Oral cancer, although not common in Australia, is one of the most prevalent malignancies in some parts of the world such as India and South-East Asia.1,2 The most predominant type of malignancy is squamous cell carcinomas (SCC) (>90% of all oral cancers).2 Its prevalence in South Australia is increasing, comprising approximately 4.0% (346) of all new cancer cases in 2006 (including cancer of the lips).3 This was significantly above the national incidence of 2.7% the previous year.3,4 Mortality rates in 2006 were also substantial with 64 deaths from oral cancer in South Australia alone (1.9% of all cancer-related deaths that year) compared with 651 deaths (1.7%) nationwide. Death rates from oral cancer alone have remained steady for both males and females over the past few decades (Fig 1).2
Dental professionals may be the first individuals to identify/suspect these lesions before referring to oral and maxillofacial surgeons and oral medicine specialists. Because the general dentist will likely follow on with the patient’s future dental care, it is important that he or she has a basic understanding of the different treatments involved in treating oral malignancies and their respective outcomes. When treating oral cancer, the aim has always been to cure the patient by removing the primary tumour and preventing spread of the disease, leaving patients in a disease-free state. In cases of incurable disease, the objective changes to improving quality of life until the patient’s death. Management options have expanded dramatically over the past century, resulting in improved control and survival rates from the disease while enhancing the patient’s quality of the life.5–14 The aim of this article is to review the evolution of treatment modalities for oral SCCs, including the four main modalities: surgery alone, surgery with postoperative radiotherapy, radiotherapy alone, and chemotherapy +/− other modalities. Treatment outcomes will be discussed for each modality, with an additional section on toxicities of radiotherapy and/or chemotherapy.
Surgical removal of malignancies has always played a dominant role in the treatment of oral cancers. With a well-established history of over a century, it was the earliest accepted method of treatment for cancers in general with the aim to completely excise the tumour with surgical margins comprised of healthy tissue.15 Advancement of surgical techniques (e.g. more conservative resection and free tissue transfer from distant sites) initially enhanced control rates and quality of life,16 but with the introduction of radiotherapy and chemotherapy as adjuncts to surgical removal, surgery alone as a treatment modality is no longer the ideal choice for most oral cancers due to its inferior treatment outcomes. Surgery alone is now only offered for accessible early staged oral cancers (stage 1/2) with no lymph node spread (N0) and no clinical or radiographic evidence of metastasis (M0) in areas of low risk for metastasis (e.g. lower lip).17
With the introduction of radical neck dissections by Crile18 and later popularized by Martin et al.,19 surgical treatment of oral cancers with a clinically positive neck became possible. After decades of modification, modified radical neck dissections (for positive neck lymph nodes) and selective/elective neck dissections (for negative neck lymph nodes) have now become routine surgical procedures in an attempt to prevent occult metastases of the cancer in the head and neck region without the morbidity that follows comprehensive/radical neck dissections.20 The type of neck dissection depends on the initial presentation of the patient with ipsilateral neck dissections being the standard option unless evidence of contralateral neck nodes are present or the primary tumour lies at/across the midline, thereby increasing the risk of contralateral/bilateral spread. Elective neck dissection may also be undertaken, even without a clinically positive neck. Bucur and Stefanescu21 found 56.5% of patients electing not to have neck dissections developed biopsy proven neck lymph node metastases within 2 years. Tumour thickness also plays an important role as an independent predictor for cervical nodal metastasis as tumours >5 mm in thickness are shown to be correlated with increased risk of cervical metastases (relative risk of 2.43).22 Numerous studies have evaluated the effectiveness of neck dissections and have found significantly improved neck control and disease-free survival rates (especially synchronous neck dissection with surgical removal of the tumour) of up to 91.4% and 80.5% respectively for 5 years in early staged cancers.5,23,24 Furthermore, Patel et al.25 recently demonstrated insignificant differences in 5-year regional control, overall disease control, and overall disease-specific survival between selective and comprehensive neck dissections in 205 patients with predominantly N2/3 oral cancers. However, 84% of patients in that study received adjuvant radiotherapy (independent of type of neck dissection) which could account for this lack of significance. The only significant result obtained was that selective neck dissections produced significantly more favourable distant control (91% vs. 75%). This modern concept of treating positive nodes with selective neck dissections is likely based on the low metastasis rate of oral malignancies to level 5 neck nodes26,27 but needs further investigation to prove its efficacy. The majority of studies done in this field conclude that the high control and survival rates only apply for early lesions, with both values dropping dramatically as the tumour progresses in staging, e.g. increasing in number of positive neck lymph nodes or increase in primary tumour size/thickness.23,24,28–30 Despite this, surgery remains the core treatment approach for most oral malignancies and acts as a foundation for newer technologies to aid its use in minimizing chances of disease recurrence.
Surgery plus postoperative radiotherapy
Surgery combined with the use of postoperative radiotherapy is a common treatment modality for oral cancers and cancers of the head and neck region. Radiotherapy is typically applied after surgery due to the difficulty of surgically removing irradiated tissue as tissues become fibrosed and tend to heal slower.31 Factors such as large primary tumours, positive or close surgical margins, and signs of perineural/lymph/vascular invasion dictate the use of radiation at the primary site but the neck is also commonly treated, especially if there are positive lymph nodes with or without extracapsular spread, to prevent potential metastasis and recurrence.32,33 Radiation doses can vary but typically total doses of approximately 60 Gray(Gy) are divided into 30 daily fractions of 2 Gy each for a period of 6 weeks.31 More favourable local and locoregional control rates have been found when treating advanced cancers in comparison to surgery alone. Vikram et al.34 reported primary recurrence rates of 39% in those with negative resection margins and 73% in positive margins in patients with stage 3/4 disease treated by surgery alone compared with only 2% and 10.5% respectively in those treated by surgery and postoperative radiotherapy. Dixit et al.28 found 3-year locoregional control rates of 48% for 61 patients with stage 3/4 SCCs of the buccal mucosa while only 11% for 115 patients with the same condition treated by surgery alone (p = 0.001). However, no significant difference was found between the different modalities for stage 1/2 disease, indicating that surgery alone is sufficient in disease control. Fang et al.35 also found similar results of 39% locoregional recurrence within a 3-year period in 57 patients with the same disease, and overall and disease-specific survival rates of 55% and 62% respectively to reinforce its effectiveness. Despite the lower local and locoregional recurrence rates, distant metastases were found to be higher by O’Brien et al.36 although this was not a common finding amongst other studies. Survival rates have also been reported to improve as the relative risk of cancer-related deaths and deaths from any cause in those treated by surgery alone are 2.21 and 1.67 times greater than that receiving adjuvant radiotherapy for head and neck SCCs.37 Despite this, disease-free survival rates were not significantly improved with the use of adjuvant radiotherapy but determined by crucial factors such as positive surgical margins and presence of lymph node metastasis which indicate a high risk of locoregional recurrence and/or systemic metastasis.36,38–42
Over the past few decades varying techniques have been developed to improve the effectiveness of postoperative radiotherapy and produce more favourable local control rates, disease-specific survival rates and quality of life. These techniques included altered fractionation by either accelerated or hyperfractionated,43,44 radiotherapy combined with chemotherapy or targeted therapy, three-dimensional conformal radiation therapy (3D–CRT) and most recently intensity-modulated radiotherapy (IMRT).6,7,9 Initially, issues such as acute side effects (e.g. mucositis) worsened following altered fractionation techniques,43,44 but modern 3D–CRT and IMRT techniques have reduced toxicities/side effects significantly while improving quality of life compared with traditional two-dimensional radiotherapy.8,45 Three-dimensional conformal radiation therapy allows for three-dimensional tailoring of radiation to the morphology of the tumour and IMRT further allows a conformal dose distribution to preserve vital organs at risk, e.g. parotid glands, optic nerve, brainstem and spinal cord.8 In terms of local control rates and survival rates, 3D-CRT and IMRT are comparable when used postoperatively after surgery and have both shown promising results with substantially less toxicity but still remain unsatisfactory for advance disease.6–10 These techniques have now replaced conventional radiotherapy regimes in routine clinical practice but long-term studies proving their effectiveness are only just starting to emerge.
Radiotherapy as a sole treatment modality is not commonly used for oral cancers (usually only if the tumour site is inoperable or the patient chooses not to have surgery). It can also be given as a palliative treatment option for more advanced/terminal cases. Radiation therapy is primarily used in combination with surgery and/or chemotherapy with the aim to kill rapidly dividing cancer cells by disrupting their DNA structure at the cost of healthy cells, which are also affected during the process.31,46 However, with the evolution of radiation techniques, it is now frequently used as a sole treatment modality for oropharyngeal and laryngeal carcinomas (e.g. faucial tonsils or base of the tongue carcinomas).47,48 Altered fractionation techniques have produced significantly better results when compared with conventional radiotherapy in 5-year local control rates of tonsillar, base of tongue and laryngeal SCCs of all stages.47–49 More recently, IMRT has achieved encouraging results when used alone to treat early and intermediate stage nasopharyngeal and oropharyngeal carcinomas with 3- and 5-year locoregional control rates of above 85% and 95% respectively.11,12 This technique is still relatively new with minimal clinical evidence but may form the basis for future management of these types of cancers. In terms of survival rate, radiation therapy alone has been found to achieve similar survival rates (up to 5 years) to surgery for early stage oral cancers and can be used for the management of tumours at certain sites (e.g. buccal mucosa or lip).46,50 However, Schwartz et al.51 found 37% of all patients with recurrences received radiotherapy alone with the majority being diagnosed as stage 1/2 cancers (26%). It should be noted that all recurrences in this group occurred locally or locoregionally without any cases of distant/regional recurrence, whereas those treated with surgery or surgery and radiotherapy had incidences of regional recurrence. The main advantages of radiotherapy alone over surgery are milder complications following treatment and improved quality of life, while surgery of advanced tumours could lead to a 1%–2% chance of postoperative death as well as extensive permanent loss of function of oral structures.52 For these reasons, radiotherapy alone is the treatment of choice for those cancers which have similar recurrence and survival rates as surgery alone or with radiotherapy in conjunction (e.g. oropharyngeal SCC).52
Chemotherapy has emerged as a prominent adjunct modality for locoregionally advanced oral SCC in recent years. It is a systemic therapy which aims to destroy rapidly dividing malignant cells in order to control tumour spread and metastasis. Although it is generally not a curative modality alone for solid head and neck or oral tumours, it can be utilized before surgery (induction), concurrently with irradiation post surgery (chemoradiotherapy) or both.53 Adjuvant chemoradiotherapy is now almost standard in treating advanced head and neck cancers. The most common regime consists of cisplatin 100 mg/m2 on days 1, 22 and 43 although other variations such as daily low-dose and weekly intermediate dose cisplatin have shown survival benefits.53 Although earlier studies provided inconsistent results/benefits on concomitant chemoradiotherapy, Pignon et al.54 published a large meta-analysis of 10 741 patients in 63 randomized clinical trials reporting an absolute survival benefit of 4% at both 2 and 5 years. An updated version of this meta-analysis including 16 640 patients in 87 randomized clinical trials showed an increase in absolute survival of 8% at both 2 and 5 years while also demonstrating a more pronounced benefit compared to induction chemotherapy.13,14 However, induction chemotherapy has several appealing theoretical and clinical advantages such as optimal drug delivery through undisturbed vasculature, prevention of early micrometastases and the ability to assess tumour response, thereby allowing for decisions to be made regarding the preservation of organs.55,56 Concomitant chemoradiotherapy also has its complications, usually related to more frequent toxicities (up to twice the incidence) than induction chemotherapy or radiotherapy alone.13,57 Induction chemotherapy has produced significant improvements in survival and locoregional control rates in a direct comparison study between induction radiochemotherapy with radical surgery and radical surgery alone.58 Two hundred and sixty-eight patients with T2-4, N0-3, M0 SCCs of the oral cavity or oropharynx received either surgery alone (141) or salvage surgery (127) and were recalled for up to 3 years. During this period, locoregional recurrences and deaths in the surgery alone group were 31% and 28% respectively compared to 15.6% and 18.6% observed in the combined modality group.
The range of drugs used for treating oral and maxillofacial cancers has expanded over the past decades with the introduction of methotrexate, 5-fluorouracil, hydroxyurea, platinum derivatives, anthracyclines, plant alkaloids, and the most recent taxoids.59 Combination chemotherapy has been extensively studied and has shown very high response rates due to its synergistic effects at the cost of greater toxicity, but has not extended survival rates, especially in recurrent and metastatic disease.53 Different dosage regimes along with radiotherapy have also been tested with some regimes better tolerated but comparable treatment outcomes were achieved regardless.60
Recently, the concept of so-called ‘targeted therapies’ for oncology treatment has been developed. For example, with respect to head and neck SCCs, cetuximab, an IgG1 monoclonal antibody, targets the ligand-binding domain of the epidermal growth factor receptor (EGFR) which is abnormally activated in epithelial malignancies including oral and head and neck cancers. Radiation to these tumours increases expression of EGFR in cancerous cells, enabling them to become more resilient to treatment and subsequently leading to poor clinical outcomes.61–65 With an agent like cetuximab, inhibiting the EGFRs should enhance the cytotoxic effects of radiation therapy. Robert et al.66 treated 16 patients with head and neck SCCs staged 3 or 4 with no metastatic disease with radiotherapy in conjunction with cetuximab and found a good tolerance of the drug with minor grade fever, nausea, asthenia, and skin toxicities (one case of grade 3 skin toxicity outside the field of radiation). Disease-free survival rates were 73% and 65% for 1 and 2 years respectively. Bonner et al.67 performed a larger scale (213 patients) randomized clinical trial with cetuximab and found a median locoregional control duration of 24.4 months when used in conjunction with radiotherapy, as opposed to 14.9 months with radiotherapy alone. Insignificant differences were found between the groups in terms of toxicity. Cetuximab is still a relatively new concept with more studies needed to confirm its clinical effectiveness. Other advancements in this field also include research into biological therapies/immunotherapy, virotherapy, gene therapy and cancer vaccines (Table 1) which are all still in developmental stages.68–71
|Type of therapy||Method of action|
|Targeted therapy||• Blocking growth factor receptors|
|• Blocking specific enzymes|
|• Modifying functions of proteins|
|• Inducing apoptosis|
|• Inhibiting angiogenesis|
|• Stimulating immune cells|
|Biological therapy/immunotherapy||Laboratory-made antibodies and cytokines used to help eliminate cancer cells or boost immune function|
|Virotherapy||Using viruses, e.g. adenovirus as a vector to carry genes into malignant cells to disrupt their growth|
|Gene therapy||Inserting genes into immune cells to boost recognition and elimination of cancer cells or inserting into cancer cells to increase cytokine production thus attracting immune cells. Viruses can be used a carriers for gene therapy|
|Cancer vaccines||Stimulates immune function by artificially introducing antigens into the body as a prevention for future disease|
Adverse toxic effects have frequently occurred during and after treatment of oral cancers with either radiotherapy and/or chemotherapy.72–76 Because of the nature of both therapies as explained above, all rapidly dividing cells within the body are at potential risk of being affected during treatment. These cells include epithelial cells of the skin (xeroderma), haemopoietic cells (haematologic toxicity) within the bone marrow, epithelial lining of the alimentary tract, including the oral mucosa (mucositis) and hair follicles (alopecia).77 Other frequent adverse effects include severe nausea and vomiting, neurotoxicity, nephrotoxicity and ototoxicity.75 These common side effects can significantly reduce the patient’s quality of life and ability to tolerate continuing treatment, especially when severe, thus decreasing the chance of cure.75 While certain complications are expected (e.g. salivary gland hypofunction in over 60% of patients after radiotherapy of the head and neck region),74 the severity of others such as mucositis, renal dysfunction, neurotoxicity, and haemotologic toxicities are less predictable and can be potentially life-threatening.75,76,78–80 Oral mucositis in particular is common in patients with head and neck malignancies receiving chemoradiotherapy and can be concomitant with chemotherapy-induced myelosuppression (bone marrow suppression) and consequently neutropaenia.73 In a clinical review, Browman et al.72 found that studies which showed a survival benefit using different platinum-based (e.g. cisplatin) chemotherapy regimes with or without radiotherapy shared common adverse effects including stomatitis, weight loss, xerostomia and haemotologic toxicity. It is well established that the severity of these side effects is dose dependent but with the common regime of chemoradiotherapy at 100 mg/m2 of cisplatin every 3 weeks and 60 Gy delivered in 30 fractions of 2 Gy each, severe toxic effects are highly frequent in patients with even slight comorbidities.75 However, this regime is the only evidence-based cisplatin regime that has been extensively studied, whereas other alternative administration schedules or dosages have not shown consistent efficacy and still produce significant toxicity.75 Other chemotherapy agents such as carboplatin and 5-fluorouracil appeared to produce more manageable side effects due to less neurotoxicity and renal dysfunction but high grade mucositis, haemotologic toxicity, and symptoms such as nausea, vomiting and diarrhoea were still frequent.75 New therapies such as virotherapy also share similar side effects such as fever and diarrhoea as observed during early clinical testing.70 Those with age-related comorbidities and/or physiological deteriorations undergoing radiotherapy and/or chemotherapy are at even more risk of developing severe toxicity than younger and healthier individuals.81 Modifying the treatment regime in order to avoid or suppress these toxicities could lead to ineffective doses and thus a poorer prognosis for the patient. Recent improvements in radiotherapy techniques (i.e. IMRT) when combined with chemotherapy produce significantly milder side effects (e.g. sparing of salivary glands), thereby reducing the incidence of salivary gland hypofunction.10–12,45,82