© The Author (2008). Published by Oxford University Press. All rights reserved
Treatment of Patients with Clinically Lymph Node-negative Squamous Cell Carcinoma of the Oral Cavity
1 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul
2 Department of Otolaryngology and Head and Neck Surgery, Seoul National University College of Medicine, Seoul
3 Department of Oral and Maxillofacial Surgery, Seoul National University College of Dentistry, Seoul
4 Cancer Research Institute, Seoul National University College of Medicine, Seoul
5 Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
For reprints and all correspondence: Hong-Gyun Wu, Department of Radiation Oncology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea. E-mail: wuhg{at}snu.ac.kr
Received April 3, 2008; accepted May 17, 2008
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Abstract |
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Objective: To evaluate treatment outcome and to determine optimal treatment strategy for patients with clinically lymph node-negative (N0) oral cavity squamous cell carcinoma (SCC).
Methods: Two hundred and twenty-seven patients with oral cavity SCC received radiotherapy with curative intent. We retrospectively analyzed 69 patients with clinically N0 disease. Forty-three patients were treated with surgery followed by radiotherapy (S+EBRT) and 26 with radiotherapy alone (EBRT). The median doses administered were 63.0 Gy for S+EBRT and 70.2 Gy for EBRT.
Results: The rates of occult metastasis were 60% for T1, 69% for T2, 100% for T3 and 39% for T4, respectively, among patients who underwent neck dissection. A contralateral occult metastasis occurred only in two patients. The median follow-up was 39 months (range, 6–170 months). The 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and regional control (RC) rates for all patients were 56, 50, 66 and 79%, respectively. The 5-year OS, DFS, LC and RC rates were 67/39% (P < 0.01), 66/24% (P < 0.01), 87/30% (P < 0.01) and 73/89% (P = 0.11) for S+EBRT/EBRT, respectively.
Conclusions: The risk for occult neck metastasis is high in patients with oral cavity SCC; therefore, elective neck treatment should be considered. Excellent RC for subclinical disease can be achieved with radiotherapy alone. However, external beam radiotherapy alone to primary tumor resulted in poor LC and combined treatment with surgery and radiotherapy appeared to be a better treatment strategy.
Key Words: oral cavity cancer • squamous cell carcinoma • lymph node-negative • radiotherapy • surgery
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INTRODUCTION |
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The oral cavity is a common site for a head and neck malignancy. Globally, oral cavity cancer accounted for 274 000 cases in 2002, with almost two-thirds of the cases in men (1). Almost 90% of these cases were a squamous cell carcinoma (SCC) (2).
It is well known that oral cavity cancer has a high propensity for regional lymph node metastasis. Of the patients with T1 and T2 oral cavity SCC clinically staged lymph node-negative (N0), 19–46 and 35–57%, respectively, had occult neck metastases at the time of surgery (3–11). The patients who experienced neck recurrence after initial treatment had poor regional control (RC) rates and more frequently died of uncontrolled neck disease (3–5,7–9). These findings suggest a strong argument in favor of elective neck treatment in the patients with clinically N0 oral cavity cancer (3–13). However, the benefits of elective neck treatment in patients with clinically N0 disease have still remained obscure, and no consensus has been reached on the optimal treatment modality.
Recently, less extensive therapeutic procedures have been used in an effort to achieve a similar level of cancer control to that obtained with traditional radical surgery or radiotherapy, while reducing treatment related morbidity (14–17). In patients with oral cavity cancer, the extent of therapy to be delivered to the neck and especially the necessity of treating the contralateral neck are very important issues.
We retrospectively analyzed the treatment outcome in patients with clinically N0 oral cavity SCC to understand occult neck metastasis, patterns of failure and prognostic factors, and to determine an optimal treatment strategy.
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PATIENTS AND METHODS |
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Patients
From January 1990 to December 2004, 227 patients with an oral cavity SCC located in the mobile tongue, floor of the mouth, gingiva, retromolar trigone, hard palate and buccal mucosa received radiotherapy with a curative intent at the Seoul National University Hospital. Sixty-nine of these patients were staged as clinically N0 and were included in this study. The patient characteristics are summarized in Table 1. The median age of the patients at the time of the initial treatment was 60 years (range, 29–82 years). Fifty-five patients were males and 14 were females. All tumors were staged according to the American Joint Committee for Cancer Staging, 6th edition, 2002 (18), and 46 patients (67%) presented with early-stage disease (T1 or T2). All patients were staged N0 after a clinical and radiological evaluation. The evaluation of the neck lymph nodes consisted of palpation only in four patients. For the rest of the patients, imaging studies were performed as follows: computed tomography (CT) (n = 17); magnetic resonance imaging (MRI) (n = 52); ultrasonography (USG) (n = 17).
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Treatment
Our general recommendation for the management of an oral cavity cancer is surgery followed by postoperative radiotherapy for high-risk pathological findings. High-risk findings included locally advanced disease (T3 or T4), multiple lymph nodes (N2 or N3), extracapsular extension, perinueral invasion or a close or positive resection margin. In early-stage disease, radiotherapy is an optional treatment. In medically inoperable or in cases of refusal of surgery, radiotherapy is recommended.
In this study, all patients received radiotherapy, and the patients were divided into two groups according to the type of treatment administered. One group of patients was treated with surgery followed by external beam radiotherapy (S+EBRT) (n = 43) and a second group of patients was treated with external beam radiotherapy (EBRT) alone (n = 26). Radiotherapy was delivered with a 4-MV or 6-MV photon beam. In almost all patients, a conventional fractionated dose of 1.8 or 2 Gy, one fraction per day, 5 days per week was applied. The initial treatment volume included the primary tumor (or tumor bed in the S+EBRT group) and the regional neck lymph nodes (generally bilateral level I–IV), using either three-dimensional conformal radiotherapy (3D-CRT) (n = 11) or a conventional three-portal technique (n = 58). After 44–45 Gy was given, the spinal cord was shielded. The primary tumor (or tumor bed) was boosted by coning down. The posterior neck lymph nodes were boosted by an electron beam if needed, generally for pathologically lymph node-positive disease. The median total doses were 63.0 Gy (range, 45.0–70.2 Gy) for the S+EBRT group and 70.2 Gy (range, 61.2–72.0 Gy) for the EBRT group, respectively.
All patients in the S+EBRT group received resection of the primary tumor. Of these patients, 33 (77%) received ipsilateral elective neck dissection (END), which included 23 supraomohyoid neck dissections (SOHNDs) and 10 modified radical neck dissections (MRNDs). In our institution, the involved areas of neck dissection were as follows: level Ib, II, III, IV and V for MRND; level Ib, II and III for SOHND.
The remaining 10 patients (23%) received elective radiotherapy for subclinical neck disease. Contralateral END was performed in four patients and the type of contralateral END was SOHND in all patients.
Twelve patients received neoadjuvant (preoperative or pre-radiotherapy) chemotherapy. The chemotherapeutic agents were as follows: 5-fluorouracil and cisplatin (n = 9); 5-fluorouracil, cisplatin and docetaxel (n = 3). An individual medical oncologist had determined the indications for chemotherapy.
Follow-up and Statistical Analysis
The data were analyzed with a closeout (study censor) date of 31 August 2007. For all patients, the median duration of follow-up was 39 months (range, 6–170 months). The median duration of follow-up for living patients was 57 months (range, 11–164 months). Overall survival (OS), disease-free survival (DFS), local control (LC) and RC were calculated by the Kaplan–Meier method and the differences were compared using log-rank tests. The Cox regression model was used to perform multivariate analysis. The follow-up time was calculated from the date of definite treatment start to the date of the last contact of the patient or death. Time-to-failure was calculated from the treatment start to the date of the relevant event. Fisher's exact test was used to compare the distribution of various clinical and pathological characteristics. P < 0.05 was considered statistically significant. All analyses were performed using the SPSS 12.0.1 for Windows (SPSS Inc. Chicago, IL USA) statistical software package.
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RESULTS |
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Treatment Time
All patients completed the planned treatment. The median duration for radiotherapy was 51 days (range, 38–68 days) for the S+EBRT group and 56 days (range, 34–87 days) for the EBRT group. For the S+EBRT group, the median interval from surgery to the start of radiotherapy was 34 days (range, 18–93 days). The time interval was >6 weeks for eight patients, mainly due to delayed wound healing. The median treatment time from surgery to completion of radiotherapy (package time) was 86 days (range, 48–131 days). The package time was >100 days for six patients.
Occult Neck Metastasis
In patients who received END, the rate of an occult metastasis was 58% (19 of 33). According to the T stage, the rate of an occult metastasis was 60% (three of five) for T1 lesions, 69% (nine of 13) for T2 lesions, 100% (two of two) for T3 lesions and 39% (five of 13) for T4 lesions, respectively. Of these patients, 89% (17 of 19) had ipsilateral neck metastases only. The remaining two patients had only a contralateral neck metastasis without an ipsilateral metastasis (level I in one patient, level I and II in another patient). Regarding the sites of an occult metastasis, there were three cases at ipsilateral level I, 10 cases at level II, three cases at level III, one case at level IV, one case at level V, two cases at contralateral level I and one case at contralateral level II, respectively (Table 2). Eleven patients had a single node metastasis, and eight patients had multiple lymph node metastases.
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Treatment Outcomes
The 5-year OS and DFS rates for all patients were 56 and 50%, respectively. By univariate analysis, only treatment modality was a significant prognostic factor for OS (P = 0.0026) and treatment modality, subsites and clinical T stage were significant prognostic factors for DFS (P < 0.05) (Table 3). For the S+EBRT/EBRT groups, the 5-year OS and DFS rates were 67/39% (P = 0.0026) and 66/24% (P < 0.0001), respectively (Fig. 1).
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The 5-year LC and RC rates were 66 and 79%, respectively. For the S+EBRT/EBRT groups, the 5-year LC and RC rates were 87/30% (P < 0.0001) and 73/89% (P = 0.1142), respectively (Fig. 1). For 46 patients with early-stage disease (T1 or T2), the 5-year OS, DFS, LC and RC rates were 68/34% (P = 0.0181), 63/14% (P = 0.0001), 90/19% (P < 0.0001), 71/86% (P = 0.1181) for the S+EBRT/EBRT groups, respectively (Fig. 2). There were fewer regional failures in patients (n = 33) who received END than in patients (n = 36) who did not receive END, but the differences in RC were not significant (81 versus 77%, P = 0.6559) (Fig. 3). For patients with early-stage disease, no significant differences in RC between patients (n = 18) with END and those (n = 28) without END were found (71 versus 82%, P = 0.4693).
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The DFS and RC rates correlated with the subsites of the lesions. The 5-year DFS and RC rates for an oral tongue cancer were 33 and 67%, and were 72 and 93% for other subsites. When these two groups were analyzed with the log-rank test, the P-value was 0.0091 for the DFS rates and 0.0125 for the RC rates.
Patterns of Failure
The patterns of failure are detailed in Table 4. Thirty-four patients experienced treatment failure as follows: local (n = 20), regional (n = 9), distant (n = 1), local plus regional (n = 3) and regional plus distant (n = 1). The most common failure site was regional in the S+EBRT group of patients and local in the EBRT group of patients. The levels of regional failure was as follows: level I in two cases; level II in one case; level IV in two cases; level V in one case; contralateral level I in two cases and contralateral level II in two cases (Table 5). Of 23 patients with local failure, nine patients had persistent local disease after radiotherapy; thus, they never had a disease-free period. Almost all failures appeared within the first 2 years after treatment, with only three patients (9%) having experienced a failure after 2 years and three patients (9%) having experienced a failure after 3 years. The latest failure appeared 87 months after radiotherapy was completed. Salvage treatment with curative intent was offered for 11 patients, and five patients (15%) were salvaged.
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Second Malignancies
For all patients, five (7%) developed a second primary malignancy after treatment for the oral cavity cancer. Three patients had a secondary cancer in the esophagus, one patient had a secondary cancer in the colon and one patient had a secondary cancer in the stomach. Of these five patients, the two patients with esophageal cancer died of their second malignancies.
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DISCUSSION |
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The biological aggressiveness of oral cavity SCC, particularly in the early stages, is reflected in its ability to metastasize to the neck lymph nodes (19). Because of the multiple and rich lymphatic network of the oral cavity, the risk of development lymph node metastases in these sites varies between 19 and 57%, even in the early stages (3–11). This metastatic disease is almost subclinical or occult at the time of the diagnosis, thereby contributing to the controversy regarding the elective treatment of the neck. Modern diagnostic modalities such as CT, MRI, USG and USG-guided fine needle aspiration cytology are recommended to use for the N0 neck, and have become routine screening procedures in recent years. However, there are limitations of all these imaging modalities for the detection of very small micrometastases within these nonpalpable neck nodes (20). In view of the high rates of occult metastases in an untreated neck and the poor salvage rates for failures at the neck, elective neck treatment of the N0 neck had been proposed by many investigators as reported in the literature (3–13). In our study, the rates of occult metastases were 60% for T1 lesions, 69% for T2 lesions, 100% for T3 lesions and 39% for T4 lesions, with a combined rate of 58%. The rates of occult metastases were higher than the findings of most series, probably because they were calculated for the patients who received neck dissection, and not for all patients.
In analyzing the patterns of occult metastases, only two patient had an occult metastasis in ipsilateral level IV or V (one in level IV and the other in level V), and two patients had an occult metastasis in the contralateral neck. Of patients with contralateral neck metastases, one patient had disease in contralateral level I and II and another patient had disease in contralateral level I. Considering this pattern, the necessity of elective treatment for ipsilateral level IV, V or the contralateral neck is questionable. Previous studies comparing the application of MRND and SOHND for the treatment of clinically N0 necks have demonstrated that the recurrence and survival rates were similar (16,17). Byers et al. (21) showed that level IV is also at significant risk from a primary oral tongue cancer and the investigators have recommended that an ‘extended' SOHND (level I–IV) is the most appropriate type of neck dissection. However, there has been no study comparing partial neck radiotherapy to whole neck radiotherapy. Spaulding et al. (22) showed that among patients with clinically N0 oral tongue SCC, the 3-year RC rate was 95% following bilateral whole neck radiotherapy. When no elective radiotherapy was given or only ipsilateral or bilateral partial neck radiotherapy was delivered, the RC rate was only 38%. In our study, considering the patterns of occult metastasis and regional failure, we concluded that ipsilateral level IV, V and the contralateral neck are at a relatively lower risk. Therefore, elective radiotherapy to only ipsilateral level I, II and III for the treatment of clinically N0 oral cavity SCC may not be harmful. However, at present, it is possible to irradiate the bilateral neck area with minimal morbidity, using an intensity modulated or a three-dimensional conformal radiotherapy technique. We concluded that the inclusion of ipsilateral level IV, contralateral level I and II in the irradiated field is more reasonable.
In general, surgery and radiotherapy offer equal rates of LC for a primary T1 or T2 oral cavity carcinoma (14,15,23). In our study, the 5-year LC rate for the EBRT group was 30%. Even in early-stage disease, a similar disappointing result was found. We think that this result was probably due to the radiotherapy technique (external beam radiotherapy alone). Wednt et al. (24) analyzed 103 patients with T1–2 N0 oral tongue SCC who received definitive radiotherapy (external beam radiotherapy, interstitial therapy or a combination of both) and showed that a high dose of interstitial therapy is necessary to secure optimum LC of an early primary tongue cancer. The 2-year LC rate was 92% for patients treated with external radiotherapy with doses of <40 Gy combined with a moderately high dose of brachytherapy, compared with a rate of 65% for patients who received external radiotherapy with doses of 
40 Gy with lower brachytherapy doses (P = 0.01). Therefore, external beam radiotherapy alone for an oral cavity SCC is inadequate and combined surgery (or brachytherapy) and external beam radiotherapy appears to be a better treatment strategy.
The RC rates were quite similar for both treatment groups (P = 0.1142). The majority of patients (81%) in the EBRT group had a primary tumor clinically staged T1 or T2, while 58% of the patients in the S+EBRT group had a primary tumor clinically staged T1 or T2, which is predictable in a retrospective patient series. Therefore, one would expect that the comparable RC rate in the S+EBRT group had been achieved with treatment that is more aggressive. However, despite a poor LC rate in the EBRT group, the RC rate was excellent. Chow et al. (25) analyzed 489 patients with head and neck primary cancers and no clinically apparent neck metastases on initial presentation, and showed that there was no statistically significant difference between the use of elective radiotherapy to the neck and END to the oral cavity. Other retrospective studies have also suggested that for early-stage lesions, elective radiotherapy to the neck and END are equivalent for the control of subclinical neck disease, when the primary tumor has been adequately controlled (14,15). Practically, there have been many other factors influencing the selection of a modality for the elective treatment of the neck. The modality that will be employed for the treatment of the primary tumor, the adverse effect of therapy, the age of the patient, medical co-morbidities, the cost of therapy, the facilities of the institution and the preferences of the patients are some of the factors that should be taken into account in choosing between radiotherapy and surgical treatment of the N0 neck.
In conclusion, the risk for an occult neck metastasis is high in patients with early oral cavity SCC as well as advanced disease; therefore, elective neck treatment should be considered. Considering the patterns of occult metastasis and regional failure, we conclude that ipsilateral level IV, V and a contralateral neck are at a relatively lower risk, and elective radiotherapy delivered to only ipsilateral level I, II and III for the treatment of clinically N0 oral cavity SCC may not be harmful. However, at present, we also conclude that the inclusion of ipsilateral level IV, contralateral level I and II in the irradiated field with a modern radiotherapy technique is more reasonable. There was no significant difference between elective radiotherapy to the neck and END and excellent RC for subclinical disease can be achieved with external beam radiotherapy alone. External beam radiotherapy alone to the primary tumor resulted in poor LC and combined treatment with surgery (or brachytherapy) and external beam radiotherapy appeared to be a better treatment strategy.
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Funding |
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This study was supported by Seoul National University Hospital General Research Fund 04-2005-050-0.
Conflict of interest statement
None declared.
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Footnotes |
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Presented as a poster at the ASTRO'S 49th Annula Meeting, October 28–November 1, 2007, Los Angeles, CA, USA.
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References |
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