The Diagnosis and Treatment of Oral Cavity Cancer

Abstract

Background

About 10 000 persons are diagnosed as having carcinoma of the oral cavity or the throat in Germany every year. Squamous-cell carcinoma accounts for 95% of cases.

Methods

We systematically reviewed the pertinent literature on predefined key questions about these tumors (which were agreed upon by a consensus of the investigators), concerning imaging, the removal of cervical lymph nodes, and resection of the primary tumor.

Results

246 clinical trials were selected for review on the basis of 3014 abstracts. There was only one randomized, controlled trial (evidence level 1–); the remaining trials reached evidence levels 2++ to 3. Patients with mucosal changes of an unclear nature persisting for more than two weeks should be examined by a specialist without delay. The diagnosis is made by computed tomography or magnetic resonance imaging along with biopsy and a standardized histopathological examination. Occult metastases are present in 20% to 40% of cases. Advanced disease (stages T3 and T4) should be treated by surgery followed by radiotherapy, with or without chemotherapy. 20% of the patients overall go on to have a recurrence, usually within 2 to 3 years of the initial treatment. The 5-year survival rate is somewhat above 50%. Depending on the radicality of surgery and radiotherapy, there may be functional deficits, osteoradionecrosis, and xerostomia. The rate of loss of implants in irradiated bone is about 10% in 3 years.

Conclusion

The interdisciplinary planning and implementation of treatment, based on the patient’s individual constellation of findings and personal wishes, are prerequisites for therapeutic success. Reconstructive measures, particularly microsurgical ones, have proven their usefulness and are an established component of surgical treatment.

The annual total of around 250 000 new cancers among men in Germany includes approximately 10 000 cases of oral cavity cancer; for women the figures are somewhat lower (ca. 3 500 out of 220 000 new cancers) (1). About 95% of these oral cavity cancers are squamous cell carcinomas, which are frequently associated with the risk factors of chronic smoking or alcohol consumption: The odds ratio (OR) is 19.8 for smokers compared with patients who have never smoked, and 5.9 for alcohol consumption (>55 drinks/week) alone. The combination of tobacco and alcohol leads to a multiplication effect (OR = 177) (2). In the past few years it has also been clearly shown that the presence of human papilloma virus (HPV 16) in serum represents a further risk factor (3). Oral cavity cancer is most frequent in men between 55 and 65 and in women between 50 and 75 (4). Because the prospects of recovery are far more favorable (ca. 70%) if the tumor is detected at an early stage (T1/T2), screening has a central part to play. The 5-year survival rate for patients whose cancers are discovered later (T3/T4) is ca. 43% (4).

On the basis of data from 30 hospitals stored in the tumor registry of the German–Austrian–Swiss Working Group for Maxillary and Facial Tumors (DÖSAK), the largest uniformly documented collective of patients with cancers of the oral cavity in existence, conclusions can be drawn with regard to the treatment approaches applied to date and the prognosis (4). Of the 9002 patients registered between April 1989 and June 1999, 8390 data sets were subjected to univariate analysis. Surgery alone with radical intent was carried out in 52% of cases, surgery with adjuvant therapy (radiotherapy, radiochemotherapy) in 30%, and nonoperative treatment was selected in 18% of patients. Among the 30 hospitals, the chances of surviving 5 years varied from 28.5% to 69.0% (total collective: 54.3%) on Cox analysis and from 40.2% to 70.6% (total collective: 52.4%) on Kaplan–Meier analysis. Ten hospitals achieved 5-year survival rates of less than 50%, while three hospitals were over 60%. The figure for recurrence-free survival after 5 years was 43.9% overall. The 5-year survival rate was 59% for the patients who underwent surgery with radical intent and 18% for those who were treated nonoperatively. The Kaplan–Meier 5-year survival rate was very similar between patients who received adjuvant radiotherapy (51.3%) and those who underwent radiochemotherapy (52.7%). The difference between these rates and the above-mentioned 59% for patients treated by surgery alone was due to a selection effect; the latter did not receive adjuvant therapy because the pretreatment findings were less severe.

We found no usable studies seeking to establish the best treatment for oral cavity cancer. One published prospective randomized trial compared the survival rates following surgery and adjuvant radiotherapy with radiotherapy alone, but its statistical power was too low because of small case numbers (5). A large number of nonrandomized, retrospective, or monocentric studies have described survival rates or quality of life after surgery and after radiotherapy. No therapy recommendations can be constructed on the basis of these studies, however, owing to deficiencies in their design or conduct.

Despite repeated campaigns to raise the profile of oral cavity cancer, public awareness is low and there are diverging opinions regarding the nature and extent of diagnosis, treatment, and follow-up care. It was therefore perceived necessary to formulate an evidence-based treatment recommendation in the form of an S3 guideline. This required close cooperation among medical and dental professional bodies. The target group primarily comprises doctors and dentists working in the prevention, diagnosis, treatment and follow-up of oral cavity cancer, together with allied professionals involved in outpatient and inpatient care. The guideline thus represents an important basis for interdisciplinary cooperation in patient management at head and neck tumor centers.

Methods

This first evidence-based guideline for oral cavity cancer was organized under the aegis of the German Guideline Program in Oncology of the German Cancer Society (DKG), German Cancer Aid (DKH), and the Association of Scientific Medical Societies in Germany (AWMF) (http://leitlinienprogramm-onkologie.de). The guideline group was composed of 33 representatives from 21 professional societies and organizations (Table 1). Under the overall leadership of the German Society for Oral, Maxillary, and Facial Surgery, the group members started by defining 37 aspects of the diagnosis, treatment, and follow-up of oral cavity cancer that required clarification. With the support of the Division of Evidence-based Medicine at the Charité in Berlin, the group conducted a systematic de novo literature review on five key questions related to imaging, neck dissection, and resection of the primary tumor. The evidence level of the publications was established. Following a systematic search for international guidelines and evaluation of the methods of potentially relevant guidelines by means of the Appraisal of Guidelines for Research and Evaluation (AGREE) tool, the SIGN-90 guideline (Scottish Intercollegiate Guidelines Network, www.sign.ac.uk) was chosen as source of established evidence for use in guideline adaptation.

Table 1. Composition of the guideline group (professional societies, institutions).

German Society for Oral, Maxillary, and Facial Surgery	Wolff K.-D., Grötz K., Reinert S., Pistner H.
German–Austrian–Swiss Working Group for Maxillary and Facial Tumors (DÖSAK)	Frerich, B.
German Working Group on Maxillofacial Surgery	Reichert, T.
German Society for Dental, Oral, and Maxillofacial Medicine	Schliephake, H.
German Society for Oto-Rhino-Laryngology, Head and Neck Surgery	Bootz F., Westhofen M.
German Medical Association	Boehme, P.
National Association of Statutory Health Insurance Physicians	Beck, J.
German Society of Pathology	Burkhardt A., Ihrler S.
German Society of Radiooncology	Fietkau R., Budach W., Wittlinger M.
German Society of Hematology and Oncology	Keilholz U., Gauler T., Eberhardt W.
German Society of Plastic and Reconstructive Surgery	Horch R., Germann G.
Head and Neck Working Group of the German Roentgen Society	Lell M.
Conference of Nurses in Oncology (KOK) of the German Cancer Society	Paradies K., Gittler-Hebestreit N.
Department of Experimental Cancer Research (AEK) of the German Cancer Society	Engers K.
Oral and Facial Pain Working Group of the German Society for the Study of Pain (DGSS)	Schmitter M.
Supportive Oncology, Rehabilitation and Social Medicine (ASORS) Working Group of the German Cancer Society	Lübbe A.
Tumor Pain Working Group of the German Society for the Study of Pain (DGSS)	Wirz S.
Patients’ representative	Mantey W.
German Association for Social Work in the Healthcare System, German National Center for Tumor Diseases	Bikowski K.
German Federal Speech Therapy Association	Nusser-Müller-Busch R.
Psychooncology (PSO) Working Group of the German Cancer Society	Singer S., Danker H.

The primary systematic de novo research into the five defined key questions was carried out in Medline and Embase, via the platform OvidSP, on 26 January 2011 (Figure 1). The 3014 relevant abstracts yielded 246 studies which were eventually narrowed down to 117 publications relevant for further analysis (Figure 2). Each was assigned a level of evidence (LoE) ranging from 1++ (high-quality meta-analysis) to 4 (expert opinion) according to the SIGN classification (Table 2). Investigation of previously published meta-analyses yielded two that were relevant to the key questions. The methodology of the literature review and search strategy is described in detail in the guideline report at http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html (in German). At a concluding consensus conference, the nominal group technique was employed to produce answers to the key questions on the basis of the research, and recommendations, divided into three categories (Table 3), were formulated. Finally, to support the implementation and documentation of the guideline’s effects on patient care, 10 quality indicators were derived from the strong guideline recommendations, defined, and agreed according to the standardized methods of the German Guideline Program in Oncology (http://leitlinienprogramm-onkologie.de/uploads/media/G-I-N2012_Updating_QI_GGPO.pdf). These quality indicators can be generated from clinical cancer registry data and will form a central component of the survey forms of the head and neck tumor module at oncology centers.

Figure 1.

Primary survey of the literature with regard to the five key questions

Figure 2.

Flow diagram of the final steps of the literature survey

Table 2. Evidence level according to SIGN^*1.

Level	Description
1++	High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of systematic error (bias)
1+	Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of systematic error (bias)
1–	Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of systematic error (bias)
2++	High quality systematic reviews of case control or cohort or studiesHigh quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+	Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2–	Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3	Nonanalytic studies, e.g., case reports and case series
4	Expert opinion

^*1www.sign.ac.uk/Guidelines/fulltext/50/annexb.html; RCT, randomized controlled trial

Table 3. Recommendation levels.

Recommendation level	Description	Syntax
A	Strongly recommended	Must
B	Recommended	Should
0	Recommendation open	Can

The evidence level of the 246 relevant studies was predominantly graded 2++ to 3. One prospective randomized controlled trial received a grade of 1–. A systematic search for existing meta-analyses and systematic reviews in Medline and Embase identified two meta-analyses, which were then also included.

In agreement with all of the professional societies, 76 statements and recommendations were formulated. Some of the most important of these will now be discussed. Statements (evidence-based, but without explicit treatment recommendations) are identified by the abbreviation “St”.

Results

Diagnosis

All patients with mucosal lesions of unknown origin and more than 2 weeks’ duration (Figures 3 and 4) should immediately be referred to a specialist (LoE good clinical practice [GCP]). This includes:

Figure 3.

A typical squamous cell carcinoma of the floor of the mouth

Figure 4.

Histological appearance of an ulcerated squamous cell carcinoma of the oral cavity; left: preserved epithelial layers; top: tumor showing infiltrative growth

• White or red spots anywhere on the oral mucosa

• A mucosal defect or ulceration

• Swelling anywhere in the oral cavity

• Loosening of one or more teeth for no known reason, not connected with periodontal disease

• Persistent foreign body sensation, particularly when unilateral

• Pain

• Difficulty or pain in swallowing

• Speech difficulties

• Reduced mobility of the tongue

• Numbness of the tongue, teeth, or lips

• Bleeding of unknown origin

• Neck swelling

• Fetor

• Altered dental occlusion.

To exclude synchronous secondary tumors, patients undergoing primary diagnosis of oral cavity cancer should also be examined by an ear, nose, and throat (ENT) specialist and endoscopy should be considered (LoE GCP). The incidence of synchronous metastases is 4% to 33%, depending on the size of the primary tumor; they are particularly frequent in stages T3 and T4 and in patients with level IV lymph node involvement (6).

Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed (LoE 3, recommendation level [RL] B) (7, e1, e2). A panoramic section is one of the basic tools in dental diagnosis and should be obtained before the commencement of specific tumor therapy (LoE GCP). Positron emission tomography (PET)-CT plays no part in the primary diagnosis of the local extension of a known oral cavity cancer (LoE 2+, St) (8, e3– e8). Patients with advanced oral cavity cancer (stage III, IV) should undergo CT of the thorax (LoE 3, RL A) to exclude pulmonary involvement (filia, metastasis) (9, 10, e9, e10). Patients with suspected tumor recurrence in the head and neck region in whom CT and/or MRI are inconclusive can proceed to PET-CT (LoE 3, RL 0) (11, 12, e11, e12). According to the results of a meta-analysis, in diagnosing recurrence PET-CT possesses higher sensitivity (80%) than the combination of CT and/or MRI (75% and 79%) (11); the specificity (86%) is lowered by false-positive findings in inflammatory lesions. Fluorodeoxyglucose (FDG)-PET, however, was found to be more reliable than CT and/or MRI, with sensitivity of 100% and specificity of 61% to 71% (12). Previously undetected primary tumors and distant metastases can also be diagnosed more reliably with PET-CT than with CT or MRI (13).

Surgical treatment

The treatment of oral cavity cancer must be decided on a case-by-case basis by an interdisciplinary tumor board with representatives from oromaxillofacial surgery, ENT, radiotherapy, oncology, pathology, and radiology (LoE GCP). The patient’s individual circumstances should be taken into account. Before deciding to operate, the interdisciplinary team must consider whether tumor-free resection margins can be achieved and what postoperative quality of life can be expected for the patient (LoE 3, RL A) (14, 15, e13– e19).

In oral cavity cancers adjudged to be curatively resectable, surgery—in combination with immediate reconstruction if required—should be performed whenever the patient’s general condition permits. Patients with advanced tumors should receive postoperative treatment (LoE 3, RL B) (14, e20– e22). Reconstructive measures should be a standard part of surgery planning which should always take into account the overall oncological situation. The expected functional or esthetic improvement must justify the measures planned (LoE 3, RL A) (15, e23, e24). In considering reconstruction, it must be recalled that a distance of less than 1 mm between the histologically demonstrated tumor margin and the resection line counts as a positive margin of resection (16, 17); a distance of 1 to 3 mm between tumor and resection line is viewed as a narrow, 5 mm or more as a safe margin. The intraoperative frozen-section histology technique may help to avoid a positive resection margin, which is associated with a poorer prognosis (LoE GCP). The continuity of the lower jaw should be preserved, provided tumor invasion of bone is found neither on diagnostic imaging nor intraoperatively (LoE 3, RL B) (18, 19, e25– e28).

In 20% to 40% of cases of oral cavity cancer there is occult metastasis to the cervical lymph nodes. Levels I to III are almost always affected, level V very rarely (LoE 3, St) (20, e29– e43). All patients with clinically normal lymph-node status (cN0), regardless of their T category, should undergo elective neck dissection (LoE 3, RL A) (21, 22, e44– e52). In the case of clinical suspicion of lymph node involvement (cN+), the appropriate lymphadenectomy—usually modified radical neck dissection—should be carried out (LoE 3, RL A) (23, 24, e53– e59). The likelihood that an oral cavity cancer involving cervical lymph nodes of levels I to III will also affect level IV is generally stated as 7% to 17%, and the corresponding figure for level V is 0 to 6% (25, 26).

The histopathology report on the resected material should encompass tumor location, size, histological type, and stage; depth of invasion; invasion of lymph vessels, blood vessels, and perineural tissues; infiltration of local structures; R status; and pT classification (27). Postoperative treatment should be discussed in the interdisciplinary tumor conference.

Conservative treatment

Postoperative radiotherapy or radiochemotherapy is advisable in the case of advanced T category (T3/T4), narrow or positive resection margin, perineural invasion, vessel invasion, or lymph node involvement (LoE 1++, RL A) (28, 29, e60– e67). The total radiotherapy dose is generally divided into a number of individual doses, either conventionally fractionated (1.8–2.0 Gy daily, 5 days/week), accelerated (>10 Gy/week), or hyperfractionated (1.1–1.2 Gy twice daily). In conventional fractionation the total dose of around 70 Gy is administered in daily doses of 1.8–2.0 Gy, 5 days per week. Possible modifications are hypofractionation, hyperfractionation, and accelerated fractionation. Hypofractionation, preferentially employed in palliative treatment, involves individual doses much higher than the usual 1.8–2.0 Gy. Hyperfractionation entails administration of smaller doses but more of them; the total dose can be increased. One meta-analysis showed that hyperfractionation achieved not only better locoregional tumor control but also a 3.4% improvement in overall 5-year survival compared with conventional fractionation (30).

Postoperative radiotherapy should be started as soon as possible and completed by no more than 11 weeks after surgery (LoE 2++, RL B) (31, 32). Primary radiochemotherapy should be preferred to radiotherapy alone in patients with advanced, nonoperable, and nonmetastized oral cavity cancer (LoE 1++, RL A) (33, 34). The relative survival advantage conferred by chemotherapy in addition to radiotherapy is particularly great in patients under 60 years of age (22% to 24%) and still appreciable in those between 60 and 70 (12%) (30, 33). Cisplatin is important in this regard: cisplatin alone and combinations including cisplatin show equal effect, but polychemotherapy without cisplatin leads to significantly poorer results (30, 33– 35).

There are indications that intensity-modulated radiotherapy (IMRT) can reduce the frequency and severity of radiation-induced xerostomia (LoE 3, St) (36).

Palliative treatment

Although chemotherapy with palliative intent can achieve response rates of 10% to 35%, there is no evidence of prolongation of survival (37). For palliative radiotherapy, too, there are no evidence-based studies demonstrating efficacy in incurable head and neck cancers. Palliatively treated patients should be referred for professional supportive therapy at an early stage.

Dental rehabilitation

Patients who have received surgical treatment and/or radiotherapy for oral cavity carcinoma should be offered either an implant or a conventional prosthesis to restore their ability to chew, with regular dental follow-up thereafter. Any dental surgery should be performed by specialists well acquainted with this clinical picture (LoE 3, RL B) (38, e68– e72). Infected osteoradionecrosis may arise in the irradiated jaw, for example after dental extraction; the frequency of this complication has been given as 5% (38). Although advances in dental implantology have considerably expanded the prosthetic options, an implant loss rate of ca. 10% after 3 years has to be expected in irradiated bone (39).

Follow-up

Around a fifth of patients treated for oral cavity cancer experience a local recurrence of their tumor. The recurrence is diagnosed within 2 years in 76% of cases and in a further 11% during the 3rd year after completion of primary treatment (40). Even in symptom-free patients, the maximum interval between follow-up visits should be 3 months in the first 2 years and 6 months in years 3 to 5. A structured follow-up plan should be drawn up for each individual patient. Patients should be regularly interrogated about their quality of life. After 5 years’ follow-up they should attend routine tumor screening (LoE GCP). The primary goal of follow-up is therefore careful clinical and radiological (CT, MRI) examination of the oral cavity and neck to exclude newly developing cancers. According to the results of a retrospective study, only 61% of such tumors are symptomatic; in other words, they go unnoticed by 39% of patients (40).

Conclusion

Treatment of oral cavity cancer is an interdisciplinary task for which an S3 guideline has now been issued. The complex diagnostic and therapeutic decision processes involved, together with the implementation of multimodal treatment plans, demand the skills and experience found only at tumor centers. Consistent adherence to the treatment recommendations laid out in the guideline will be crucial to its success. The implementation of the guideline and its effect on patient care can be assessed on the basis of 10 interdisciplinarily agreed indicators for the quality of diagnosis, treatment, and follow-up which will be measured and evaluated at the clinical cancer registries and certified centers.

The newly published clinical practice guideline for oral cavity cancer can be downloaded from the following websites (in German):

• www.awmf.org/leitlinien/aktuelleleitlinien.html

• www.leitlinienprogramm-onkologie.de/OL/leitlinien.html

• www.krebsgesellschaft.de/wub_llevidenzbasiert,120884.html

• www.krebshilfe.de

• www.mkg-chirurgie.de