Int J Clin Oncol (2014) 19:423–430 DOI 10.1007/s10147-014-0689-z
REVIEW ARTICLE
Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma Ken Omura
Received: 14 March 2014 / Published online: 1 April 2014 Ó Japan Society of Clinical Oncology 2014
Abstract The primary treatment modality of oral cancer is generally determined according to the stage of the disease, with surgical treatment remaining the mainstay of multimodal treatment. When selecting the treatment, many factors are taken into consideration, and the treatment should be tailored individually to the patient’s needs and consider the quality of life as well as the survival of the patient. Early-stage disease is primarily managed with surgery or brachytherapy without functional morbidity, whereas for advanced-stage disease multidisciplinary treatment is recommended, not only for enhanced survival but also for improved quality of life. After resection of large primary tumors, reconstructive surgery is required. Free tissue transfer currently represents one of the most popular and reliable techniques for oral reconstruction. For cN0 neck, elective neck dissection is recommended when the risk of occult metastases is [20 %, when the neck is entered either for resection of the primary tumor or for reconstruction, or when the patient is unlikely to return for a close follow-up. Sentinel node biopsy is performed investigationally. Modified radical neck dissection is the gold standard for cN? neck. For patients with multiple node metastases or extracapsular spread, postoperative radiotherapy or chemoradiotherapy is recommended, with the lymph nodes situated outside the confines of the radical neck dissection, such as the lingual and retropharyngeal nodes, receiving considerable attention. Targeted therapy for oral cancer is still a relatively new concept, and more
K. Omura (&) Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan e-mail: [email protected]
studies are needed to confirm the clinical effectiveness of these drugs. Keywords Multidisciplinary treatment Postoperative chemoradiotherapy Quality of life
Introduction The oral cavity is the uppermost part of the aerodigestive tract. The oral cavity begins at the lips, and ends at the anterior surface of the faucial arch. It is lined by squamous cell epithelium with interspersed minor salivary glands. The oral cavity can be subdivided into 5 sites: the tongue, floor of the mouth, maxillary/mandibular gingiva, buccal mucosa (including the retromolar trigone), and hard palate. Oral cancer is the sixth most common cancer worldwide, accounting for approximately 4 % of all cancer cases. The incidence and mortality from the disease vary geographically. In Japan, 7,000 new cases are diagnosed each year, and it accounts for 1 % of all cancers. According to data from the Japanese oral cancer registry, the tongue is the most commonly affected site, followed by the gingiva, buccal mucosa, and floor of the mouth, whereas lip cancer accounts for only 1 % of all oral cancers. Histologically, more than 90 % of the tumors are squamous cell carcinoma (SCC), followed by adenoid cystic carcinoma and mucoepidermoid carcinoma [1]. The primary treatment modality of oral cancer is determined according to the stage of the disease, and surgical treatment remains the mainstay of multimodal treatment. Therefore, accurate staging based on the findings of the physical examination and imaging studies is required. Recent advances in modern technology have provided various imaging modalities, such as computed tomography
123
424
(CT), magnetic resonance imaging (MRI), ultrasonography, and positron emission tomography (PET)-CT. Of these, CT and MRI are primarily recommended to assess the locoregional disease. Moreover, at staging of the disease, endoscopic examination of the upper digestive tract is also recommended, as 7 % of oral cancer patients reportedly have a concomitant second primary lesion in this area [2, 3]. The most important functions of the oral cavity are mastication, deglutition, maintenance of oral competency, and articulation of speech. Therefore, when choosing the treatment modality, many factors must be taken into consideration and the treatment should be tailored individually to each patient’s needs in order to ensure good quality of life as well as favorable survival. In this review, the surgical management of oral SCC is discussed for each of the 5 sites.
Surgical management of primary tumors The ultimate aim of surgical resection is adequate clearance of tumor tissue. Inadequate clearance of tumor cells results in increased risks of local and regional recurrences, and decreased long-term survival rates [4]. However, in oral SCC, increasing the resection margins may result in increased esthetic and functional morbidities. In oral cancer surgery, three-dimensional 1-cm resection margins are considered acceptable [5–7], and in primary tumor resection, vital staining with iodine solution is recommended as an adjunct, in order to detect and delineate the dysplastic epithelium accompanying the cancerous lesion [8–10]. After resection of the primary tumor, reconstructive surgery is usually required to restore oral function and cosmetic appearance. The most appropriate reconstruction method is determined by many factors, including the characteristics of the primary site and defects, the general medical condition and social history of the patient, the prognosis, and the skills of the surgeon. The methods of reconstruction usually follow a ‘‘reconstructive ladder,’’ beginning from a skin graft to a microvascular free flap. Free tissue transfers currently represent one of the most popular and reliable techniques for oral reconstruction. There are various free flap options available; however, there is currently no single flap that can resolve the entire spectrum of oral defects [11, 12].
Tongue The tongue is the most commonly affected site of oral tumors, accounting for 60 % of all oral cancers [1]. Within this site, the majority of tumors occur on the lateral borders and ventral surface.
123
Int J Clin Oncol (2014) 19:423–430
Small tumors (stage T1 and early-T2 tumors: tumors \3 cm in diameter) can be managed by partial glossectomy if the resection does not substantially involve the floor of the mouth. Partial glossectomy may be performed in a horizontal spindle fashion, resulting in the defect becoming primarily closed, with a functionally excellent and normal-shaped tongue. Large tumors may require hemiglossectomy or subtotal or total glossectomy. Hemiglossectomy defects can be reconstructed with a radial forearm free flap, with acceptable speech and swallowing functions [13], whereas subtotal or total glossectomy defects may need to be convexly reconstructed with an anterolateral thigh or rectus abdominis free flap. Convex reconstruction of large glossectomy defects may be essential for acceptable postoperative functions [14–16]. When the resection extends to the tongue base and/or lateral pharyngeal wall, a mandibular swing or visor flap with the mandibular lingual releasing approach may be required to gain access to these regions. Reconstruction of large glossectomy defects usually needs to be accompanied by procedures aimed at preventing postoperative aspiration, such as laryngeal suspension, laryngoplasty, and cricopharyngeal myotomy [17, 18].
Floor of the mouth The floor of the mouth is a relatively common site for oral cancer, with approximately 10 % of all oral cancers developing at this site. Within the site, the majority of tumors arise in the anterior portion [1]. Small tumors arising at the anterior floor of the mouth are commonly excised in conjunction with the ventral surface of the tongue [19], and the submandibular ducts may be included in the surgical specimen for fear of possible tumor extension along the duct. The stump of the duct needs to be repositioned at the margin of resection, and any surgical defects can generally be reconstructed with a split thickness skin graft (STSG). The tumor may deeply invade the floor of the mouth and abut to the mandible [20]. In such situations, wide local excision of the tumor in conjunction with rim resection of the mandible may need to be carried out. In general, any defects can be satisfactorily reconstructed with a radial forearm free flap. When the mandible is resected segmentally, the reconstruction can be achieved with a free compound flap, such as fibula osteocutaneous and scapula osteocutaneous flaps. In some cases of advanced-stage disease, considering the patient’s age and poor prognosis, the mandibular defects may be reconstructed with a titanium mandibular reconstruction plate and the soft tissue defects may be restored with a free rectus abdominis flap wrapping around the plate to avoid extrusion of the plate [21–23].
Int J Clin Oncol (2014) 19:423–430
Buccal mucosa The buccal mucosa is the most common site for oral cancer in South-east Asia, accounting for up to 40 % of oral cancers there. However, in Japan, as well as in North America and Western Europe, it accounts for only approximately 10 % [1]. T1 and T2 tumors can be excised perorally, with the buccinator muscle usually being included at the deep margin [24]. When the parotid duct is included in the surgical specimen, the stump is repositioned if possible. Surgical defects can be primarily closed in some selected patients; however, STSG or a mucosal graft is usually required to secure postoperative mouth opening. Large buccal tumors require a lower cheek flap approach, and are excised together with the buccal fat pad and maxilla and/or mandible. Microvascular free flap reconstruction with a radial forearm or anterolateral thigh flap is used to restore the thickness of the cheek [25]. Large tumors often require a through-and-through resection of the cheek. In such cases, the defects can be reconstructed with a bi-paddled and folded flap, resurfacing the skin and mucosal defects [26].
Retromolar trigone The retromolar trigone is a relatively unusual site for carcinomas of the oral cavity, accounting for only 3 % of all oral cancers. Small tumors of the retromolar trigone may be resected perorally. However, a lower cheek flap approach or mandibular swing approach is often required, because of its posterior location and the frequent extension of the tumor into adjacent sites [27, 28]. Even if the mandible shows no radiological signs of involvement, a posterior marginal resection of the mandible may be performed to achieve clear margins. These tumors may require extended surgery, including of the mandible, maxilla, soft palate, tongue base, and buccal mucosa. Moreover, these tumors may require careful considerations on reconstruction, as the defects may be both extensive and highly complex, and may occasionally cause trismus. In such situations, dual free flaps may provide ideal soft tissue and bony reconstruction. However, these are associated with an increased risk of complications.
Maxillary gingiva and hard palate Maxillary gingival carcinoma accounts for 6 % of all oral cancers, making it approximately half as common as mandibular gingival cancer. Carcinomas of the hard palate
425
are relatively rare, accounting for only 3 % of all oral cancers [1]. Small tumors arising in the maxillary gingiva may be amenable to transoral wide excision with resection of the involved mucoperiosteum and the underlying bone. Surgical defects are usually restored with a maxillary prosthesis. In some cases, surgical closure of defects may be achieved with a local flap, such as a palatal flap and buccal fat pad. However, large tumors may require partial or subtotal maxillectomy using an upper cheek flap approach. These maxillary tumors often extend posteriorly to the pterygoid region. In such cases, a pterygoid dissection may be required in conjunction with the maxillectomy. On the other hand, soft tissue defects require lining with an STSG for good restoration with a maxillary prosthesis. For more posteriorly and/or superiorly extending tumors, a subciliary incision may be combined with Ferguson’s incision to access the infratemporal fossa. In such cases, the extended surgical defects can be reconstructed with a free rectus abdominis flap.
Mandibular gingiva Mandibular gingival carcinoma represents 12 % of all oral cancers [1]. Mandibular gingival tumors may easily enter into the mandibular bone, mainly through the periodontal space and cortical deficiencies in dentate non-irradiated and edentulous mandibles, respectively. Moreover, the tumors occasionally spread along the periosteum [29–31]. There is some controversy regarding the T4 criteria of mandibular gingival cancer. The TNM classification of the UICC defines T4 tumors as tumors invading through the cortical bone, whereas, according to the level of mandibular canal criteria, which are widely accepted in Japan, T4 tumors are defined as tumors involving the level of the mandibular canal [32]. In surgery for lower gingival cancer, one of the most critical issues is whether marginal resection is adequate or not [33–39]. The type of mandibulectomy is decided clinically, and is based on the T-stage and radiological pattern of bone resorption. Radiologically, mandibular bone resorption is divided into two types: erosive and invasive [40]. The erosive type is defined as a defect showing sharply outlined U-shaped excavation. Histologically, tumors of this type usually show an expansive pattern of bone involvement, and the margins of the destroyed mandible are well defined and smooth. A small amount of connective tissue can generally be seen between the tumor and bone. The invasive type is defined as defects showing irregular and ill-defined bone margins. This type of tumor is often accompanied by widening of the mandibular canal. Histologically, the majority of tumors of this type show an infiltrative pattern
123
426
Int J Clin Oncol (2014) 19:423–430
Neck node management It is well known that the cervical lymph node status is one of the most important prognostic factors for oral SCCs. Currently, neck dissection is the only accepted standard treatment for cervical node metastases. For the past several decades, surgical treatment of cervical node metastases has consisted of radical neck dissection (RND). Since then, RND has been modified in various ways to reduce postoperative morbidity, and has given rise to several different types of neck dissections [45]. Moreover, while recent advances in technology have provided various diagnostic imaging modalities, none of these can accurately detect cervical lymph node metastases. cN0 neck
Fig. 1 a A 52-year-old male patient diagnosed with cT4aN2c mandibular gingival carcinoma. b The patient underwent segmental resection of the anterior part of the mandible in conjunction with bilateral neck dissection. c Segmental defect of the mandible was reconstructed with a scapular osteocutaneous free flap. The scapular bone was osteotomized at 2 sites to restore mandibular contour. Two years after reconstruction, after thinning of the scapular flap, 4 osseointegrated implants were installed (panoramic X-ray). d, e The implant-supported prosthesis provides a functional restoration and support of the lower lip
of involvement, irregular margins of the destroyed bone, and involvement of the mandibular canal through the marrow space [41, 42]. On the basis of these clinicopathological findings, marginal resection can be applied for T1 tumors and for T2/3 tumors with no or erosive bone resorption [43, 44], whereas segmental resection is recommended for T2/3 tumors with invasive resorption and for T4 tumors [33, 34]. When the depth of the mandible after marginal resection is \10 mm, the mandible may be reinforced with a titanium plate. Segmental defects of the mandible require reconstruction of mandibular continuity, especially by the use of a free vascularized bone flap. The donor site is selected on the basis of the bony defect along with the accompanying soft tissue defects. Free vascularized bone flaps clearly provide significant advantages for mandibular reconstruction; however, combined use of reconstruction plates and soft-tissue flaps remains a reconstructive option in some selected patients who have poor medical conditions or prognoses [21–23]. Dental rehabilitation using a prosthesis or osseointegrated dental implants is an important part of the reconstruction to restore the esthetics and functions (Fig. 1).
123
Approximately 20–30 % of clinical N0 necks have occult node metastasis, and thus cervical lymph node status is predicted by clinical and pathological evaluation of the primary tumor [46–52]. Management of clinical N0 neck is controversial, with some clinicians advocating the ‘‘wait and see’’ approach, whereas others favor elective neck dissection [53–55]. However, patients with delayed neck node metastases generally have a poor prognosis. For this reason, elective neck dissection is often considered for late-T2 and T3 cases in Japan [56]. That said, there are currently no definite surgical guidelines for treatment of clinical N0 neck, although, in general, elective neck dissection is considered warranted when the risk of occult metastases is [20 % [57]. Other indications for elective neck dissection include the need to enter the neck, either for resection of the primary tumor or for reconstruction. It may also be indicated when the patient is unlikely to return for a close follow-up. When the neck is treated electively, supraomohyoid neck dissection is generally performed [58, 59]. However, there is some reported evidence that level IV nodes are also at risk [60, 61], and, accordingly, these have to be included in the procedure in a subset of patients. Recent prospective multiinstitutional studies have demonstrated that sublevel IIB lymph nodes rarely involve isolated metastases from oral cancers, except from some tongue cancers. Thus, it is justifiable to omit dissection of sublevel IIB nodes in elective treatment of most cases of oral cancer [62]. Recently, sentinel node biopsy has received considerable attention as a means of avoiding unnecessary lymph node dissection. In the past, it has been mainly applied to cases of malignant melanoma and breast cancer, but has recently gained much attention as an investigational tool for head and neck cancer as well [63–65].
Int J Clin Oncol (2014) 19:423–430
427
Fig. 2 a A 76-year-old male patient was diagnosed with cT4aN2b retromolar trigone carcinoma. b MRI showed retropharyngeal node metastasis. c The patient underwent parapharyngeal dissection in conjunction with maxillo-mandibular resection and neck dissection
cN1–3 neck
Adjuvant therapy
For clinical N1–3 neck, it is generally recommended to perform a standard or modified RND (MRND) [66]. MRND, especially that sparing the spinal accessory nerve, has become the gold standard for neck disease. In addition, supraomohyoid neck dissection can be chosen for clinical N1 neck with level IB metastasis [57]. Because patients with multiple node metastases or extracapsular spread of tumors often present with neck failure and/or distant metastasis after neck dissection, postoperative radiotherapy or concurrent chemoradiotherapy is recommended [67–70]. Oral cancer may metastasize to the nodes situated outside the confines of the RND, such as the lingual and retropharyngeal nodes. The lingual nodes are small, inconstant, interrupting nodes that are divided into lateral and median lingual nodes. Lateral nodes are present in 30 % of all individuals, and are located on the external aspect of the genioglossus muscle or on the hyoglossus muscle, along the lingual artery and vein. Conversely, the median nodes are present in approximately 15 % of all individuals, and are found in the median plane of the tongue between the genioglossus muscles. It is recommended that theses nodes be removed by a pull-through operation [71, 72]. The retropharyngeal nodes are located at the base of the skull, close to the internal carotid artery. They receive lymph flow from the nasopharynx, maxilla, and posterior part of the oral cavity, and drain into the upper jugular nodes [73–75]. These nodes can be eradicated by retropharyngeal node or parapharyngeal dissections, which are systematic approaches for en bloc resection of the retro- and parapharyngeal spaces, respectively [76, 77] (Fig. 2).
Radiotherapy is typically applied postoperatively owing to the difficulty of surgically removing irradiated tissue, because tissues become fibrosed and thus tend to heal slower. Factors such as large primary tumors, positive or close surgical margins, and signs of perineural, lymph, and/ or vascular invasion generally dictate the use of radiotherapy at the primary site; however, the neck is also commonly treated, especially if there are positive nodes with or without extracapsular spread, in order to prevent potential metastasis and recurrence. Radiotherapy is recommended to begin within 6 weeks after surgery [78], and, while the radiation doses vary, a total dose of approximately 60 Gy is typical. In recent years, chemotherapy has emerged as a prominent adjunct modality for locoregionally advanced oral SCC. Although it is generally not considered a curative modality for oral cancers alone, it can be utilized before surgery (as induction therapy) or concurrently with irradiation (chemoradiotherapy) before or after surgery. Adjuvant chemoradiotherapy has almost become a standard treatment for advanced oral cancers. Currently, the most common regimen consists of CDDP 80–100 mg/m2 on days 1, 22, and 43, although other variations such as daily low-dose and weekly intermediate-dose CDDP have also shown survival benefits. In 1997, Robbins et al. [79] first reported marked results with RADPLAT, a superselective intra-arterial infusion of high-dose CDDP in combination with radiotherapy, for advanced head and neck cancer. Since then, the standard treatment in Japan for advanced head and neck cancer has been shifting from radical surgery to various organ preservation therapies, such as
123
428
Int J Clin Oncol (2014) 19:423–430
radiation therapy with concurrent superselective intraarterial chemotherapy. For oral lesions, superselective catheterization can be performed through the femoral artery or the superficial temporal artery and/or occipital artery [80, 81]. The local control rate of oral cancer treated by superselective intra-arterial chemoradiation is high, and it is thus recommended for T4 and unresectable tumors [82]. Lastly, overexpression of epidermal growth factor receptor (EGFR) has been confirmed in oral SCC, and has been reported to be associated with a poor prognosis [83]. The addition of a targeted agent, such as a monoclonal antibody EGFR inhibitor, has been reported to improve survival outcomes as compared with primary radiotherapy alone in head and neck SCCs [84]. Recently, the RTOG 0920 trial was launched in order to evaluate whether the addition of cetuximab, an EGFR inhibitor, to postoperative radiotherapy will improve overall survival in postoperative intermediate-risk oral cancer patients. Targeted therapies such as cetuximab are still a relatively new concept in head and neck cancer, and further studies are hence needed to confirm its clinical effectiveness. Conflict of interest
There are no conflicts of interest to declare.
References 1. Ariyoshi Y, Shimahara M, Omura K et al (2008) Epidemiological study of malignant tumors in the oral and maxillofacial region: survey of member institutions of the Japanese Society of Oral and Maxillofacial Surgeons, 2002. Int J Clin Oncol 13:220–228 2. McGuirt WF (1982) Panendoscopy as a screening examination for simultaneous primary tumors in head and neck cancer: a prospective sequential study and review of the literature. Laryngoscope 92:569–576 3. Saikawa M, Ebihara S, Yoshizumi T et al (1991) Multiple primary cancers in patients with squamous cell carcinoma of the oral cavity. Jpn J Cancer Res 82:40–45 4. Sutton DN, Brown JS, Rogers SN et al (2003) The prognostic implications of the surgical margin in the oral squamous cell carcinoma. Int J Oral Maxillofac Surg 32:30–34 5. McMahon J, O’Brien CJ, Pathak I et al (2003) Influence of condition of surgical margins on local recurrence and diseasespecific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg 41:224–231 6. Mistry RC, Qureshi SS, Kumaran C (2005) Post-resection mucosal margin shrinkage in oral cancer: quantification and significance. J Surg Oncol 91:131–133 7. Meier JD, Oliver DA, Varvares MA (2005) Surgical margin determination in head and neck oncology: current clinical practice. The results of an International American Head and Neck Society Member Survey. Head Neck 27:952–958 8. Kurita H, Kurashina K (1996) Vital staining with iodine solution in delineating the border of oral dysplastic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:275–280 9. Xiao T, Kurita H, Shimane T et al (2013) Vital staining with iodine solution in oral cancer: iodine infiltration, cell proliferation, and glucose transporter 1. Int J Clin Oncol 18:792–800
123
10. Petruzzi M, Lucchese A, Baldoni E et al (2010) Use of Lugol’s iodine in oral cancer diagnosis: an overview. Oral Oncol 46:811–813 11. Hidalgo DA, Disa JD, Cordeiro PG et al (1998) A review of 716 consecutive free flaps for oncologic surgical defects: refinements in donor site selection and technique. Plast Reconstr Surg 102:722–732 12. Sakuraba M, Miyamoto S, Kimata Y et al (2013) Recent advances in reconstructive surgery: head and neck reconstruction. Int J Clin Oncol 18:561–565 13. Kudoh M (2010) Longitudinal assessment of articulatory and masticatory functions following glossectomy for tongue carcinoma. Kokubyo Gakkai Zasshi 77:27–34 14. Lam L, Samman N (2013) Speech and swallowing following tongue cancer surgery and free flap reconstruction—a systematic review. Oral Oncol 49:507–524 15. Kimata Y, Sakuraba M, Hishinuma S et al (2003) Analysis of the relations between the shape of the reconstructed tongue and postoperative functions after subtotal or total glossectomy. Laryngoscope 113:905–909 16. Yanai C, Kikutani T, Adachi M et al (2008) Functional outcome after total and subtotal glossectomy with free flap reconstruction. Head Neck 30:909–918 17. Biller HF, Lawson W, Baek SM (1983) Total glossectomy. A technique of reconstruction eliminating laryngectomy. Arch Otolaryngol 109:69–73 18. Fujimoto Y, Hasegawa Y, Yamada H et al (2007) Swallowing function following extensive resection of oral or oropharyngeal cancer with laryngeal suspension and cricopharyngeal myotomy. Laryngoscope 117:1343–1348 19. McColl HA Jr, Horwood J (1978) ‘Localized’ carcinoma of the mobile tongue and floor of mouth—a lesion frequently misjudged and undertreated. J Surg Oncol 10:337–345 20. Hicks WL Jr, Lorre TR, Garcia RI et al (1997) Squamous cell carcinoma of the floor of mouth: a 20-year review. Head Neck 19:400–405 21. Boyd JB, Mulholland RS, Davidson J et al (1995) The free flap and plate in oromandibular reconstruction: long-term review and indications. Plast Reconstr Surg 95:1018–1028 22. Head C, Alam D, Sercarz JA et al (2003) Microvascular flap reconstruction of the mandible: a comparison of bone grafts and bridging plates for restoration of mandibular continuity. Otolaryngol Head Neck Surg 129:48–54 23. Takushima A, Harii K, Asato H et al (2001) Mandibular reconstruction using microvascular free flap: a statistical analysis of 178 cases. Plast Reconstr Surg 108:1555–1563 24. Hao SP, Cheng MH (2004) Cancer of the buccal mucosa and retromolar trigone. Oper Tech Otolaryngol 15:239–251 25. Ozkan O, Mardini S, Chen HC et al (2006) Repair of buccal defects with anterolateral thigh flaps. Microsurgery 26:182–189 26. Liu WW, Yang AK, Ou YD (2011) The harvesting and insetting of a chimeric anterolateral thigh flap to reconstruct through and through cheek defects. Int J Oral Maxillofac Surg 40:1421–1423 27. Mendenhall WM, Morris CG, Amdur RJ et al (2005) Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery. Cancer 103:2320–2325 28. Genden FM, Ferito A, Shaha AR et al (2003) Management of cancer of the retromolar trigone. Oral Oncol 39:633–637 29. McGregor AD, MacDonald DG (1988) Routes of entry of squamous cell carcinoma to the mandible. Head Neck 10:294–301 30. Totsuka Y, Usui Y, Tei K et al (1991) Mandibular involvement by squamous cell carcinoma of the lower alveolus. Analysis and comparative study of histologic and radiologic features. Head Neck 13:40–50 31. Virag MM, Bunarevic´ A, Aljinovic´ N (1991) Recurrences of oral cancer due to discontinuous periosteal involvement. Am J Surg 162:388–392
Int J Clin Oncol (2014) 19:423–430 32. Fujibayashi T (2004) Level of mandibular canal (LMC) criteria of lower gingival carcinomas and mode of mandibulectomy according to LMC criteria and bone invasion pattern. J Jpn Soc Oral Tumors 16:35–48 33. Totsuka Y, Usui Y, Tei K et al (1991) Results of surgical treatment for squamous carcinoma of the lower alveolus: segmental vs marginal resection. Head Neck 13:114–120 34. Ord RA, Sarmadi M, Papadimitrou J (1997) A comparison of segmental and marginal bony resection for oral squamous cell carcinoma involving the mandible. J Oral Maxillofac Surg 55:470–477 35. Politi M, Costa F, Robiony M et al (2000) Review of segmental and marginal resection of the mandible in patients with oral cancer. Acta Otolaryngol 120:569–579 36. Wax MK, Bascom DA, Myers LL (2002) Marginal mandibulectomy vs segmental mandibulectomy, indication and controversies. Arch Otolaryngol Head Neck Surg 128:600–603 37. Genden EM, Rinaldo A, Jacobson A et al (2005) Management of mandibular invasion: when is a marginal mandibulectomy appropriate? Oral Oncol 41:776–782 38. O’Brien CJ, Adams JR, McNeil EB et al (2003) Influence of bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and oropharynx. Int J Oral Maxillofac Surg 32:492–497 39. Patel RS, Dirven R, Clark JR et al (2008) The prognostic impact of extent of bone invasion and extent of bone resection in oral carcinoma. Laryngoscope 118:780–785 40. Swearingen AG, McGraw JP, Palumbo VD (1966) Roentgenographic pathologic correlation of carcinoma of the gingival involving the mandible. Am J Roentogenol 96:15–18 41. Wong RJ, Keel SB, Glynn RJ et al (2000) Histological pattern of mandibular invasion by oral squamous cell carcinoma. Laryngoscope 110:65–72 42. Nomura T, Shibahara T, Cui NH et al (2005) Patterns of mandibular invasion by gingival squamous cell carcinoma. J Oral Maxillofac Surg 63:1489–1493 43. Tei K, Totsuka Y, Iizuka T et al (2004) Marginal resection for carcinoma of the mandibular alveolus and gingiva where radiologically detected bone defects do not extend beyond the mandibular canal. J Oral Maxillofac Surg 62:834–839 44. Werning JW, Byers RM, Novas MA et al (2001) Preoperative assessment for and outcomes of mandibular conservation surgery. Head Neck 23:1024–1030 45. Robbins KT, Clayman G, Levine PA et al (2002) Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg 128:751–758 46. Sheahan P, O’Keane C, Sheahan JN et al (2003) Predictors of survival in early oral cancer. Otolaryngol Head Neck Surg 129:571–576 47. Veness MJ, Morgan GJ, Sathiyaseelan Y et al (2005) Anterior tongue cancer and the incidence of cervical lymph node metastases with increasing tumour thickness: should elective treatment to the neck be standard practice in all patients? ANZ J Surg 75:101–105 48. Mark Taylor S, Drover C, Maceachern R et al (2010) Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer? Oral Oncol 46:38–41 49. Kurokawa H, Yamashita Y, Takeda S et al (2002) Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck 24:731–736 50. Sparano A, Weinstein G, Chalian A et al (2004) Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 131:472–476
429 51. Lim SC, Zhang S, Ishii G et al (2004) Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 10:166–172 52. Chien CY, Su CY, Hwang CF et al (2006) High expressions of CD105 and VEGF in early oral cancer predict potential cervical metastasis. J Surg Oncol 94:413–417 53. Capote A, Escorial V, Mun˜oz-Guerra MF et al (2007) Elective neck dissection in early-stage oral squamous cell carcinoma. Does it influence recurrence and survival ? Head Neck 29:3–11 54. Dias FL, Kligerman J, Matos de Sa´ G et al (2001) Elective neck dissection versus observation in stage I squamous cell carcinomas of the tongue and floor of the mouth. Otolaryngol Head Neck Surg 125:23–29 55. Keski-Santti H, Atula T, To¨rnwall J et al (2006) Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 42:96–101 56. Asakage T, Kishimoto S, Saikawa M et al (2005) The standardization of neck dissection for tongue carcinoma. Jpn Head Neck Cancer 31:536–540 57. Weiss M, Harrison LB, Isaacs RS (1994) Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg 120:699–702 58. Majoufre C, Faucher A, Laroche C et al (1999) Supraomohyoid neck dissection in cancer of the oral cavity. Am J Surg 178:73–77 59. Yu S, Li J, Zhang W et al (2006) Efficacy of supraomohyoid neck dissection in patients with oral squamous cell carcinoma and negative neck. Am J Surg 191:94–99 60. Byers RM, Weber RS, Andrews T et al (1997) Frequency and therapeutic implications of ‘‘skip metastases’’ in the neck from squamous carcinoma of the oral tongue. Head Neck 19:14–19 61. Dias FL, Lima RA, Kligerman J et al (2006) Relevance of skip metastases for squamous cell carcinoma of the oral tongue and the floor of the mouth. Otolaryngol Head Neck Surg 134:460–465 62. Ferlito A, Silver CE, Rinaldo A (2009) Elective management of the neck in oral cavity squamous carcinoma: current concepts supported by prospective studies. Br J Oral Maxillofac Surg 47:5–9 63. Terada A, Hasegawa Y, Yatabe Y et al (2011) Follow-up after intraoperative sentinel node biopsy of N0 neck oral cancer patients. Eur Arch Otorhinolaryngol 268:429–435 64. Melkane AE, Mamelle G, Wycisk G et al (2012) Sentinel node biopsy in early oral squamous cell carcinomas: a 10-year experience. Laryngoscope 122:1782–1788 65. Broglie MA, Haerle SK, Huber GF et al (2013) Occult metastases detected by sentinel node biopsy in patients with early oral and oropharyngeal squamous cell carcinomas: impact on survival. Head Neck 35:660–666 66. O’Brien CJ, Urist MM, Maddox WA (1987) Modified radical neck dissection. Terminology, technique, and indications. Am J Surg 153:310–316 67. Kowalski LP, Bagietto R, Lara JR et al (2000) Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 22:207–214 68. Shingaki S, Nomura T, Takada M et al (1999) The impact of extranodal spread of lymph node metastases in patients with oral cancer. Int J Oral Maxillofac Surg 28:279–284 69. Cooper JS, Pajak TF, Forastiere AA et al (2004) Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937–1944 70. Bernier J, Domenge C, Ozsahin M et al (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945–1952 71. Ozeki S, Tashiro H, Okamoto M et al (1985) Metastasis to the lingual lymph node in carcinoma of the tongue. J Maxillofac Surg 13:277–281
123
430 72. Ando M, Asai M, Asakage T et al (2009) Metastatic neck diseases beyond the limits of a neck dissection: attention to the ‘para-hyoid’ area in T1/2 oral tongue cancer. Jpn J Clin Oncol 39:231–236 73. Tseng JR, Ho TY, Lin CY et al (2013) Clinical outcomes of patients with oral cavity squamous cell carcinoma and retropharyngeal lymph node metastasis identified by FDG PET/CT. PLoS One 8(11):e79766 74. Gross ND, Ellingson TW, Wax MK et al (2004) Impact of retropharyngeal lymph node metastasis in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130:169–173 75. Umeda M, Shigeta T, Takahashi H et al (2009) Metastasis to the lateral retropharyngeal lymph node from squamous cell carcinoma of the oral cavity: report of three cases. Int J Oral Maxillofac Surg 38:1004–1008 76. Hasegawa Y, Matsuura H (1994) Retropharyngeal node dissection in cancer of the oropharynx and hypopharynx. Head Neck 16:173–180 77. Omura K, Shimada F, Takemiya S (1985) Dissection of parapharyngeal space in head and neck cancer. Auris Nasus Larynx 12(Suppl 2):S56–S60 78. Huang J, Barbera L, Brouwers M et al (2003) Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 21:555–563
123
Int J Clin Oncol (2014) 19:423–430 79. Robbins KT, Kumar P, Regine WF et al (1997) Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Phys 38:263–271 80. Furusaka T, Asakawa T, Tanaka A et al (2012) Efficacy of multidrug superselective intra-arterial chemotherapy (docetaxel, cisplatin, and 5-fluorouracil) using the Seldinger technique for tongue cancer. Acta Otolaryngol 132:1108–1114 81. Tohnai I, Fuwa N, Hayashi Y et al (1998) New superselective intra-arterial infusion via superficial temporal artery for cancer of the tongue and tumour tissue platinum concentration after carboplatin (CBDCA) infusion. Oral Oncol 34:387–390 82. Mitsudo K, Shigetomi T, Fujimoto Y et al (2011) Organ preservation with daily concurrent chemoradiotherapy using superselective intra-arterial infusion via a superficial temporal artery for T3 and T4 head and neck cancer. Int J Radiat Oncol Biol Phys 79:1428–1435 83. Chen IH, Chang JT, Liao CT et al (2003) Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis. Br J Cancer 89:681–686 84. Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578
REVIEW ARTICLE
Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma Ken Omura
Received: 14 March 2014 / Published online: 1 April 2014 Ó Japan Society of Clinical Oncology 2014
Abstract The primary treatment modality of oral cancer is generally determined according to the stage of the disease, with surgical treatment remaining the mainstay of multimodal treatment. When selecting the treatment, many factors are taken into consideration, and the treatment should be tailored individually to the patient’s needs and consider the quality of life as well as the survival of the patient. Early-stage disease is primarily managed with surgery or brachytherapy without functional morbidity, whereas for advanced-stage disease multidisciplinary treatment is recommended, not only for enhanced survival but also for improved quality of life. After resection of large primary tumors, reconstructive surgery is required. Free tissue transfer currently represents one of the most popular and reliable techniques for oral reconstruction. For cN0 neck, elective neck dissection is recommended when the risk of occult metastases is [20 %, when the neck is entered either for resection of the primary tumor or for reconstruction, or when the patient is unlikely to return for a close follow-up. Sentinel node biopsy is performed investigationally. Modified radical neck dissection is the gold standard for cN? neck. For patients with multiple node metastases or extracapsular spread, postoperative radiotherapy or chemoradiotherapy is recommended, with the lymph nodes situated outside the confines of the radical neck dissection, such as the lingual and retropharyngeal nodes, receiving considerable attention. Targeted therapy for oral cancer is still a relatively new concept, and more
K. Omura (&) Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan e-mail: [email protected]
studies are needed to confirm the clinical effectiveness of these drugs. Keywords Multidisciplinary treatment Postoperative chemoradiotherapy Quality of life
Introduction The oral cavity is the uppermost part of the aerodigestive tract. The oral cavity begins at the lips, and ends at the anterior surface of the faucial arch. It is lined by squamous cell epithelium with interspersed minor salivary glands. The oral cavity can be subdivided into 5 sites: the tongue, floor of the mouth, maxillary/mandibular gingiva, buccal mucosa (including the retromolar trigone), and hard palate. Oral cancer is the sixth most common cancer worldwide, accounting for approximately 4 % of all cancer cases. The incidence and mortality from the disease vary geographically. In Japan, 7,000 new cases are diagnosed each year, and it accounts for 1 % of all cancers. According to data from the Japanese oral cancer registry, the tongue is the most commonly affected site, followed by the gingiva, buccal mucosa, and floor of the mouth, whereas lip cancer accounts for only 1 % of all oral cancers. Histologically, more than 90 % of the tumors are squamous cell carcinoma (SCC), followed by adenoid cystic carcinoma and mucoepidermoid carcinoma [1]. The primary treatment modality of oral cancer is determined according to the stage of the disease, and surgical treatment remains the mainstay of multimodal treatment. Therefore, accurate staging based on the findings of the physical examination and imaging studies is required. Recent advances in modern technology have provided various imaging modalities, such as computed tomography
123
424
(CT), magnetic resonance imaging (MRI), ultrasonography, and positron emission tomography (PET)-CT. Of these, CT and MRI are primarily recommended to assess the locoregional disease. Moreover, at staging of the disease, endoscopic examination of the upper digestive tract is also recommended, as 7 % of oral cancer patients reportedly have a concomitant second primary lesion in this area [2, 3]. The most important functions of the oral cavity are mastication, deglutition, maintenance of oral competency, and articulation of speech. Therefore, when choosing the treatment modality, many factors must be taken into consideration and the treatment should be tailored individually to each patient’s needs in order to ensure good quality of life as well as favorable survival. In this review, the surgical management of oral SCC is discussed for each of the 5 sites.
Surgical management of primary tumors The ultimate aim of surgical resection is adequate clearance of tumor tissue. Inadequate clearance of tumor cells results in increased risks of local and regional recurrences, and decreased long-term survival rates [4]. However, in oral SCC, increasing the resection margins may result in increased esthetic and functional morbidities. In oral cancer surgery, three-dimensional 1-cm resection margins are considered acceptable [5–7], and in primary tumor resection, vital staining with iodine solution is recommended as an adjunct, in order to detect and delineate the dysplastic epithelium accompanying the cancerous lesion [8–10]. After resection of the primary tumor, reconstructive surgery is usually required to restore oral function and cosmetic appearance. The most appropriate reconstruction method is determined by many factors, including the characteristics of the primary site and defects, the general medical condition and social history of the patient, the prognosis, and the skills of the surgeon. The methods of reconstruction usually follow a ‘‘reconstructive ladder,’’ beginning from a skin graft to a microvascular free flap. Free tissue transfers currently represent one of the most popular and reliable techniques for oral reconstruction. There are various free flap options available; however, there is currently no single flap that can resolve the entire spectrum of oral defects [11, 12].
Tongue The tongue is the most commonly affected site of oral tumors, accounting for 60 % of all oral cancers [1]. Within this site, the majority of tumors occur on the lateral borders and ventral surface.
123
Int J Clin Oncol (2014) 19:423–430
Small tumors (stage T1 and early-T2 tumors: tumors \3 cm in diameter) can be managed by partial glossectomy if the resection does not substantially involve the floor of the mouth. Partial glossectomy may be performed in a horizontal spindle fashion, resulting in the defect becoming primarily closed, with a functionally excellent and normal-shaped tongue. Large tumors may require hemiglossectomy or subtotal or total glossectomy. Hemiglossectomy defects can be reconstructed with a radial forearm free flap, with acceptable speech and swallowing functions [13], whereas subtotal or total glossectomy defects may need to be convexly reconstructed with an anterolateral thigh or rectus abdominis free flap. Convex reconstruction of large glossectomy defects may be essential for acceptable postoperative functions [14–16]. When the resection extends to the tongue base and/or lateral pharyngeal wall, a mandibular swing or visor flap with the mandibular lingual releasing approach may be required to gain access to these regions. Reconstruction of large glossectomy defects usually needs to be accompanied by procedures aimed at preventing postoperative aspiration, such as laryngeal suspension, laryngoplasty, and cricopharyngeal myotomy [17, 18].
Floor of the mouth The floor of the mouth is a relatively common site for oral cancer, with approximately 10 % of all oral cancers developing at this site. Within the site, the majority of tumors arise in the anterior portion [1]. Small tumors arising at the anterior floor of the mouth are commonly excised in conjunction with the ventral surface of the tongue [19], and the submandibular ducts may be included in the surgical specimen for fear of possible tumor extension along the duct. The stump of the duct needs to be repositioned at the margin of resection, and any surgical defects can generally be reconstructed with a split thickness skin graft (STSG). The tumor may deeply invade the floor of the mouth and abut to the mandible [20]. In such situations, wide local excision of the tumor in conjunction with rim resection of the mandible may need to be carried out. In general, any defects can be satisfactorily reconstructed with a radial forearm free flap. When the mandible is resected segmentally, the reconstruction can be achieved with a free compound flap, such as fibula osteocutaneous and scapula osteocutaneous flaps. In some cases of advanced-stage disease, considering the patient’s age and poor prognosis, the mandibular defects may be reconstructed with a titanium mandibular reconstruction plate and the soft tissue defects may be restored with a free rectus abdominis flap wrapping around the plate to avoid extrusion of the plate [21–23].
Int J Clin Oncol (2014) 19:423–430
Buccal mucosa The buccal mucosa is the most common site for oral cancer in South-east Asia, accounting for up to 40 % of oral cancers there. However, in Japan, as well as in North America and Western Europe, it accounts for only approximately 10 % [1]. T1 and T2 tumors can be excised perorally, with the buccinator muscle usually being included at the deep margin [24]. When the parotid duct is included in the surgical specimen, the stump is repositioned if possible. Surgical defects can be primarily closed in some selected patients; however, STSG or a mucosal graft is usually required to secure postoperative mouth opening. Large buccal tumors require a lower cheek flap approach, and are excised together with the buccal fat pad and maxilla and/or mandible. Microvascular free flap reconstruction with a radial forearm or anterolateral thigh flap is used to restore the thickness of the cheek [25]. Large tumors often require a through-and-through resection of the cheek. In such cases, the defects can be reconstructed with a bi-paddled and folded flap, resurfacing the skin and mucosal defects [26].
Retromolar trigone The retromolar trigone is a relatively unusual site for carcinomas of the oral cavity, accounting for only 3 % of all oral cancers. Small tumors of the retromolar trigone may be resected perorally. However, a lower cheek flap approach or mandibular swing approach is often required, because of its posterior location and the frequent extension of the tumor into adjacent sites [27, 28]. Even if the mandible shows no radiological signs of involvement, a posterior marginal resection of the mandible may be performed to achieve clear margins. These tumors may require extended surgery, including of the mandible, maxilla, soft palate, tongue base, and buccal mucosa. Moreover, these tumors may require careful considerations on reconstruction, as the defects may be both extensive and highly complex, and may occasionally cause trismus. In such situations, dual free flaps may provide ideal soft tissue and bony reconstruction. However, these are associated with an increased risk of complications.
Maxillary gingiva and hard palate Maxillary gingival carcinoma accounts for 6 % of all oral cancers, making it approximately half as common as mandibular gingival cancer. Carcinomas of the hard palate
425
are relatively rare, accounting for only 3 % of all oral cancers [1]. Small tumors arising in the maxillary gingiva may be amenable to transoral wide excision with resection of the involved mucoperiosteum and the underlying bone. Surgical defects are usually restored with a maxillary prosthesis. In some cases, surgical closure of defects may be achieved with a local flap, such as a palatal flap and buccal fat pad. However, large tumors may require partial or subtotal maxillectomy using an upper cheek flap approach. These maxillary tumors often extend posteriorly to the pterygoid region. In such cases, a pterygoid dissection may be required in conjunction with the maxillectomy. On the other hand, soft tissue defects require lining with an STSG for good restoration with a maxillary prosthesis. For more posteriorly and/or superiorly extending tumors, a subciliary incision may be combined with Ferguson’s incision to access the infratemporal fossa. In such cases, the extended surgical defects can be reconstructed with a free rectus abdominis flap.
Mandibular gingiva Mandibular gingival carcinoma represents 12 % of all oral cancers [1]. Mandibular gingival tumors may easily enter into the mandibular bone, mainly through the periodontal space and cortical deficiencies in dentate non-irradiated and edentulous mandibles, respectively. Moreover, the tumors occasionally spread along the periosteum [29–31]. There is some controversy regarding the T4 criteria of mandibular gingival cancer. The TNM classification of the UICC defines T4 tumors as tumors invading through the cortical bone, whereas, according to the level of mandibular canal criteria, which are widely accepted in Japan, T4 tumors are defined as tumors involving the level of the mandibular canal [32]. In surgery for lower gingival cancer, one of the most critical issues is whether marginal resection is adequate or not [33–39]. The type of mandibulectomy is decided clinically, and is based on the T-stage and radiological pattern of bone resorption. Radiologically, mandibular bone resorption is divided into two types: erosive and invasive [40]. The erosive type is defined as a defect showing sharply outlined U-shaped excavation. Histologically, tumors of this type usually show an expansive pattern of bone involvement, and the margins of the destroyed mandible are well defined and smooth. A small amount of connective tissue can generally be seen between the tumor and bone. The invasive type is defined as defects showing irregular and ill-defined bone margins. This type of tumor is often accompanied by widening of the mandibular canal. Histologically, the majority of tumors of this type show an infiltrative pattern
123
426
Int J Clin Oncol (2014) 19:423–430
Neck node management It is well known that the cervical lymph node status is one of the most important prognostic factors for oral SCCs. Currently, neck dissection is the only accepted standard treatment for cervical node metastases. For the past several decades, surgical treatment of cervical node metastases has consisted of radical neck dissection (RND). Since then, RND has been modified in various ways to reduce postoperative morbidity, and has given rise to several different types of neck dissections [45]. Moreover, while recent advances in technology have provided various diagnostic imaging modalities, none of these can accurately detect cervical lymph node metastases. cN0 neck
Fig. 1 a A 52-year-old male patient diagnosed with cT4aN2c mandibular gingival carcinoma. b The patient underwent segmental resection of the anterior part of the mandible in conjunction with bilateral neck dissection. c Segmental defect of the mandible was reconstructed with a scapular osteocutaneous free flap. The scapular bone was osteotomized at 2 sites to restore mandibular contour. Two years after reconstruction, after thinning of the scapular flap, 4 osseointegrated implants were installed (panoramic X-ray). d, e The implant-supported prosthesis provides a functional restoration and support of the lower lip
of involvement, irregular margins of the destroyed bone, and involvement of the mandibular canal through the marrow space [41, 42]. On the basis of these clinicopathological findings, marginal resection can be applied for T1 tumors and for T2/3 tumors with no or erosive bone resorption [43, 44], whereas segmental resection is recommended for T2/3 tumors with invasive resorption and for T4 tumors [33, 34]. When the depth of the mandible after marginal resection is \10 mm, the mandible may be reinforced with a titanium plate. Segmental defects of the mandible require reconstruction of mandibular continuity, especially by the use of a free vascularized bone flap. The donor site is selected on the basis of the bony defect along with the accompanying soft tissue defects. Free vascularized bone flaps clearly provide significant advantages for mandibular reconstruction; however, combined use of reconstruction plates and soft-tissue flaps remains a reconstructive option in some selected patients who have poor medical conditions or prognoses [21–23]. Dental rehabilitation using a prosthesis or osseointegrated dental implants is an important part of the reconstruction to restore the esthetics and functions (Fig. 1).
123
Approximately 20–30 % of clinical N0 necks have occult node metastasis, and thus cervical lymph node status is predicted by clinical and pathological evaluation of the primary tumor [46–52]. Management of clinical N0 neck is controversial, with some clinicians advocating the ‘‘wait and see’’ approach, whereas others favor elective neck dissection [53–55]. However, patients with delayed neck node metastases generally have a poor prognosis. For this reason, elective neck dissection is often considered for late-T2 and T3 cases in Japan [56]. That said, there are currently no definite surgical guidelines for treatment of clinical N0 neck, although, in general, elective neck dissection is considered warranted when the risk of occult metastases is [20 % [57]. Other indications for elective neck dissection include the need to enter the neck, either for resection of the primary tumor or for reconstruction. It may also be indicated when the patient is unlikely to return for a close follow-up. When the neck is treated electively, supraomohyoid neck dissection is generally performed [58, 59]. However, there is some reported evidence that level IV nodes are also at risk [60, 61], and, accordingly, these have to be included in the procedure in a subset of patients. Recent prospective multiinstitutional studies have demonstrated that sublevel IIB lymph nodes rarely involve isolated metastases from oral cancers, except from some tongue cancers. Thus, it is justifiable to omit dissection of sublevel IIB nodes in elective treatment of most cases of oral cancer [62]. Recently, sentinel node biopsy has received considerable attention as a means of avoiding unnecessary lymph node dissection. In the past, it has been mainly applied to cases of malignant melanoma and breast cancer, but has recently gained much attention as an investigational tool for head and neck cancer as well [63–65].
Int J Clin Oncol (2014) 19:423–430
427
Fig. 2 a A 76-year-old male patient was diagnosed with cT4aN2b retromolar trigone carcinoma. b MRI showed retropharyngeal node metastasis. c The patient underwent parapharyngeal dissection in conjunction with maxillo-mandibular resection and neck dissection
cN1–3 neck
Adjuvant therapy
For clinical N1–3 neck, it is generally recommended to perform a standard or modified RND (MRND) [66]. MRND, especially that sparing the spinal accessory nerve, has become the gold standard for neck disease. In addition, supraomohyoid neck dissection can be chosen for clinical N1 neck with level IB metastasis [57]. Because patients with multiple node metastases or extracapsular spread of tumors often present with neck failure and/or distant metastasis after neck dissection, postoperative radiotherapy or concurrent chemoradiotherapy is recommended [67–70]. Oral cancer may metastasize to the nodes situated outside the confines of the RND, such as the lingual and retropharyngeal nodes. The lingual nodes are small, inconstant, interrupting nodes that are divided into lateral and median lingual nodes. Lateral nodes are present in 30 % of all individuals, and are located on the external aspect of the genioglossus muscle or on the hyoglossus muscle, along the lingual artery and vein. Conversely, the median nodes are present in approximately 15 % of all individuals, and are found in the median plane of the tongue between the genioglossus muscles. It is recommended that theses nodes be removed by a pull-through operation [71, 72]. The retropharyngeal nodes are located at the base of the skull, close to the internal carotid artery. They receive lymph flow from the nasopharynx, maxilla, and posterior part of the oral cavity, and drain into the upper jugular nodes [73–75]. These nodes can be eradicated by retropharyngeal node or parapharyngeal dissections, which are systematic approaches for en bloc resection of the retro- and parapharyngeal spaces, respectively [76, 77] (Fig. 2).
Radiotherapy is typically applied postoperatively owing to the difficulty of surgically removing irradiated tissue, because tissues become fibrosed and thus tend to heal slower. Factors such as large primary tumors, positive or close surgical margins, and signs of perineural, lymph, and/ or vascular invasion generally dictate the use of radiotherapy at the primary site; however, the neck is also commonly treated, especially if there are positive nodes with or without extracapsular spread, in order to prevent potential metastasis and recurrence. Radiotherapy is recommended to begin within 6 weeks after surgery [78], and, while the radiation doses vary, a total dose of approximately 60 Gy is typical. In recent years, chemotherapy has emerged as a prominent adjunct modality for locoregionally advanced oral SCC. Although it is generally not considered a curative modality for oral cancers alone, it can be utilized before surgery (as induction therapy) or concurrently with irradiation (chemoradiotherapy) before or after surgery. Adjuvant chemoradiotherapy has almost become a standard treatment for advanced oral cancers. Currently, the most common regimen consists of CDDP 80–100 mg/m2 on days 1, 22, and 43, although other variations such as daily low-dose and weekly intermediate-dose CDDP have also shown survival benefits. In 1997, Robbins et al. [79] first reported marked results with RADPLAT, a superselective intra-arterial infusion of high-dose CDDP in combination with radiotherapy, for advanced head and neck cancer. Since then, the standard treatment in Japan for advanced head and neck cancer has been shifting from radical surgery to various organ preservation therapies, such as
123
428
Int J Clin Oncol (2014) 19:423–430
radiation therapy with concurrent superselective intraarterial chemotherapy. For oral lesions, superselective catheterization can be performed through the femoral artery or the superficial temporal artery and/or occipital artery [80, 81]. The local control rate of oral cancer treated by superselective intra-arterial chemoradiation is high, and it is thus recommended for T4 and unresectable tumors [82]. Lastly, overexpression of epidermal growth factor receptor (EGFR) has been confirmed in oral SCC, and has been reported to be associated with a poor prognosis [83]. The addition of a targeted agent, such as a monoclonal antibody EGFR inhibitor, has been reported to improve survival outcomes as compared with primary radiotherapy alone in head and neck SCCs [84]. Recently, the RTOG 0920 trial was launched in order to evaluate whether the addition of cetuximab, an EGFR inhibitor, to postoperative radiotherapy will improve overall survival in postoperative intermediate-risk oral cancer patients. Targeted therapies such as cetuximab are still a relatively new concept in head and neck cancer, and further studies are hence needed to confirm its clinical effectiveness. Conflict of interest
There are no conflicts of interest to declare.
References 1. Ariyoshi Y, Shimahara M, Omura K et al (2008) Epidemiological study of malignant tumors in the oral and maxillofacial region: survey of member institutions of the Japanese Society of Oral and Maxillofacial Surgeons, 2002. Int J Clin Oncol 13:220–228 2. McGuirt WF (1982) Panendoscopy as a screening examination for simultaneous primary tumors in head and neck cancer: a prospective sequential study and review of the literature. Laryngoscope 92:569–576 3. Saikawa M, Ebihara S, Yoshizumi T et al (1991) Multiple primary cancers in patients with squamous cell carcinoma of the oral cavity. Jpn J Cancer Res 82:40–45 4. Sutton DN, Brown JS, Rogers SN et al (2003) The prognostic implications of the surgical margin in the oral squamous cell carcinoma. Int J Oral Maxillofac Surg 32:30–34 5. McMahon J, O’Brien CJ, Pathak I et al (2003) Influence of condition of surgical margins on local recurrence and diseasespecific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg 41:224–231 6. Mistry RC, Qureshi SS, Kumaran C (2005) Post-resection mucosal margin shrinkage in oral cancer: quantification and significance. J Surg Oncol 91:131–133 7. Meier JD, Oliver DA, Varvares MA (2005) Surgical margin determination in head and neck oncology: current clinical practice. The results of an International American Head and Neck Society Member Survey. Head Neck 27:952–958 8. Kurita H, Kurashina K (1996) Vital staining with iodine solution in delineating the border of oral dysplastic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:275–280 9. Xiao T, Kurita H, Shimane T et al (2013) Vital staining with iodine solution in oral cancer: iodine infiltration, cell proliferation, and glucose transporter 1. Int J Clin Oncol 18:792–800
123
10. Petruzzi M, Lucchese A, Baldoni E et al (2010) Use of Lugol’s iodine in oral cancer diagnosis: an overview. Oral Oncol 46:811–813 11. Hidalgo DA, Disa JD, Cordeiro PG et al (1998) A review of 716 consecutive free flaps for oncologic surgical defects: refinements in donor site selection and technique. Plast Reconstr Surg 102:722–732 12. Sakuraba M, Miyamoto S, Kimata Y et al (2013) Recent advances in reconstructive surgery: head and neck reconstruction. Int J Clin Oncol 18:561–565 13. Kudoh M (2010) Longitudinal assessment of articulatory and masticatory functions following glossectomy for tongue carcinoma. Kokubyo Gakkai Zasshi 77:27–34 14. Lam L, Samman N (2013) Speech and swallowing following tongue cancer surgery and free flap reconstruction—a systematic review. Oral Oncol 49:507–524 15. Kimata Y, Sakuraba M, Hishinuma S et al (2003) Analysis of the relations between the shape of the reconstructed tongue and postoperative functions after subtotal or total glossectomy. Laryngoscope 113:905–909 16. Yanai C, Kikutani T, Adachi M et al (2008) Functional outcome after total and subtotal glossectomy with free flap reconstruction. Head Neck 30:909–918 17. Biller HF, Lawson W, Baek SM (1983) Total glossectomy. A technique of reconstruction eliminating laryngectomy. Arch Otolaryngol 109:69–73 18. Fujimoto Y, Hasegawa Y, Yamada H et al (2007) Swallowing function following extensive resection of oral or oropharyngeal cancer with laryngeal suspension and cricopharyngeal myotomy. Laryngoscope 117:1343–1348 19. McColl HA Jr, Horwood J (1978) ‘Localized’ carcinoma of the mobile tongue and floor of mouth—a lesion frequently misjudged and undertreated. J Surg Oncol 10:337–345 20. Hicks WL Jr, Lorre TR, Garcia RI et al (1997) Squamous cell carcinoma of the floor of mouth: a 20-year review. Head Neck 19:400–405 21. Boyd JB, Mulholland RS, Davidson J et al (1995) The free flap and plate in oromandibular reconstruction: long-term review and indications. Plast Reconstr Surg 95:1018–1028 22. Head C, Alam D, Sercarz JA et al (2003) Microvascular flap reconstruction of the mandible: a comparison of bone grafts and bridging plates for restoration of mandibular continuity. Otolaryngol Head Neck Surg 129:48–54 23. Takushima A, Harii K, Asato H et al (2001) Mandibular reconstruction using microvascular free flap: a statistical analysis of 178 cases. Plast Reconstr Surg 108:1555–1563 24. Hao SP, Cheng MH (2004) Cancer of the buccal mucosa and retromolar trigone. Oper Tech Otolaryngol 15:239–251 25. Ozkan O, Mardini S, Chen HC et al (2006) Repair of buccal defects with anterolateral thigh flaps. Microsurgery 26:182–189 26. Liu WW, Yang AK, Ou YD (2011) The harvesting and insetting of a chimeric anterolateral thigh flap to reconstruct through and through cheek defects. Int J Oral Maxillofac Surg 40:1421–1423 27. Mendenhall WM, Morris CG, Amdur RJ et al (2005) Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery. Cancer 103:2320–2325 28. Genden FM, Ferito A, Shaha AR et al (2003) Management of cancer of the retromolar trigone. Oral Oncol 39:633–637 29. McGregor AD, MacDonald DG (1988) Routes of entry of squamous cell carcinoma to the mandible. Head Neck 10:294–301 30. Totsuka Y, Usui Y, Tei K et al (1991) Mandibular involvement by squamous cell carcinoma of the lower alveolus. Analysis and comparative study of histologic and radiologic features. Head Neck 13:40–50 31. Virag MM, Bunarevic´ A, Aljinovic´ N (1991) Recurrences of oral cancer due to discontinuous periosteal involvement. Am J Surg 162:388–392
Int J Clin Oncol (2014) 19:423–430 32. Fujibayashi T (2004) Level of mandibular canal (LMC) criteria of lower gingival carcinomas and mode of mandibulectomy according to LMC criteria and bone invasion pattern. J Jpn Soc Oral Tumors 16:35–48 33. Totsuka Y, Usui Y, Tei K et al (1991) Results of surgical treatment for squamous carcinoma of the lower alveolus: segmental vs marginal resection. Head Neck 13:114–120 34. Ord RA, Sarmadi M, Papadimitrou J (1997) A comparison of segmental and marginal bony resection for oral squamous cell carcinoma involving the mandible. J Oral Maxillofac Surg 55:470–477 35. Politi M, Costa F, Robiony M et al (2000) Review of segmental and marginal resection of the mandible in patients with oral cancer. Acta Otolaryngol 120:569–579 36. Wax MK, Bascom DA, Myers LL (2002) Marginal mandibulectomy vs segmental mandibulectomy, indication and controversies. Arch Otolaryngol Head Neck Surg 128:600–603 37. Genden EM, Rinaldo A, Jacobson A et al (2005) Management of mandibular invasion: when is a marginal mandibulectomy appropriate? Oral Oncol 41:776–782 38. O’Brien CJ, Adams JR, McNeil EB et al (2003) Influence of bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and oropharynx. Int J Oral Maxillofac Surg 32:492–497 39. Patel RS, Dirven R, Clark JR et al (2008) The prognostic impact of extent of bone invasion and extent of bone resection in oral carcinoma. Laryngoscope 118:780–785 40. Swearingen AG, McGraw JP, Palumbo VD (1966) Roentgenographic pathologic correlation of carcinoma of the gingival involving the mandible. Am J Roentogenol 96:15–18 41. Wong RJ, Keel SB, Glynn RJ et al (2000) Histological pattern of mandibular invasion by oral squamous cell carcinoma. Laryngoscope 110:65–72 42. Nomura T, Shibahara T, Cui NH et al (2005) Patterns of mandibular invasion by gingival squamous cell carcinoma. J Oral Maxillofac Surg 63:1489–1493 43. Tei K, Totsuka Y, Iizuka T et al (2004) Marginal resection for carcinoma of the mandibular alveolus and gingiva where radiologically detected bone defects do not extend beyond the mandibular canal. J Oral Maxillofac Surg 62:834–839 44. Werning JW, Byers RM, Novas MA et al (2001) Preoperative assessment for and outcomes of mandibular conservation surgery. Head Neck 23:1024–1030 45. Robbins KT, Clayman G, Levine PA et al (2002) Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology–Head and Neck Surgery. Arch Otolaryngol Head Neck Surg 128:751–758 46. Sheahan P, O’Keane C, Sheahan JN et al (2003) Predictors of survival in early oral cancer. Otolaryngol Head Neck Surg 129:571–576 47. Veness MJ, Morgan GJ, Sathiyaseelan Y et al (2005) Anterior tongue cancer and the incidence of cervical lymph node metastases with increasing tumour thickness: should elective treatment to the neck be standard practice in all patients? ANZ J Surg 75:101–105 48. Mark Taylor S, Drover C, Maceachern R et al (2010) Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer? Oral Oncol 46:38–41 49. Kurokawa H, Yamashita Y, Takeda S et al (2002) Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck 24:731–736 50. Sparano A, Weinstein G, Chalian A et al (2004) Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 131:472–476
429 51. Lim SC, Zhang S, Ishii G et al (2004) Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 10:166–172 52. Chien CY, Su CY, Hwang CF et al (2006) High expressions of CD105 and VEGF in early oral cancer predict potential cervical metastasis. J Surg Oncol 94:413–417 53. Capote A, Escorial V, Mun˜oz-Guerra MF et al (2007) Elective neck dissection in early-stage oral squamous cell carcinoma. Does it influence recurrence and survival ? Head Neck 29:3–11 54. Dias FL, Kligerman J, Matos de Sa´ G et al (2001) Elective neck dissection versus observation in stage I squamous cell carcinomas of the tongue and floor of the mouth. Otolaryngol Head Neck Surg 125:23–29 55. Keski-Santti H, Atula T, To¨rnwall J et al (2006) Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 42:96–101 56. Asakage T, Kishimoto S, Saikawa M et al (2005) The standardization of neck dissection for tongue carcinoma. Jpn Head Neck Cancer 31:536–540 57. Weiss M, Harrison LB, Isaacs RS (1994) Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg 120:699–702 58. Majoufre C, Faucher A, Laroche C et al (1999) Supraomohyoid neck dissection in cancer of the oral cavity. Am J Surg 178:73–77 59. Yu S, Li J, Zhang W et al (2006) Efficacy of supraomohyoid neck dissection in patients with oral squamous cell carcinoma and negative neck. Am J Surg 191:94–99 60. Byers RM, Weber RS, Andrews T et al (1997) Frequency and therapeutic implications of ‘‘skip metastases’’ in the neck from squamous carcinoma of the oral tongue. Head Neck 19:14–19 61. Dias FL, Lima RA, Kligerman J et al (2006) Relevance of skip metastases for squamous cell carcinoma of the oral tongue and the floor of the mouth. Otolaryngol Head Neck Surg 134:460–465 62. Ferlito A, Silver CE, Rinaldo A (2009) Elective management of the neck in oral cavity squamous carcinoma: current concepts supported by prospective studies. Br J Oral Maxillofac Surg 47:5–9 63. Terada A, Hasegawa Y, Yatabe Y et al (2011) Follow-up after intraoperative sentinel node biopsy of N0 neck oral cancer patients. Eur Arch Otorhinolaryngol 268:429–435 64. Melkane AE, Mamelle G, Wycisk G et al (2012) Sentinel node biopsy in early oral squamous cell carcinomas: a 10-year experience. Laryngoscope 122:1782–1788 65. Broglie MA, Haerle SK, Huber GF et al (2013) Occult metastases detected by sentinel node biopsy in patients with early oral and oropharyngeal squamous cell carcinomas: impact on survival. Head Neck 35:660–666 66. O’Brien CJ, Urist MM, Maddox WA (1987) Modified radical neck dissection. Terminology, technique, and indications. Am J Surg 153:310–316 67. Kowalski LP, Bagietto R, Lara JR et al (2000) Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 22:207–214 68. Shingaki S, Nomura T, Takada M et al (1999) The impact of extranodal spread of lymph node metastases in patients with oral cancer. Int J Oral Maxillofac Surg 28:279–284 69. Cooper JS, Pajak TF, Forastiere AA et al (2004) Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937–1944 70. Bernier J, Domenge C, Ozsahin M et al (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945–1952 71. Ozeki S, Tashiro H, Okamoto M et al (1985) Metastasis to the lingual lymph node in carcinoma of the tongue. J Maxillofac Surg 13:277–281
123
430 72. Ando M, Asai M, Asakage T et al (2009) Metastatic neck diseases beyond the limits of a neck dissection: attention to the ‘para-hyoid’ area in T1/2 oral tongue cancer. Jpn J Clin Oncol 39:231–236 73. Tseng JR, Ho TY, Lin CY et al (2013) Clinical outcomes of patients with oral cavity squamous cell carcinoma and retropharyngeal lymph node metastasis identified by FDG PET/CT. PLoS One 8(11):e79766 74. Gross ND, Ellingson TW, Wax MK et al (2004) Impact of retropharyngeal lymph node metastasis in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130:169–173 75. Umeda M, Shigeta T, Takahashi H et al (2009) Metastasis to the lateral retropharyngeal lymph node from squamous cell carcinoma of the oral cavity: report of three cases. Int J Oral Maxillofac Surg 38:1004–1008 76. Hasegawa Y, Matsuura H (1994) Retropharyngeal node dissection in cancer of the oropharynx and hypopharynx. Head Neck 16:173–180 77. Omura K, Shimada F, Takemiya S (1985) Dissection of parapharyngeal space in head and neck cancer. Auris Nasus Larynx 12(Suppl 2):S56–S60 78. Huang J, Barbera L, Brouwers M et al (2003) Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 21:555–563
123
Int J Clin Oncol (2014) 19:423–430 79. Robbins KT, Kumar P, Regine WF et al (1997) Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Phys 38:263–271 80. Furusaka T, Asakawa T, Tanaka A et al (2012) Efficacy of multidrug superselective intra-arterial chemotherapy (docetaxel, cisplatin, and 5-fluorouracil) using the Seldinger technique for tongue cancer. Acta Otolaryngol 132:1108–1114 81. Tohnai I, Fuwa N, Hayashi Y et al (1998) New superselective intra-arterial infusion via superficial temporal artery for cancer of the tongue and tumour tissue platinum concentration after carboplatin (CBDCA) infusion. Oral Oncol 34:387–390 82. Mitsudo K, Shigetomi T, Fujimoto Y et al (2011) Organ preservation with daily concurrent chemoradiotherapy using superselective intra-arterial infusion via a superficial temporal artery for T3 and T4 head and neck cancer. Int J Radiat Oncol Biol Phys 79:1428–1435 83. Chen IH, Chang JT, Liao CT et al (2003) Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis. Br J Cancer 89:681–686 84. Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578
