Head and Neck Cancers Management
Head and neck cancers including both nasopharyngeal carcinoma (NPC) and Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most common cancers in Singapore with about 500 cases per year, of which nearly eighty percent are treated at the National Cancer Centre Singapore (NCCS). Although the term head and neck cancer comprises cancers of different etiology and from different subsites, they do share a common anatomical region, which is characterised by a plenitude of crucial structures with vital physiological function (e.g. swallowing, breathing, facial expression) packaged into a very small confined space that is aesthetically important. This unique relation between space, function and aesthetics accounts for the gravity of symptomatology caused by the tumour, as well as, the possible deleterious effects of the prescribed treatment. As such, the management of Head and Neck Cancers demands careful consideration of the extent of tumour involvement, the best treatment option and its oncological outcome, possible functional impairment and aesthetic effect. This complex task is best undertaken by a team of experts comprising surgical oncologists, medical oncologists, radiation oncologists, radiologists, plastic surgeons, maxillofacial prosthodontists, dentists, physical therapists, speech therapists, nurses, dietitians and social workers. This multi-disciplinary approach underpins the management philosophy of every head and neck cancer managed in NCCS.
What is New?
Radiotherapy
Improvement in computer technology and innovation has contributed to many of the recent advances in the field of radiotherapy. For instance, the availability of faster computers has made intensity-modulated radiotherapy (IMRT) possible. With multiple fields IMRT, radiation oncologists can now manipulate radiation beams that can contour around the tumour providing precise targeted therapy with minimal collateral damage to important organs and tissues such as spinal cord and orbit.
At the NCCS, nasopharyngeal cancer (NPC) patients are treated using IMRT as a standard radiotherapy treatment. In addition, patients in the advanced stage and who are fit also have concurrent chemotherapy to further improve disease control as has been demonstrated in a randomised trial that we have recently conducted and published in Journal of Clinical Oncology (fig. 1)[1]. We have also established ourselves as one of the main treatment centres in the world contributing to good trial data on NPC.
Recently, image-guided radiotherapy (IGRT) has added an additional dimension to the already impressive 3-D nature of IMRT, that of the dimension of ‘time’. Before treatment, the exact location of the tumour is ascertained by imaging (by X-rays or with CT). Instead of only a single snap shot in time, with IGRT, the patient is imaged continuously at all points in a complete respiratory cycle so that the full extent of all body and organ movements are captured for planning in the computer. Using sophisticated techniques like respiratory gating and fiduciary markers, these machines will shoot only when the tumour moves into the parameter coordinates within the treatment field. This allows consistent delivery of radiation to the targeted area taking into consideration minute movement of tissue during respiratory cycle. This enables the radiation oncologist to minimise toxicity, and increase precision without sacrificing tumour control.
Looking into the future, NCCS is looking into building a proton therapy facility. The use of particle therapy (in this case proton) has the advantage that it has a very narrow Bragg peak, which minimises damage to surrounding normal tissue and thus for the reasons mentioned above, is particularly useful in the treatment of head and neck cancer.
Molecular Targeted Therapy
The increased understanding of the molecular biology of Head and Neck Cancer has led to efforts to develop compounds that target these molecular pathways. The epidermal growth factor receptor (EGFR) and its ligands {epidermal growth factor (EGF) and tumour growth factor (TGF-á) are fundamental for cell proliferation, motility, adhesion, invasion and angiogenesis.
Interestingly, these receptors are over-expressed up to 90% of HNSCC. One of the EGFR antibodies, cetuximab, has shown great promise in the treatment of recurrent or metastatic HNSCC in combination with cisplatin and 5-FU [2]. Equally, it has been shown to increase overall survival of advanced HNSCC when used in combination with radiotherapy compared to radiotherapy alone (Fig 2) [3]. In other words, there is level I evidence that cetuximab has the ability to potentiate the effect of both chemotherapy and radiotherapy. Importantly, this was achieved without significantly increasing the treatment toxicity. It will be therefore be most interesting to see if EGFR antibody can enhance the efficacy of concomitant chemoradiation. To specifically address this question, NCCS has initiated an international multi-center Phase III, double-blind, placebo-controlled trial to compare post-operative adjuvant concurrent chemoradiotherapy with or without nimotuzumab (a new generation EGFR receptor antibody) for stage III/IV head and neck squamous cell cancer. This NMRC sponsored trial has 22 participating centers from 12 different countries to accrue 710 patients and will interrogate the role of EGFR antibody in the setting of post-operative adjuvant therapy. We envisage that the trial will open towards the end of 2009. The successful execution of a trial of this magnitude will further cement NCCS role as an important trial centre for head and neck cancer globally.
Imaging – The Evolving Role of PET
PET imaging exploits the glucose metabolic pathway, through the use of the most commonly used PET radio-tracer [F-18] fluoro-deoxyglucose (FDG). Various molecular derangements in malignant cells, including increased glycolytic rates and upregulated glucose transporters, result in increased cellular uptake of FDG. A FDG-PET scan can detect and localise such abnormal concentrations of FDG.
In NCCS, we perform many oncologic PET/CT imaging which combines PET with CT within a single scanner. PET/CT has been used to 1) attain diagnosis, 2) evaluate staging, 3) assess response to chemotherapy/radiotherapy in head and neck cancer and 4) detect disease recurrence. In terms of attaining diagnosis, PET/CT is particularly useful in the clinical setting of cervical lymph node metastases with ‘unknown’ primary. This functional imaging technique can detect small volume or submucosal lesions that may be missed in pan-endoscopy and structural imaging technique such as CT and MRI. To accurately determine the tumour staging is important not only to prognosticate but also helps decide on the type of treatment prescribed. As a whole body imaging technique, PET/CT is invaluable in the detection of distant metastases. It is also very useful to help determine the nature of cervical lymph nodes that are of borderline significance by size criteria in structural imaging. In the setting of post-chemo/radiotherapy, PET/CT is normally performed 8-12 weeks after the completion of treatment and has been shown to have very high negative predictive value. In other words, if PET/CT post-treatment showed no SUV uptake in the primary tumour site or cervical lymph nodes, the patient is likely to have complete response even if clinical examination and structural imaging may suggest remnant unresolved mass. Similarly, PET/CT can be useful in detecting recurrences posttreatment particularly in patients with post-radiation fibrosis that render clinical examination difficult or where the interpretation of structural imaging are difficult due to altered anatomy.
Role of Surgery
Surgery remains the treatment of choice for cancer of the oral cavity. It is also the first line treatment in advanced tumours of the larynx or hypopharynx where organ preservation is no longer an option. In oropharyngeal cancer that has invaded the mandible, surgery is again the best treatment option for attaininglocal control. Over the last two decades, the progress made in microvascular techniques and the evolution of free flaps, have ‘liberated’ the hands of surgical oncologists who can now attempt more extensive resections with wide surgical margins that were previously difficult to close.
Laryngeal Conservation Surgery:
The advent of transoral endoscopic laryngeal surgery has opened up debates in the management of early laryngeal carcinomas, an entity that was conventionally treated with radiotherapy. Recent reports from large series of early laryngeal carcinomas that underwent endoscopic laser resection showed local control in the region of 90% [4]. This is comparable with outcome of treatment by radiotherapy from historical data. Furthermore, in the event of local recurrence after initial resection, there is an option for re-excision either by endoscopic laser surgery or open partial laryngectomy. Alternatively, it is still possible to attempt radiotherapy to achieve tumour eradication without sacrificing the larynx. In contrast, in patients previously treated by radiotherapy upfront, salvage organ preservation surgery could be difficult. This is partly because post-radiation recurrences in HNSCCs, tend to be multi-focal and sometimes sub-mucosal and thus mandate a wider margin of excision, which would make organ preservation difficult [5]. However, radiotherapy confers better voice quality post-treatment whilst the voice quality can be unpredictable after organ preservation surgery. As such, both radiotherapy and surgery clearly have their place in the organ preservation protocol of early ca larynx. Figure 3 outlined the treatment paradigm schematically.
Salvage Surgery:
As concomitant chemoradiation becomes the standard of care in the non-surgical management of advanced Head and Neck Cancer, the role of salvage surgery after failed chemoradiation will be increasingly important. Total laryngectomy for laryngeal carcinoma that recurs after chemoradiation is probably the most commonly performed salvage surgery and, in most studies, has shown good loco-regional control. Salvage surgery for other head and neck cancers (particularly Ca hypopharynx) are less common and the benefit of extensive surgery (e.g. total pharyngolarygectomy) in a heavily treated field, with tissues at the edge of tolerable toxicity, remains controversial.
However, recent report suggested that in highly selected cases, salvage surgery after failed chemoradiation in nonlaryngeal carcinomas could provide long term survival (40% at 5 year) with acceptable morbidity [6]. A clear and
pragmatic criterion for selecting patients who are most likely to benefit from salvage surgery is the key to reduce unnecessary morbidity and mortality. This should be the theme for future study.
Robotic Surgery:
Another recent development is the application of robotic surgery in head and neck cancer. The precision and the dexterity of the robotic arms make transoral excision of hard-to-reach sites (e.g. nasopharynx, larynx, hypopharynx, and oropharynx) technically feasible. However, this surgical modality remains experimental in most centres and detail study of cost vs. efficacy is required before it can become more widely accepted.
Tumour Biology – The New Frontier
It is hard to fully grasp the impact that advances in molecular biology will have on the management of head and neck
cancer. The discovery of new molecular targets provides new possibilities of treatment. As mentioned above, EGFR targeted therapy is one such example. Other molecular targets such as vascular endothelial growth factor (VEGF) and ErbB2 are also undergoing further evaluation for the treatment of head and neck cancer.
An exciting prospect that molecular biology can offer would be the stratification of patients that would permit prognostication of disease and tailoring of treatment. Kian Ang et al. has demonstrated tumours with EGFR expression above the median level, in a cohort of patients enrolled in a randomised trial, had significantly worse overall survival and disease free survival (Fig 4) [7].
The causal effect between Human papilloma virus and oropharyngeal squamous cell carcinomas has only recently been established [8]. This is an important finding for the following reasons: 1) HPV positive oropharyngeal SCCs tend to be associated with younger patients; with a rising incidence in developed countries and now comprise about 40% of all oropharyngeal SCCs in United States, 2) they are more radiosensitive and carry a better prognoses compared to HPV negative oropharyngeal SCCs and 3) potentially, like HPV associated cervical cancers, they may be prevented by vaccination against the cancer causing strains of HPV.
These are a few examples of how tumour biology can impact on the current paradigm of cancer management. The onus is now on the clinicians to harness the potential benefit that this explosion of new knowledge can provide. This will be the greatest challenge facing head and neck oncologists, or for that matter, any oncologists in the coming decades.
References
1) Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW et al: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005, 23(27):6730-6738.
2) Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D et al: Platinumbased chemotherapy plus cetuximab in head and neck cancer. The New England journal of medicine 2008, 359(11):1116-1127.
3) Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England journal of medicine 2006, 354(6):567-578.
4) Ansarin M, Santoro L, Cattaneo A, Massaro MA, Calabrese L, Giugliano G, Maffini F, Ostuni A, Chiesa F: Laser surgery for early glottic cancer: impact of margin status on local control and organ preservation. Archives of otolaryngology--head & neck surgery 2009, 135(4):385-390.
5) Zbaren P, Nuyens M, Curschmann J, Stauffer E: Histologic characteristics and tumor spread of recurrent glottic carcinoma: analysis on whole-organ sections and comparison with tumor spread of primary glottic carcinomas. Head & neck 2007, 29(1):26-32.
6) Tan HK, Giger R, Auperin A, Bourhis Jean, Janot F, Temam S: Salvage surgery after concomittant chemoradiation in head and neck squamous cell carcinomas - stratification for postsalvage survival. Head & neck 2009 (in press)
7) Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer research 2002, 62(24):7350-7356.
8) D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML: Case-control study of human papillomavirus and oropharyngeal cancer. The New England journal of medicine 2007, 356(19):1944-1956.