Head and neck cancer—Part 2: Treatment and prognostic factors

Site and TNM stage

The most important prognostic factors are site and TNM (tumour, node, metastasis) stage. The table⇓ details the survival rates of patients diagnosed with head and neck cancer at different sites. Patients with tumours that are larger and have spread to nodes and other tissues have poorer survival. Guidelines for head and neck carcinomas from the Royal College of Pathologists state that other accepted features related to clinical outcome are grade, pattern of invasion, proximity of carcinoma to resection margins, and the presence of extranodal spread. A large meta-analysis showed that extranodal spread more than halved the chances of surviving for five years (odds ratio 2.7, 95% confidence interval 2.1 to 3.7).1 ^w1

Comorbid illness

The results of large meta-analyses of clinical trial data show that poor performance status (poor fitness and presence of comorbidities) is associated with an adverse prognosis.2 3 A systematic review of the effect of comorbidity on survival from head and neck cancer found that for laryngeal cancer, for example, the risk of death is significantly related to comorbidity (hazard ratio 1.5-13.5, depending on the comorbidity).4 A systematic quantitative review of the association of anaemia and survival in patients with cancer showed that anaemia increased the relative risk of death in patients with head and neck cancer by 47%.^w2 Meta-analyses of clinical trial data show that advancing age is associated with a decreased probability of survival.2 3 ^w3

Molecular markers

Molecular markers of prognosis have been studied but none has yet entered routine clinical reporting. A systematic review and meta-analysis found no conclusive value for p53 as a prognostic factor because of heterogeneity across studies.^w4 Another meta-analysis of tumour expression of the angiogenic vascular endothelial growth factor in 1002 patients found that patients who were positive for this growth factor had nearly double the risk of death (relative risk 1.88, 1.43 to 2.45) at two years.^w5 A large body of evidence associates tumour hypoxia with adverse prognosis, and hypoxia associated markers have shown promising results, in particular hypoxia inducible factor 1α and carbonic anhydrase 9.5 High tumour expression of the epidermal growth factor receptor was linked with a poor prognosis in several studies, and also predicted benefit from accelerated radiotherapy.^{w6 w7}

Early stage tumours

Case series, often retrospective and from single centres, have shown that for early stage tumours in many sites surgical excision or radiotherapy have similar cure rates but a different side effect profile.7 ^w8 Radiotherapy may offer better organ preservation, and for some cancers where function is important it is the treatment of choice. For example, radiotherapy allows preservation of natural speech and swallowing in carcinomas of the tongue base. A recent advance in surgical treatment, transoral carbon dioxide laser (fig 1⇓), reduces morbidity with improved organ preservation compared with open surgery. Prospective and retrospective case series have shown good outcomes for organ preservation in certain cancers, such as early glottic cancers and tonsillar cancers, because this technique causes less tissue damage than open surgery.^{w9 w10} However, there have been no randomised comparisons of radiotherapy and carbon dioxide laser surgery. For some sites (such as the oral cavity), mainly retrospective single centre case series have shown that surgical excision alone may be curative,7 and that it is associated with a highly satisfactory functional outcome.^w11

Fig 1 Cancer of the left vocal cord before resection (left) and immediately after resection with a carbon dioxide laser (right)

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Advanced tumours

For advanced squamous cell carcinoma of the head and neck, single modality treatment (surgery or radiotherapy) is associated with poorer outcomes,8 and randomised studies have shown that combined use of surgery and postoperative radiotherapy, or combined chemotherapy and radiotherapy, offer the highest chance of achieving a cure.8 9

Primary reconstruction, using microvascular free flaps, of large defects after surgical resection of oral tumours especially, and laryngopharyngectomy (removal of the larynx and pharynx), is now a standard treatment that improves functional abilities and quality of life.^{w12 w13}

Patients with HPV related cancer

Retrospective analyses of samples from patients recruited in large randomised trials and retrospective case series show that patients with HPV related oropharyngeal carcinoma seem to respond better to a variety of treatments, including chemoradiotherapy or surgery and radiotherapy,10 11 12 than those with non-HPV related head and neck tumours. Because these patients are generally younger, they may survive for several decades with substantial side effects and functional impairment as a consequence of the treatment they receive, and this may have implications for carers, the health system, and social care.

Recent advances in surgery

Transoral surgery using the carbon dioxide laser under microscope guidance is now a widely accepted technique that can help in organ preservation, mainly in early disease.^w10 More recently, robotic surgery (fig 2⇓) has been used and evaluated, especially for transoral resection of cancers of the base of the tongue and the tonsils. The high definition stereoscopic view, with three dimensional input, and the manoeuvrability of the robotic grasper provide improved access and visualisation. This technique allows resection of more extensive tumours located in difficult to reach areas than is possible using traditional transoral resection with microscopic guidance.^w14 Reports of early outcomes using robotic surgery, usually in combination with postoperative radiotherapy, show functional outcomes comparable to other treatment modalities.^w14 A recent prospective feasibility study of 45 patients reported no involved margins, but 56% and 17.8% patients needed postoperative chemoradiotherapy or radiotherapy respectively.^w14 No data on long term outcomes are available yet.

Fig 2 Surgical robot. Intuitive Surgical, with permission

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Reconstruction of large defects using microvascular free flaps comes at a considerable economic cost through substantial investment in microvascular expertise and postoperative care, as well as rehabilitation and support services. Newer techniques that result in less donor site morbidity and may have better functional outcomes, such as anterolateral thigh free flaps, circumflex iliac flaps, and scapular flaps, are increasingly used in preference to other more established flaps.

Patients undergoing bony reconstruction may now have osseo-integrated implants placed at the same time to allow dental and prosthetic rehabilitation after treatment has been completed. This has improved functional and aesthetic outcomes and increased patient satisfaction in retrospective and prospective case series.^w15

Recent advances in radiotherapy

In recent years radiotherapy has benefited from advances in cancer imaging, high speed computer software that optimises treatment planning (intelligently selecting the most appropriate beam direction and shape), and developments in radiation delivery technology. It is now one of the most technology driven branches of medicine. A tightly fitted moulded perspex mask, which is custom made for the patient, is used to immobilise the patient in the same specific orientation and position on the table during the delivery of the daily radiotherapy on an outpatient basis. Radiation treatment is delivered by computer driven linear accelerators with sub-millimetre accuracy, so that radiation is focused on the tumour bearing tissues and radiation of normal tissue structures is minimised.

A recent UK randomised trial of 88 patients found that intensity modulated radiotherapy, a new form of radiotherapy that allows better control of radiation dose delivery to the head and neck, reduced radiation induced xerostomia (the main long term side effect of standard radiotherapy) from 75% to 39% (P=0.004) at 12 months after treatment (fig 3⇓).13 A similar improvement in side effects was seen in a randomised controlled study for patients with nasopharyngeal cancer.14

Fig 3 Dosimetry planning for a patient being treated with intensity modulated radiotherapy. The diagram shows the doses of radiotherapy delivered to each organ. Through use of sophisticated planning and delivery methods, this technique enables the one parotid gland (arrow) to be spared high doses of radiotherapy

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Large randomised controlled studies have shown improvements in local tumour control with accelerated radiotherapy (radiation delivered over a shorter time period) or hyperfractionated radiotherapy (delivery of a higher dose of radiation in two to three low dose fractions a day).15 These treatments have not shown consistent improvements in overall survival, but have resulted in increased short term mucosal toxicity; they have therefore not been adopted widely outside of North America.

Newer developments using particle therapy, such as proton therapy or stereotactic radiotherapy, may spare particularly radiosensitive organs close to tumours (such as the brain and spinal cord). However, these new technologies, especially proton therapy, are not yet widely available, their benefits have not been proved, and they cost considerably more than standard radiotherapy techniques.

Recent advances in chemotherapy

In a large meta-analysis of 93 trials and more than 17 000 patients, concomitant chemotherapy (given during radiotherapy) was shown to improve locoregional control rates and was associated with a 6.5% increase in survival (P<0.0001). The benefits were largely confined to chemotherapy given during radiotherapy rather than in the adjuvant or neoadjuvant setting. In addition, combining chemotherapy with radiation improves the rates of organ conservation. Cisplatin chemotherapy schedules were the most effective.16 ^{w16 w17}

Two randomised controlled trials have shown that concomitant use of cisplatin and radiotherapy after surgery increases tumour control and overall survival in high risk patients with positive resection margins or extracapsular lymph node spread.17 18

Recently, the concurrent administration of cetuximab, an antiepidermal growth factor receptor antibody, with radiotherapy, was shown to increase overall survival and locoregional control in patients with squamous cell carcinoma of the head and neck in a large randomised controlled trial.19 ^w18 This was the first time that a biologically targeted treatment was shown to be effective in the treatment of head and neck cancer.

Although concomitant chemotherapy has been shown to improve outcomes for head and neck cancer, the role of neoadjuvant chemotherapy (chemotherapy given before start of radiotherapy) remains controversial. Two recent phase II and phase III randomised studies suggested that the addition of docetaxel to cisplatin and fluorouracil given before definitive radiotherapy improved survival. However, the use of non-standard radiotherapy and chemoradiation schedules in these trials has led to uncertainty about the benefits of this approach when standard chemoradiotherapy is prescribed.20 21

Surgical complications

Surgical procedure times vary from one to 12 hours, and patients often have a high burden of concurrent medical illness. These patients are prone to complications arising from prolonged anaesthesia, such as pulmonary consolidation and deep venous thrombosis. Depending on the nature of the procedure, patients may also be at increased risk of postoperative aspiration and its consequences. Although it is not a complication, the end stoma resulting from laryngectomy may affect patients’ activities of daily living because of problems with body image and the need for daily tracheo-oesophageal valve care to maintain speech through the valve.

Because most surgical procedures are of the clean-contaminated variety, where the oral or pharyngeal lumen is opened at some point in the procedure, case series report postoperative surgical site infection rates of 20-40%.^{w19 w20}

Other early complications include haemorrhage from major vessels and wound breakdown, the last of which is especially common in patients who have had radiation before surgery. In a prospective study of the outcome of surgical salvage of failed chemoradiotherapy for laryngeal cancer in patients from a randomised controlled trial, a third of patients developed a salivary fistula into the neck.22 Rarely, injury to the lymphatic duct on the left side of the neck can lead to a lymph leak that can take up to a few weeks to settle.

Surgery can injure or require sacrifice of important neuromuscular structures to ensure tumour clearance. Injury to the spinal accessory nerve, which leads to shoulder dysfunction, and removal of the sternocleidomastoid muscle, which causes loss of contour to the neck, may also occur. Other cranial nerves (VII, X, and XII) and the sympathetic chain are also prone to injury depending on the extent of the tumour. Although microvascular free flap reconstructions have a consistently high success rate (>95%), failure of a flap can have considerable complications that can lead to prolonged hospital stay and a delay in any planned postoperative radiotherapy.

In the longer term, patients present with functional problems such as impaired swallowing and speech and voice problems, or weak shoulder. They may have to care for an end stoma. These sequelae will require input from various health professionals to achieve rehabilitation.

Complications of chemoradiotherapy

Acute complications of radiotherapy to the head and neck region include radiation dermatitis, xerostomia, excessive mucus production, and painful mucositis. Consequently, patients often reduce their intake of food and liquids and some may require nasogastric feeding or percutaneous gastrostomy to maintain adequate nutrition. The addition of concomitant chemotherapy may exacerbate the severity and duration of these acute effects. The acute effects of radiation typically settle four to six weeks after treatment is completed.

Serious late radiation toxicity is seen in as many as 82% of patients at five years,23 and it may include xerostomia, fibrosis of soft tissues, dysphagia, and osteo-radionecrosis of the mandible.23 These complications are important because they are usually permanent. Some, like xerostomia, improve over time,13 but others, such as pharyngeal stenosis, are occasionally progressive and sometimes resistant to treatment. Minimising the volume of the tissues receiving radiotherapy (for example, by sparing salivary glands or bone) can reduce the rate of these complications, as shown in the PARSPORT trial.13