because the sections are not rectangular in all of the spatial planes. Nevertheless, this method does not introduce bias associated with classification into the categories that were used in the statistical analysis. The 5-year OS rates published in the literature range from 40% to 56%. 2,5,7 The relatively lower rate (43%) in our study is probably partly because of a higher proportion of patients with cancers of the oropharynx and hypopharynx, which carry a poor prognosis. In their study on 914 patients, Mamelle et al 2 found 5-year OS rates for each site very similar to ours: 54% for the oral cavity, 36% for the oropharynx, 63% for the larynx, and 31% for hypopharynx. Capsule rupture has often been quoted as a prognostic indicator for survival, although only in univariate analyses. 2,5,7 9,21 25 Mamelle et al did not find this factor to be independently related to OS in a multivariate analysis. Similarly, our own analysis found this factor to be associated with OS, MFS, and RFS in univariate analysis but not in multivariate analysis. As capsule rupture is very closely linked to pn status and pt classification, as well as to the number of invaded lymph nodes and to tumor volume, this explains why this relation disappears when both are taken into account in multivariate analysis. In addition, invasion of sections is 1,26 28 Our also a known prognostic indicator. results show that survival is better when there is no section invasion, although these differences were not statistically significant. Finally, cell differentiation is not known to be a prognostic indicator for survival. 24 We found this indicator to be significantly associated with MFS and RFS in univariate analysis and independently with RFS in multivariate analysis. However, these results should be interpreted with caution in view of the surprising absence of a consistent increase in relative risk with the degree of cell differentiation. We have not found any explanation for the apparent protective effect of poorly differentiated carcinomas on RFS. Most authors have studied OS as a function of 3,10,13,29 31 clinical T classification and N status. 806 Prognostic Indicators in Head and Neck Cancer HEAD & NECK September 2005

7 Rapoport et al 11 studied the influence of pathologic pt classification and pn status on OS in cancers of the hypopharynx. They found 2-year OS rates of 42% and 32% for pt1 pt2 and pt3 pt4 disease, respectively, and 76%, 23%, and 0% for pn0, pn1 and pn2 or pn3 disease, respectively. Our results confirm the very important prognostic value of these indicators, because they remain statistically significant in multivariate analysis. Our study, therefore, belongs to the very few studies that stress the importance of pt classification and pn status in this respect. In addition, the tumor volume seems to be an independent prognostic indicator for MFS. Kurek et al 15 reported similar results. Furthermore, the greater the number of invaded lymph nodes, the lower the 5-year OS rate, falling to 20% for four to nine invaded lymph nodes and to 8% for more than 10 invaded lymph nodes. Mamelle et al 2 and O Brien et al 5 reported a 5-year OS rate of 15% when more than three lymph nodes were invaded. Ono et al reported a rate of 21% when more than five lymph nodes were invaded. Rapoport et al, in a multivariate analysis of OS, found a relative risk of 4.46 for more than three invaded lymph nodes compared with no lymph node invasion. In our multivariate analysis, the number of lymph nodes invaded does not carry additional prognostic information. pn status is, therefore, a better indicator to predict survival than the number of lymph nodes invaded. These results, therefore, lead us to recommend stratifying future therapeutic trials on the following prognostic indicators: pt classification and pn status. The decision to perform adjuvant chemotherapy to prevent early metastases should rely on tumor volume, whenever available, rather than on pt classification. REFERENCES 1. Sanderson RJ, Ironside JAD. Squamous cell carcinomas of the head and neck. 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