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Combined and sequential treatment of oral and maxillofacial malignancies: an evolving concept and clinical protocol

ZHENG, Jia-wei; QIU, Wei-liu; ZHANG, Zhi-yuan

Section Editor(s): LIU, Dong-yun

Review article
Free
SDC

Objective To introduce the concept and rational regimens and present the latest development of combined treatment of oral and maxillofacial malignancies.

Data sources The related published literature was searched through the CNKI database and MEDLINE using the terms of oral cancer, oral and maxillofacial malignancies, combined and sequential therapy, multidisciplinary approach.

Study selection The available related literature was read and evaluated. Studies that met the inclusion criteria were selected.

Results The results show that oral and maxillofacial malignancies diagnosed at an early stages (stages I and II) can be well treated with surgery alone and/or radiotherapy with optimal outcome, but advanced or recurrent diseases should be treated with rational combined and sequential treatment modalities. The use of concomitant chemoradiotherapy, taxane-containing, three-drug induction regimens and Cetuximab in combination with chemotherapy or radiotherapy demonstrated favorable results in previously untreated patients with head and neck squamous cell carcinoma.

Conclusions The concept of combined and sequential treatment of advanced oral and maxillofacial malignancies should be widely accepted, and the rational regimen for individual and each type of entity should be determined based on the anatomical site and the patient's performance status.

Edited by

Department of Oral and Maxillofacial Surgery, College of Stomatology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China (Zheng JW, Qiu WL and Zhang ZY)

Correspondence to: Prof. ZHANG Zhi-yuan, Department of Oral and Maxillofacial Surgery, College of Stomatology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China (Tel: 86–21–63138341 ext 5385. Fax: 86–21–63136856. Email: zhzhy@omschina.org.cn) This study was supported by a grant from the National Science and Technology Supporting Project (No. 2007BAI18B03).

(Received April 9, 2008)

Oral and maxillofacial malignancies are among the scope of head and neck cancers and still remain a significant cause of morbidity worldwide, with approximately 34 360 new cases of oral cancer diagnosed each year, an estimated 7550 people (5180 men and 2370 women) died of these cancers in 2007.1 Early diseases (stages I and II) can be well treated with surgery alone and/or radiation therapy with optimal outcome. Most patients, however, are in an advanced stage of disease (stages III and IV) at their first visit. For these patients, due to the anatomical restrictions and functional considerations, extended surgical resection is sometimes impossible and even with refined surgical skills there is a limited value for surgery to improve the survival rate of these patients. Therefore, patients at an advanced stage of disease, those presenting with spread to regional cervical lymph nodes or with T3 and T4 primary tumors, should be treated with combined modality treatment. Currently, surgical resection followed by postoperative radiation therapy is considered the gold standard for patients with stage III and stage IV squamous cell carcinomas of the oral and maxillofacial regions.

The ultimate goal of treating oral and maxillofacial malignancies are to cure the cancer, preserve or restore facial contour and function, minimize the sequelae of treatment and prevent multiple primary tumors. The currently available therapeutic modalities to achieve these goals include surgery, radiotherapy, chemotherapy, combined treatment modality and primary and secondary prevention strategies that include lifestyle changes and chemoprevention. With given advantages and disadvantages, surgery, radiation therapy and chemotherapy can compensate each other. Surgery is the major treatment for most solid tumors. However, for some solid tumors, especially those involving special anatomical location such as nasopharyngeal carcinoma (NPC) and undifferentiated or low-differentiated carcinomas, radiation therapy is more sensitive and preferable. On the other hand, radiation therapy and chemotherapy play a more important role in the treatment of non-solid tumors such as lymphoma and myeloma. Recent basic science discoveries have contributed to our understanding of the etiology of oral cancer and allowed us to consider innovative approaches to therapy, especially to coordinate surgery with radiation therapy and chemotherapy in order to reduce complications and improve the final treatment outcome.2

With respect to the treatment results, both surgery and radiation therapy are local therapy which focus on the loco-regional lesions. Malignant tumors in the early stages are restricted within certain regions, but usually invade surrounding tissues and spread distally in the later stages through lymphatic channels and/or blood vessels. Therefore, early treatment should focus on the regional lesions to prevent and control the growth and metastasis, especially cervical lymph node metastasis, of the regional lesions.

Chemotherapy is a systemic therapy deemed to destroy cancer cells, to control tumor spread and metastasis. Through the use of multi-courses and adequate dose of anti-cancer drugs, chemotherapy can kill the vast majority of cancer cells. There are over 50 different chemotherapy drugs. Some are given on their own but often several drugs are given together as combination chemotherapy. Chemotherapy may be used alone to treat some types of cancers but, most often, it is used with other types of treatments such as surgery, radiotherapy, biological therapies or a combination of these in the treatment of oral and maxillofacial malignancies. At the present time, the role of chemotherapy in the management of oral cancer still remains investigational.

Biotherapy has emerged as a relatively new addition to the family of cancer treatments in the 1980s with the development of several disciplines such as immunobiology, immuno-oncology and molecular biology. It is the core concept of this treatment that it modifies, either directly or indirectly, the interactions between the host and the tumor with bioactive substances or biological agents, thus changing the biological response of the host to cancer cells to fight malignancies. With the use of immunomodulators, cytokines, adoptive immunotherapy, monoclonal antibodies and active specific immunotherapy, modern biotherapy combines contemporary immuno-oncology and biological engineering, intending to achieve a balance between the host and the cancer to prevent the genesis of new cancer and to kill all the cancer cells. Traditional Chinese medicine, which exerts effect by boosting and regulating the immune system, is also within the scope of biotherapy. It has been proved by both clinical3 and basic scientific studies4 that the Chinese prescription “Shen Yang” can regulate and boost the immune system as a biotherapy to increase the survival time of patients. In a clinical prospective study of 238 patients with oral squamous cell carcinoma, Lin et al3 found that the 3-year, 5-year, 8-year and 10-year survival rate of patients taking “Shen Yang” was improved by 8.46%, 9.26%, 9.04% and 8.57%, respectively, in contrast to those who did not take “Shen Yang”; although the differences between the two groups were not statistically significant (P=0.1936).

According to National Cancer Database (NCDB), the survival rate of patients with oral and maxillofacial malignancies after treatment has remained unchanged during the past decade. The overall 5-year, disease-specific survival is 64.0% for head and neck cancer. Cancer of the lip demonstrated the best survival at 91.1% and cancer of the hypopharynx the worst survival at 31.4%. The overall 5-year, disease-specific survival is 64.7% for carcinomas of the major salivary glands.5 Therefore, there is still a lot to be done to improve the survival rate of these patients while a lot of problems concerning facial reconstruction and functional rehabilitation remain to be solved. Because of the intrinsic flaws in any single treatment, the concepts of multidisciplinary therapy, a team approach, or combined treatment modality have been proposed and widely accepted since the 1990s.

Currently, combined therapy dominated by surgery and radiotherapy is the mainstay in the treatment of advanced oral and maxillofacial malignancies. However, it should be noted that combined therapy is not a simple combination of these therapies but a well planed regime with the goal of enhancing the treatment outcome by achieving a complete resection of the tumor, preserving or restoring function or aesthetics and preventing recurrences or new primary tumors.6 Therefore, a planned and reasonable individualized treatment regime for each specific individual and stage of the malignancy should be formulated, when possible, by the consensus of clinicians specialized in oncology. In addition, combined and sequential therapy is a cooperative or multidisciplinary approach based on evidence-based medicine and abundant randomized clinical trials. The treatment protocol for combined and sequential therapy for oral and maxillofacial malignancies is still under investigation. This review article presents the state of the art knowledge and some advances in combined and sequential treatment of oral and maxillofacial malignancies from the last five years.

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COMBINED AND SEQUENTIAL THERAPY DOMINATED BY SURGERY

Combined and sequential therapy, dominated by surgery, includes two main modalities: surgery plus postoperative radiotherapy, induction chemotherapy plus surgery and/or radiotherapy. The details of surgery are beyond the scope of this review.

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POSTOPERATIVE RADIATION THERAPY

Currently, surgery is still the main treatment modality for oral and maxillofacial malignancies. It is applicable either alone or in combination for the management of malignancies that are non-sensitive or moderately sensitive to radiation and/or chemotherapy, such as squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenocarcinoma not otherwise specified, osteosarcoma, fibrosarcoma, myosarcoma (except embryonal rhabdomyosarcoma), liposarcoma and malignant melanoma. Squamous cell carcinoma accounts for the majority of oral and maxillofacial malignancies. According to the studies done in the 1960s and 1970s, locoregional relapses are common in those patients who underwent a complete resection of advanced squamous cell carcinoma. Surgery alone for stages III and IV disease has been retrospectively compared with surgery and postoperative radiotherapy by Vikram et al7 at Memorial Sloan-Kettering Cancer Center in New York. The study demonstrated that primary site recurrence occurred in 39% of patients with negative histological resection margins and in 73% with positive margins. The recurrence rates were reduced by elective postoperative radiotherapy to 2.0% and 10.5%, respectively. Furthermore, recurrence rates were higher when radiotherapy was delayed more than 6 weeks after surgery; suggesting that significant tumor repopulation occurs during such a time interval.

A planned combined surgical and radiotherapeutic approach in patients with advanced tumors, either at the primary site or in the neck, is therefore appropriate. Elective postoperative radiotherapy, rather than preoperative radiotherapy, has become standard practice following the results of the RTOG 73–03 phase III trials.8 These studies together establish a standardized adjuvant treatment modality for oral and laryngeal cancers, i.e. 60 Gy of radiation in 30 fractions is given within 6 weeks postoperatively. Postoperative therapy is effective even for those non-sensitive tumors. However, postoperative radiation should be applied as early as possible and radiation within 6 weeks postoperatively is most favorable and advisable. It is recommended that a sufficient-dose of radiation be delivered within the defined time. For patients with oral malignancies, postoperative radiation should be finished within 100 days.

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NEOADJUVANT CHEMOTHERAPY

Neoadjuvant chemotherapy, also known as induction chemotherapy, is the use of chemotherapy as the primary treatment before definitive surgery or radiation therapy. Advantages of this treatment modality include an intact vascular bed for better drug delivery, reduced tumor bulk, and early eradication of regional and distant micrometastases. Disadvantages include delay of surgery, morbidity of “overtherapy” and patient noncompliance after chemotherapy.

It has been more than 20 years since the first application of induction therapy (cisplatinum-containing schedules) in the treatment of oral and maxillofacial tumors. The combination of cisplatin (CDDP 100 mg/m2, day 1) and 5-fluorouracil (5-Fu) (1 g/m2, day 3 to day 5) has been most commonly employed in an attempt to downstage disease prior to definitive local therapies and to reduce the incidence of distant metastasis. An important clinical objective has been to achieve “organ preservation” by avoiding ablative surgery in advanced disease and improve the quality of life. A large number of randomized trials designed to investigate induction chemotherapy have now been reported but have drawn conflicting conclusions, primarily because the majority include a small sample size. By 2000, results from almost 11 000 patients from 63 randomized trials had become available. Most of the effect appears to relate to improved local and regional disease control, with less conclusive evidence for a reduction in the incidence of distant metastases and a survival advantage.9

The recent development of taxane-containing, three-drug induction regimens that are capable of producing significantly better response rates than the older cisplatin and fluorouracil combination has also raised the possibility of a new and more important role for induction chemotherapy.10 Docetaxel, cisplatin and 5-Fu appears to be the most effective induction chemotherapy regimen and is the new induction “standard” that is currently being used by many cancer centers and intergroups. It is also a new platform that will be used to add new targeted agents to induction chemotherapy.11

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COMBINED AND SEQUENTIAL THERAPY DOMINATED BY RADIATION THERAPY

The origin of the therapeutic use of ionizing radiation dates back to the end of the 19th century, following the discovery of radium by Marie and Pierre Curie. Radiotherapy, initially developed from diagnostic radiology, uses low energy X-ray equipment for external beam delivery and radium as a means of administering interstitial or intracavitary therapeutic irradiation. Ionization of atoms in living tissue by therapeutic doses of irradiation is thought to primarily cause nuclear DNA damage which, if irreparable, may result in cell death. The mechanism of action is therefore relatively unselective between tumor and normal tissue. Radiotherapy techniques have been developed to enhance the therapeutic ratio by using multiple beams directed at the tumor volume in order to minimize the radiation dose to surrounding normal tissues and by delivering the total dose of radiation in multiple fractions over a period of several weeks.

Radiation therapy is mainly applied to radiation-sensitive tumors such as malignant lymphoma, plasma cell sarcoma, undifferentiated carcinoma, poorly-differentiated carcinoma, lymphepthelioma, Ewing's sarcoma and those involving special anatomical locations such as nasopharyngeal carcinoma (NPC), oropharyngeal carcinoma and carcinoma of the base of tongue. After a sufficient dose of irradiation, these tumors can be eradicated or well controlled. However, as the volume of the primary tumor and/or nodal metastasis increases and with it the tumor clongenic population, the probability of achieving control with radiotherapy decreases. The frequency of salvage surgery and/or immediate reconstruction using various compound flaps therefore increases and is associated with significant postoperative morbidity of up to 40% in head and neck cancer.12

Encouraging results have recently been reported in patients with locally advanced unresectable squamous cell carcinoma of the head and neck when concurrent chemoradiotherapy is used. A meta-analysis13 of concomitant radiation and chemotherapy in patients with previously untreated locoregionally advanced head and neck cancer demonstrated an 8% improvement in 5-year survival rates, although higher survival rates have been reported in some more recent randomized trials. Patients receiving postoperative concurrent chemoradiation have a longer disease-free survival and a lower local and regional relapse rate than those receiving radiation alone.14,15 However, concurrent chemoradiation is associated with a doubling of acute grade 3/4 toxicities (mucositis, dermatitis) compared with radiation alone (41% vs 21% for mucositis and 77% vs 34% for dermatitis).14,15 Fortunately, there appears to be no increase in the incidence of delayed adverse effects with concurrent chemoradiation regimens.15

The phase II study by Rapidis et al16 showed that docetaxel (TXT), cisplatin (CDDP) and 5-Fu based induction chemotherapy followed by the same regimen coupled with radiotherapy improves local control. Patients that showed a complete response (CR) after induction chemotherapy continued to maintain that disease status during radiotherapy. Patients who showed a CR after both induction chemotherapy and radiotherapy presented a 4-year survival rate of 74% compared to 30% for partial responders. A recent meta-analysis by Budach et al17 found that radiotherapy combined with simultaneous 5-Fu, cisplatin, carboplatin and mitomycin C as single drug or combinations of 5-Fu with one of the other drugs results in a large survival advantage irrespective of the radiation schedule employed. If radiation therapy is used as a single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival. These results of concurrent chemoradiotherapy in the treatment of patients with advanced unresectable head and neck cancer are encouraging and further study of the toxicity and follow-up is needed to validate the treatment effectiveness.

Cetuximab is a chimeric human and murine monoclonal antibody that competitively binds to the extracellular domain of EGFR. The benefits of monoclonal antibodies as potential therapies include their specificity for targets unique to malignant cells, leading to fewer side effects. Cetuximab is approved in combination with chemotherapy by the FDA for the treatment of advanced colorectal cancer, and has shown second-line activity in head and neck squamous cell carcinoma (HNSCC). In locoregionally advanced HNSCC, an international phase 3 study18 of high-dose radiation therapy with or without cetuximab demonstrated favorable results in previously untreated patients. Patients receiving a combination of radiation therapy and cetuximab had median 2- and 3-year survivals of 62% and 57%, vs 55% and 44% with radiation alone. The combination regimen did increase the risk of grade 3/4 skin reactions (34% vs 18%), but there was no difference in grade 3/4 mucositis.

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COMBINED AND SEQUENTIAL THERAPY DOMINATED BY CHEMOTHERAPY

Effective chemotherapy treatment of solid tumors emerged with the introduction of anthracyclines and platinum chemotherapy in the late 1970s, at first with palliative intent, and later extended into the adjuvant setting. High response rates led to the belief that systemic chemotherapy might improve locoregional control and also decrease the risk of distant metastases. A new strategy advocated cisplatin-based neoadjuvant chemotherapy before definitive local treatment with either surgery or radiotherapy. Response to neoadjuvant chemotherapy was viewed as a favorable prognostic sign, which allows the selection of patients most likely to benefit from radiotherapy or chemoradiotherapy.

Of the various types of oral and maxillofacial malignancies, combined and sequential therapy dominated by chemotherapy is suitable only for treatment of undifferentiated carcinomas, lowly differentiated carcinomas, hematopoietic and lymphoid malignancies. Treatment with chemotherapy has yielded impressive responses in certain patients with squamous cell carcinoma, but alone it is not yet curative. Therefore, historically, it has been used to treat advanced unresectable cancers in the palliative setting. In the past decade multiple clinical studies have examined various ways to integrate systemic therapy with standard loco-regional treatment in the hope of improving the final outcomes. Three main objectives have been pursued: (1) to improve the chances of a cure; (2) to improve functional and/or cosmetic outcome by avoiding surgical procedures (i.e. organ preservation); (3) to decrease the incidence of distant metastases and second primary cancers. Achievement of these objectives has not been demonstrated to date, however, the future of chemotherapy remains promising. It should be noted that nearly all studies have been conducted on late stage (T3, 4), recurrent or metastatic disease only.

Many drugs have been used for the management of oral and maxillofacial malignancies, including methotrexate, 5-Fu, hydroxyurea and platinum derivatives (cisplatin, carboplatin). Of the anthracyclines, doxorubicin is the most commonly used agent. Of the plant alkaloids, vincristine, vinblastine and more recently vinorelbine have been used. The taxoids (paclitaxel and docetaxel) are the newest group of agents with very encouraging activity.

It should be mentioned that no response rate for any single agent has been higher than 30%-35%. Combination chemotherapy has been proved to be the ideal way to administer these agents. The goal is to find agents that act synergistically and that do not have the same primary toxicity profile. Cisplatin and 5-Fu have been the most extensively studied, and have resulted in response rates as high as 90%. However, no single agent or combination regimen has yet proved to extend survival in recurrent and metastatic disease.

To improve the treatment efficacy of oral and maxillofacial malignancies, several treatment modalities have been proposed. Immunotherapy is based on the theory of immunosurveillance, which postulates that specific effector molecules and cells of the immune system recognize and eradicate neoplastic cells, thus preventing tumor formation. There are two ways to achieve these goals. One is the “boosting” of the patient's own immune system in an attempt to increase the patients own tumoricidal response. The other is the identification of tumor specific antigens so that monoclonal antibodies may be created and directed at these antigens.

Analysis of tumor-infiltrating lymphocytes (TILs) in situ revealed that they have decreased proliferative and cytolytic activity relative to peripheral lymphocytes. TILs also exhibit decreased cytokine production and decreased natural killer cell activity. Patients with oral and maxillofacial malignancies have been found to have higher serum levels of PGE2 than normal controls, and these levels were seen to decrease after tumor treatment and increase with tumor recurrence. Consequently, immunomodulation by specific inhibitors of prostaglandin synthesis may be of potential benefit in the treatment of head and neck cancer.

A phase 2 multicenter study of cetuximab in combination with platinum-based chemotherapy in platinum-refractory metastatic or recurrent HNSCC demonstrated a response rate of 10% and a disease control rate of 53%. The median time to progression and overall survival were 85 and 183 days, respectively. The treatment was well tolerated, with an acneiform rash the most common cetuximab-related adverse event.19

In a recently published multi-institutional randomized phase 3 trial (E5397), Burtness and colleagues20 found that the addition of cetuximab to cisplatin improved relative risk (26% for cetuximab/cisplatin vs 10% for placebo), but had no significant effect on progression-free survival or overall survival in recurrent/metastatic HNSCC. Notably, a survival advantage was associated with the development of any grade of skin toxicity. The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% confidence interval, 0.21 to 0.86).

Combined chemotherapy and thermotherapy, photodynamic therapy (PDT) and gene therapy have also been extensively investigated in recent years. Combined chemotherapy and thermotherapy was successfully used for treatment of superficially located tumors such as lip cancers. PDT was mostly used for palliation in inoperable patients with advanced stage cancers. During the last decade, enormous progress has been made in the identification of the genetic factors that underlie head and neck squamous cell carcinoma and adenoid cystic carcinoma (ACC) of the salivary glands.21 Somatic gene therapy aiming to treat these diseases by introduction of therapeutic genes into somatic cells was explored. However, the currently used gene transfer systems are not able to target HNSCC cells selectively. Among the possible solutions to the problem are the use of targeting vehicles, e.g. monoclonal antibodies, and the exploration of tissue-specific promoters.

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COMBINED AND SEQUENTIAL THERAPY FOR ORAL AND MAXILLOFACIAL MALIGNANCIES AT DIFFERENT SITES

Oral and maxillofacial malignancies can occur at any sites of this region including the paranasal sinus, salivary gland, lip, oral cavity, gingiva, tongue, palate and pharynx, etc. The largest proportion of cases arose in the larynx (20.9%) and oral cavity, including the lip (17.6%) and thyroid gland (15.8%). The majority (55.8%) are squamous cell carcinomas arising in the mucous membrane of the mouth and pharynx, followed by adenocarcinoma (19.4%) and lymphoma (15.1%).4

In choosing the appropriate treatment modality, several important factors should be considered. Tumor factors include site of the primary tumor, location in the oral cavity (anterior or posterior), size (T stage), proximity to maxilla or mandible, status of cervical lymph nodes, histology (type, grade and depth of invasion) and previous treatment. Patient factors include age, general medical condition, tolerance, occupation, acceptance and compliance, lifestyle (smoking/drinking) and socio-economic status. Physician factors include surgical skills, radiotherapy skills, chemotherapy expertise, dental and prosthetic services, rehabilitation services and support services.

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ORAL AND MAXILLOFACIAL SQUAMOUS CELL CARCINOMA

As mentioned above, treatment of oral and maxillofacial squamous cell carcinoma depends on a number of factors, including the location, size, type and extent of the tumor and stage of the disease. Multidisciplinary approach is the advocated modality nowadays which involves the efforts of surgeons, radiation oncologists, chemotherapy oncologists, dental practitioners, nutritionists and rehabilitation and restorative specialists. Generally, early diagnosis and treatment result in a much better outcome. Oral and maxillofacial squamous cell carcinomas at early stages are usually treated by surgery and/or radiotherapy, while those at later stages should be treated by combined modalities as follows: induction chemotherapy, followed by ablative surgery with or without immediate reconstruction, subsequent postoperative radiotherapy (within 6 weeks), addition of biological therapy (including traditional Chinese medicine or other biomodifiers) and rehabilitation therapy (speech therapy, physical and mouth opening exercise, etc) in selected cases. The actual curative treatment modalities are usually surgery and radiation, with chemotherapy added to decrease the possibility of metastasis, to sensitize the malignant cells to radiation, or for those patients who have confirmed distant metastasis of the disease.

Oral health care is addressed during cancer therapy. This is to minimise oral disease and post-therapeutic complications. It appears that up to 97% of patients require oral healthcare before treatment of cancer can begin. Some of the complications that may occur post treatment are radiotherapy- or chemotherapy-induced mucositis (inflamed mouth), oral ulceration, bleeding, infections, pain, xerostomia and caries.

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CARCINOMAS OF THE SALIVARY GLAND

Salivary gland neoplasms are remarkable for their histologic diversity. These neoplasms can be of epithelial, mesenchymal and lymphoid origin. Carcinoma of the salivary glands accounts for less than 1% of all head and neck malignant neoplasms; yet it provides a challenge both for the surgeon and the radiation oncologist. Histologic grading of salivary gland carcinomas is important to determine the proper treatment approach, though it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. The minimum therapy for low-grade malignancies of the superficial portion of the parotid gland is a superficial parotidectomy. For all other lesions, a total parotidectomy is often indicated. The facial nerve or its branches should be resected if involved by tumor; repair can be done simultaneously. Growing evidence suggests that postoperative radiation therapy augments surgical resection, particularly for the high-grade neoplasms, when margins are close or involved, when tumors are large, or when histologic evidence of lymph node metastases is present. In a series of 224 previously untreated patients, Mendenhall et al22 found that a substantial proportion of patients with salivary gland carcinoma were cured with surgery combined with adjuvant radiotherapy. Radiotherapy alone was used for patients with unresectable tumors and cured approximately 20% of those with advanced-stage disease. Thus, it can be concluded that postoperative radiotherapy is recommended in bulky tumors with high grade irrespective of the surgical margins. Surgery followed by postoperative radiotherapy is the norm for management in our department where a majority of patients present at advanced stages or with recurrent disease.

There are several clinical trials indicating that fast neutron-beam radiation improves disease-free and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms. Accelerated hyperfractionated photon-beam radiation therapy has also resulted in high rates of long-term local regional controls.23 The use of chemotherapy for malignant salivary gland tumors remains under evaluation, in a multivariate Cox analysis, only the use of platinum-based chemotherapy was identified as an independent predictor of an increased survival (P=0.01) for patients with incurable salivary gland neoplasms.24

The type of surgery was usually planned on the basis of the primary site and the locoregional occurrence of metastasis, and it may involve partial or total maxillectomy, parotidectomy and transoral resections. Patients with cervical metastasis underwent neck dissection according to the levels of the metastasis, ranging from radical to selective neck dissection. On the basis of the published data, an elective neck dissection is recommended in carcinomas with high risk of lymphatic spread in the N0 neck, in patients with primary tumors greater than T2 and in patients with lymphangiosis carcinomatosa.

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MALIGNANT MELANOMA

Malignant melanoma is the most serious form of skin cancer in the Western countries, yet it is more often found to occur in the oral mucosa in China. The standard treatments for malignant melanoma of the skin, like for other cancers, have been to remove the cancerous tumor and if necessary use radiation, chemotherapy, and/or biological agents to kill off the remaining cancer cells. Mucosal melanoma of the head and neck remains a difficult disease to treat, with high locoregional recurrence rates and poor prognosis despite aggressive therapy. The aggressiveness of this entity and the absence of any standardized treatment protocol make the prognosis poor.25 Our preferred treatment protocol for this disease entity is cryotherapy for the primary site first, followed by chemotherapy. In cases with cervical lymph node metastasis or uncontrolled primary diseases, radical neck dissection and/or radical local resection is performed. Bacillus Calmette-Guerin (BCG) vaccine is routinely applied to the upper arm on an area of 5 cm×5 cm by scarification, which may facilitate remission of melanoma, by means of antigenic cross-reactivity between BCG and surface components of human melanoma cells. During treatment, maintenance of oral hygiene is very important and other supportive measures should be strengthened.

Chemotherapeutic medications for the treatment of oral melanoma do not reliably reduce tumor volume. Interferon, dacarbazine and BCG have been tried with marginal and unpredictable results. New protocols with interferon (Intron A) and other immunotherapies are being investigated. Multimodal therapy offers the best likelihood of relapse-free survival compared with any single therapy. Kirkwood et al26 showed that surgery followed by high-dose interferon alfa-2b in high-risk, cutaneous melanoma appears to be more beneficial than surgery followed by melanoma antigen vaccination. Although not evaluated in mucosal sites, these approaches may provide valuable adjuncts to the treatment of oral mucosal melanoma.

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MALIGNANT LYMPHOMA OR UNDIFFERENTIATED CARCINOMA

The cornerstone of treatment remains chemotherapy and, to a minor extent, radiotherapy. New treatment modalities such as the use of monoclonal antibodies, high-dose therapy or allogenic transplantation have improved the treatment results in the last decade. Surgery, one of the most important therapeutic tools in oncology, has a limited role in the treatment of lymphoma. Historically radiotherapy had a very important role, having been the first treatment capable of inducing long-term remission, and even cures, in a number of patients at the beginning of the last century. Its role remains very important in the treatment of Hodgkin's disease, while in non-Hodgkin's lymphoma, where localised disease is less frequent and tumour spread less predictable, its role is more and more confined to the exceptional cases of stage I disease or for the consolidation of remission in patients initially presenting with bulky disease.

Chemotherapy has been used for many decades and many drugs have been shown to be active in lymphomas. Among them are the alkylatingagents, which were the first class of drugs showing activity (such as chlorambucil, melphalan and cyclofosfamide). Anthracyclins or anthracyclin-liked drugs, such as doxorubicine and mitoxantrone, are also important drugs, as are etoposide, vincristine and vinblastine. Steroids are frequently used for the treatment of lymphoid malignancies: their activity is explained by the induction of apoptosis in normal and pathological lymphoid cells. Other drugs such as ifosfamide, cisplatin, citarabine, high-dose methotrexate and, more recently, gemcitabine have shown activity as well. These latter drugs are primarily used in the second line treatment, but new protocols are being developed which try to integrate them into the first line in an attempt to achieve higher remission rates. High-dose myelo-ablative chemotherapy is an extension of the use of some of these drugs, developed thanks to the improvements in the understanding of the biology of haematopoiesis. Another process is the use of passive immunotherapy, which consists of infusing the patient with antibodies directed against antigens present on the surface of lymphoma cells. A number of antibodies have been, and are still being developed, but the anti-CD20 antibody rituximab has already gained widespread use in clinical practice. Rituximab has shown activity in all B-cell lymphomas, either used in monotherapy or combined with chemotherapy.

Allogeneic bone marrow transplant is also considered an immunologically based treatment, which is based on the graft vs lymphoma effect, in which the intact immune system of the donor recognizes lymphoma cells of the host as foreign and elicits an immune response against them. The recently developed technique of “mini-allogeneic transplant”,27 in which the patient does not receive a myeloablative preparative treatment, but only immuno-suppression followed by donor cell infusion, is based on this principle.

In cases with residual lesions after standard chemo-and/or radiation therapy, or uncontrolled diseases arising from the jaw bones, surgery may be considered the definitive treatment.

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SOFT TISSUE SARCOMA OR OSTEOGENIC SARCOMA

Surgery is the mainstay of treatment for these patients. Radiation therapy is suitable for those with positive margins or residual lesions. However, for embryo-originated sarcomas, e.g. embryonal rhabdomyosarcoma, radiation therapy is the first choice of treatment. For rhabdomyosarcoma, triple therapy including chemotherapy, surgery and radiation therapy is recommended. When applied to osteosarcoma and Ewing's sarcoma, the triple therapy can reduce the metastatic rate and improve the survival rate. The survival rate of osteosarcoma can be raised from 20% to 60% when treated with mitoxantrone chemotherapy plus surgery.

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CONCLUSION

Successful management of oral and maxillofacial malignancies now requires a cooperative approach among a broad group of medical disciplines that includes head and neck surgery, radiation oncology, medical oncology, medical imaging, clinical pathology and lab medicine, social work, nutrition and others. Despite advances on a number of fronts, disease recurrence that is not amenable to salvage surgery is still a frequent cause of death for patients with oral and maxillofacial malignancies. Further clinical investigation of novel agents and treatment strategies and a better understanding of the molecular biology of oral and maxillofacial malignancies are needed to optimally develop safe and effective targeted therapeutics.

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Keywords:

oral cancer; oral and maxillofacial malignancies; combined and sequential therapy; multidisciplinary approach

© 2008 Chinese Medical Association