|KEY NOTE ADDRESS
|Year : 2016 | Volume
| Issue : 2 | Page : 50-58
A century of progress in head and neck cancer
Jatin P Shah
Professor of Surgery, E W Strong Chair in Head and Neck Oncology, Memorial Sloan Kettering Cancer Center, New York, USA
|Date of Web Publication||20-Dec-2016|
Jatin P Shah
Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY. 10065
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Shah JP. A century of progress in head and neck cancer. J Head Neck Physicians Surg 2016;4:50-8
Delivered at the joint meeting of the Foundation for Head and Neck Oncology (FHNO), and the World Tour program of the International Federation of Head and Neck Oncologic Societies (IFHNOS), at New Delhi, on Oct 12, 2016.
| Introduction|| |
Head and neck cancer is the 6 th most common cancer worldwide. It is more prevalent in certain regions of the world where consumption of tobacco in any form is very common. For example, consumption of chewing tobacco in South Asian nations has resulted in the highest incidence of oral cancer in these populations. Head and neck cancer is thus a major challenge for the medical profession since it not only leads to loss of life for those affected by the disease, but also causes a significant impact on the form and function of the afflicted individual and has an indirect impact on their families and society. In the past century, however, great strides have been made in the improvement of cure rates for this disease and more importantly in the improvement of quality of life of patients suffering from head and neck cancer. Hundreds of major publications in literature are a testament to the continuing advances in this specialty. These advances range from improvement in surgical techniques, and integrating technological advances in surgery, to the application and integration of radiation therapy (RT) in multidisciplinary treatment programs and continuing evaluation and introduction of new drugs in the treatment of these tumors. Coupled with the therapeutic advances are major strides in understanding the biology of head and neck cancer and advances in basic research, particularly in the field of genomics of these tumors, and the study of mutations identified in these tumors to detect, treat, and prevent these devastating human neoplasms. To summarize all the advances made in the past century in one manuscript would be an impossible task. Even one volume of publication cannot accommodate all the important advances that have been made in the specialty of head and neck cancer.
| The Process of Selection of Important Advances|| |
The first clinical service dedicated to the treatment of patients with head and neck cancer was established at Memorial Sloan Kettering Cancer Center in 1914. On its centennial celebration, an attempt was made to review all the major advances made in the field of head and neck cancer and publish it in a summary format called, "A Century of Progress in Head and Neck Cancer."  This volume contains 100 abstracts and commentaries on the impact of these contributions in the specialty by contemporary experts. This compendium covers few selected topics of clinical relevance in the field of head and neck cancer. Clearly, this is an overview of major paradigm-shifting contributions and introduction of new concepts by contributors during the past century. This compilation by no means is a complete report on major advances made in the specialty of head and neck oncology but an overview of selected publications worthy of inclusion in the view of the editors.
The specialty of head and neck cancer was divided into approximately twenty topics. Leading experts in the field were then polled to recommend ten best publications in the topic assigned to them. A total of 2100 manuscripts were recommended. An Editorial Committee of eight leaders in the specialty were then asked to pick out ten best articles per topic, trimming the list to 200 articles. The editors then selected 100 most important contributions of clinical relevance to include in the book. The current article includes a few selected advances from these which have impacted on how we provide clinical care today. The highlights from these are presented here.
| Biology, Epidemiology, and Risk Factors|| |
The concept of "Field cancerization in oral stratified squamous epithelium and its clinical implications of multicentric origin" was published by Slaughter in 1953 where he reviewed 783 squamous cell carcinomas of the oral cavity, lip, and pharynx and showed multifocal growth of tumors and concluded that foci of neoplasia grow independently, had a lateral spread rather than deep infiltration, and margins had abnormalities ranging from atypia to carcinoma in situ.  The role of alcohol and tobacco in multiple primary cancers of the upper aerodigestive tract, larynx, and lung was demonstrated in a prospective study conducted by Schottenfeld et al. in 1974. This prospective study included 733 patients with squamous cell carcinoma of the head and neck, showing a 7.3% incidence of second primary cancer within 6 years. The average annual incidence of second primary was 1.8% in men and 1.5% in women. The increased risk of second primary tumor was shown with combined exposure to tobacco and alcohol prior to index cancer.  Gupta et al. in 1980 reported on the incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Fifty thousand villagers were screened and followed up for an average of 7 years. They reported an oral cancer incidence rate of 45/100,000. They also showed that the highest risk of leukoplakia in the oral cavity was demonstrated in persons with the habit of chewing tobacco. The rate of transformation for leukoplakia to cancer was 7% or 1% per year of follow-up.  These observations paved the way for a study by Sankaranarayanan et al. in 2005, showing improved survival with early detection.  Doll and Peto reported on the causes of cancer and quantified estimates of avoidable risks of cancer in the United States. In their study from 1970 to 1975, they reported that 80% of cancer deaths may have been preventable by avoidance of modifiable risk factors. Up to 30% of cancer deaths were due to tobacco, and alcohol consumption accounted for 7% of cancer-related deaths in male and 3% in female. 
| Staging|| |
The concept of developing a staging system for cancer to include factors related to the primary tumor (T), regional lymph nodes (N), and distant metastases (M) was first introduced by Denoix in 1944.  This staging system has stood the test of time and remains an important tool for the current staging of most cancers. Inclusion of comorbidity in a staging system for head and neck cancer was proposed by Piccirillo, who used conjunctive consolidation to incorporate comorbidity into the staging system. This accounted for performance status, symptom severity, and comorbidity. He concluded that adding comorbidity improved prognostication over tumor, node, and metastasis (TNM) staging alone.  A comparison of published head and neck stage groupings in cancer of the oral cavity was reported by Groome et al. in 2001. They tested the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) and seven other staging systems for the estimation of prognosis and comparison of therapies in oral cancer. The parameters of comparison were hazard consistency, hazard discrimination, outcome prediction, and balanced distribution. They concluded that the TNM staging system could be improved using empirically derived schemes. 
| Paranasal Sinuses, Skull Base, and Paragangliomas|| |
Improvement in the outcomes of surgery for tumors of the paranasal sinuses and ethmoid region was not observed over several decades in the first half of the past century, due to the proximity or invasion of skull base by these tumors. Pioneering work by Ketcham et al., who described a combined intracranial facial approach to the paranasal sinuses, was reported in 1963. They reported a significant improvement in local control and survival. Their experience paved the way for skull base surgery worldwide.  In a review of 100 cases of temporal bone resection, Lewis reported innovative techniques using hypotensive anesthesia, high-speed drills, and repair of the surgical defect, reducing operative mortality to 5%. He achieved a 5-year cure rate of 27%, double that of achieved by RT.  Surgery of the lateral skull base was pioneered by Fisch et al., who described the infratemporal fossa approach, with its three variations based on the location of the lesion. Their approach addressed the petrous carotid artery, the venous sinuses, and the facial nerve.  In an international collaborative study of anterior craniofacial resections in 1307 patients, Patel et al. reported a 60% 5-year disease-specific survivorship, with an operative mortality of 4% and a complication rate of 30%. Their results provided benchmark data and showed that the histology of the primary tumor, its intracranial extent, and the status of margins of resection were independent parameters of prognosis on multivariate analysis. 
| Paragangliomas|| |
The first systematic and large study of carotid body tumors describing its behavior, diagnosis, and management was reported by Shamblin et al. who hinted observation as a logical approach. They classified tumors into three categories, and Shamblin's classification of carotid body tumors remains the gold standard in the management of patients with chemodectomas of the carotid body. Their classification provides selection of patients for safe surgery versus hazardous and debilitative surgery or even mortality from operation. This is a valuable contribution for selection of patients for safe surgery in these difficult tumors.  Observation rather than surgery was reported by a Dutch group showing normal life expectancy for paraganglioma patients in a 50-year-old cohort study. This study by De Flins et al. shifted paradigms in the management of paragangliomas of the head and neck. Observation rather than disabling surgery causing cranial nerve deficit offered equal long-term survival and quality of life. This paradigm shift is now the standard of care for paragangliomas of the lower cranial nerves. 
| Skin Cancer and Melanoma|| |
The groundbreaking work of Frederick Mohs in chemosurgical treatment of cancer of the skin, a microscopically controlled method of excision first reported in 1948, shifted the paradigms in the management of small skin cancers. This seminal paper on chemosurgery in 814 cases showed cure rates better than the standard wide excision or radiation at that time. He showed that reliable tumor control can be achieved with tissue-sparing surgery.  This paradigm-shifting report led to the development of micrographic surgery for skin cancers practiced worldwide today. The importance and prognostic outcome of perineural invasion in squamous cell carcinoma of the head and neck was reported by Goepfert et al. in 1984. They compared outcomes in 520 patients who had squamous cell carcinoma with and without perineural invasion. This landmark study demonstrated worse clinical outcome with perineural invasion, now recognized as a high-risk pathologic feature. They linked perineural invasion of major nerve trunks to the increased risk of nodal metastases, distant metastases, and decreased survival.  Tumor thickness, cross-sectional areas, and depth of invasion in the prognosis of cutaneous melanoma were first reported by Breslow in 1970. His initial hypothesis was to estimate tumor volume by assessing the depth and diameter of cutaneous melanoma. He correlated the prognosis and incidence of nodal metastasis with tumor thickness. He concluded that tumor thickness of cutaneous melanoma is more important than histological depth of invasion.  Tumor thickness is now used as a standard parameter in staging and assessment of prognosis of cutaneous melanoma.
| Oral Cavity|| |
Martin introduced aggressive surgical management of head and neck cancers with advances in anesthesia, blood transfusion, control of infection/antibiotics, surgical instruments, and techniques for safer radical surgery. He ushered in the era of radical surgery and is rightfully called the "father of Head and Neck Surgery."  Whole-organ serial-sectioning studies of surgical specimen of resected mandibles from 46 patients, by McGregor and MacDonald, showed that the nonradiated mandible was involved by oral cancer through the alveolar process. However, in the radiated mandible, tumor invasion can occur both through the alveolar process and the intact lingual cortex. These findings allowed conservative management of the mandible at risk of tumor invasion from oral cancer. 
| Nasopharynx and Oropharynx|| |
Lee et al. reported one of the largest series of nasopharyngeal carcinoma managed under the leadership of Dr. John Ho and Anne Lee in Hong Kong. This retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985 reports the overall survival and patterns of failure. The study provides benchmark data on outcomes and showed the need for elective radiation to the N0 neck. The study also showed that re-irradiation is feasible and provided data for improvement in AJCC and UICC staging systems. This study set the standard for continuing improvement in the treatment and outcomes of nasopharyngeal carcinoma.  The quantification of plasma Epstein-Barr virus (EBV) DNA in patients with advanced nasopharyngeal carcinoma was reported by Lin et al. in 2004. In their study of 99 patients with advanced nasopharyngeal carcinoma, the EBV DNA was detectable prior to treatment in 95% of patients. The EBV DNA concentration reflected the volume of disease pretreatment and the study showed that these levels were either low or undetectable in patients with complete remission of the tumor. Rebound EBV DNA was seen with a relapse of the cancer and they showed that persistent detectable EBV DNA portends lower survival. Thus, EBV DNA is a valuable marker for monitoring response to therapy in nasopharyngeal carcinoma. 
The first report of a causal association between human papillomavirus (HPV) and a subset of head and neck cancers was published by Gillison et al. in 2000. They investigated 253 patients with head and neck cancer and showed that HPV was detected in 25% of patients and high-risk tumorigenic HPV-16 in 90% of HPV-positive patients. These tumors were of poor histological grade, and oropharyngeal primary site was the most frequently reported site. This tumor was more common in nonsmokers and had basaloid histology and better survival. Their report showed that HPV-positive tumors had a 59% reduction in the risk of death from cancer compared to HPV-negative cancer.  A follow-up study to Gillison's groundbreaking report was conducted by Fakhry et al. who showed improved survival of patients with HPV-positive head and neck squamous cell carcinoma in a prospective clinical trial. This was the first prospective trial of HPV-positive and HPV-negative oropharyngeal cancers in an Eastern Cooperative Oncology Group-sponsored phase II trial of 96 patients. Response rates to induction chemotherapy were 82% in HPV-positive patients compared to 55% in HPV-negative patients, leading to a 2-year overall survival of 95% versus 62%. They concluded that HPV status was strongly associated with response to therapy and survival.  HPV positivity and survival of patients with oropharyngeal cancer were reported by Eng et al. in a retrospective analysis of patients included in the Radiation Therapy Oncology Group (RTOG) 0129 trial. This trial compared the accelerated fractionation of radiation versus standard fractionation with chemotherapy in both arms. The report by Ang showed that survival and toxicity were similar in both arms of the study, but survival in HPV-positive and HPV-negative tumors was 82% and 57%, respectively. HPV-positive patients had a 58% reduction in the risk of death. The data from this study allowed defining low-, intermediate-, and high-risk groups based on HPV status, smoking, T-stage, and nodal stage. 
| Larynx and Hypopharynx|| |
Preservation of larynx by nonsurgical means in patients with advanced laryngeal cancer requiring laryngectomy was studied in a prospective trial comparing induction chemotherapy followed by radiation compared to surgery followed by radiation. The Department of Veterans Affairs Laryngeal Cancer trial was reported by Wolfe et al. in 1991. This was a prospective randomized trial of 332 patients with Stage III and IV laryngeal carcinoma comparing three cycles of chemotherapy followed by radiation versus surgery followed by radiation. The larynx was able to be preserved in 64% of patients in the study arm, but the 2-year survival of 68% was comparable in both arms. This study introduced the concept of organ preservation with addition of chemotherapy to radiation.  Larynx preservation in pyriform sinus cancer was reported in a phase III trial of the European Organization for Research and Treatment of Cancer of larynx preservation in 202 patients with hypopharyngeal carcinoma, with induction chemotherapy followed by radiation alone in patients with complete response compared to surgery and postoperative RT. Complete response was seen in approximately 52% of patients in the induction arm; however, the median survival was equivalent. Functional larynx preservation was possible in 35% of patients with complete response in the induction chemotherapy arm at 5 years.  The RTOG 91-11 trial of concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer was reported by Forestiere et al. in 2003. This was the first study comparing induction chemotherapy followed by radiation to concurrent chemoradiation to radiation alone in a randomized trial of 547 patients. Larynx preservation could be achieved in 84% of patients receiving concurrent chemotherapy compared to 72% in induction arm and 67% in radiation alone arm. Concurrent chemoradiotherapy thus became the standard of care for larynx preservation.  An endoscopic technique for restoration of voice after laryngectomy was first reported by Singer and Blom in 1980. Diversion of pulmonary air to pharynx for speech production after laryngectomy was largely unsuccessful in the past. An endoscopic technique using unique valve prosthesis was described in sixty patients with a 90% achievement of fluent speech. Tracheoesophageal puncture and valve prosthesis thus became standards of care after laryngectomy for voice rehabilitation. 
| Cervical Lymph Node Metastases|| |
The results of surgical management of cervical lymph node metastases with improved outcomes were first reported in a paper published by Crile entitled, "Excision of cancer of the head and neck with special reference to the plan of dissection based on 132 operations" in 1906. In this manuscript, he shows technical details of the operation illustrated by drawings. His concept was to remove in a comprehensive manner a "zone of lymphatic spread" in a monobloc fashion. Radical neck dissection became the standard of surgical care for neck metastases thereafter.  The cytologic diagnosis of metastatic cancer in a lymph node was first reported by Martin and Ellis in 1930 by aspiration using a needle and syringe, achieving an accuracy of 60%. This practice has now been universally adopted, and fine needle aspiration cytology of a neck mass is the standard of care to establish tissue diagnosis.  The importance of extracapsular spread (ECS) of tumors in cervical node metastasis was first reported by Johnson et al. in 1981. Their retrospective study of 177 radical neck dissection specimens showed that 65% of lymph nodes under 3 cm had ECS. Patients with ECS had a poor survival, and ECS was an independent prognostic feature. They proposed that the ECS should be incorporated into the AJCC/UICC staging system.  Extra nodal spread is now included in the latest revision of the Nodal staging system by AJCC. The patterns of cervical lymph node metastasis from squamous cell carcinoma of the upper aerodigestive tract were reported by Shah in 1990. He studied the distribution of metastatic carcinoma in 1019 neck dissection specimens and reported patterns of neck metastasis for each primary site. A select group of nodes are at a risk of initial involvement and skip metastasis are rare. The observations of this study provided data to support the use of selective neck dissections to avoid morbidity of radical neck dissection. 
| Reconstructive Surgery|| |
Bakamjian introduced a two-stage method of pharyngoesophageal reconstruction with a primary deltopectoral (DP) skin flap in 1965. He introduced the concept of primary reconstruction of pharyngoesophageal defects with pectoral skin. The DP flap was medially based and tubed for pharyngeal reconstruction. The reconstruction could be completed in only two stages over 3-5 weeks. The DP flap was the workhorse for pharyngeal reconstruction for nearly 15 years thereafter.  Ariyan in 1979 first described the anatomy of the blood supply to the pectoral skin and was the first to demonstrate the technique of raising the pectoralis major myocutaneous flap and its various applications in immediate reconstruction in the head and neck. The pectoralis major myocutaneous flap became the mainstay of immediate reconstruction in the head and neck in the 1980s.  The radial forearm-free flap, a versatile method for intraoral reconstruction, was first reported by Soutar et al. in 1983 in the English literature. The report described vascular anatomy and technical details of radial forearm-free flap for oral cavity reconstruction. They also described osteocutaneous flap with the radius. The radial forearm-free flap revolutionized oral cavity reconstruction.  It remains currently the workhorse for soft tissue and lining in the oral cavity reconstruction. Hidalgo first reported on the technique of fibula-free flap reconstruction on 12 patients in 1989 and showed that osteotomy of the fibula was possible to create the shape of the mandible. He used native mandibular condyle on fibula to create temporomandibular joint. Introduction of fibula-free flap by Hidalgo set the standard of mandible reconstruction for the past 30 years.  In a series of 672 anterolateral thigh (ALT) flaps employed between 1996 and 2000, Wei et al. described their experience of using the ALT flap in head and neck, extremities, and trunk. The flap provided reliable vasculature on septocutaneous perforators and described the flap as a versatile flap multifaceted to reconstruct a variety of defects. 
| Thyroid, Parathyroids, and Salivary Glands|| |
Relationship of the age of the patient to the natural history and prognosis of carcinoma of the thyroid was first reported in 1953 by George Crile Jr et al. They reported different outcomes in patients under the age of 40 compared to those over the age of 60. They described papillary and nonpapillary cancers of the thyroid gland and reported a poor histology in older patients.  Thus, age became the most important prognostic factor and was employed in staging of thyroid cancer in the subsequent years. The patterns of failure in differentiated thyroid carcinoma based on risk groups were reported by Shaha et al. who described low-, intermediate-, and high-risk groups based on the known prognostic factors in over 1000 patients followed for 20 years. Intermediate-risk group consisted of young patients with bad tumors and older patients with good tumors. Recurrence and disease-specific survival were very low in the low-risk group and quite high in the high-risk group. A risk stratified approach to treatment and follow-up was recommended.  The risk of second primary malignancies in thyroid cancer patients receiving radioactive iodine was reported by Rubino et al. in 2003. Pooled data from Swedish, French, and Italian cohorts were analyzed to report the late effects of radioactive iodine. A 27% increased risk of second primary malignancy was observed with increasing doses of radioactive iodine. The increased risk was for leukemia and solid tumors including bone and soft-tissue sarcomas, colorectal and salivary gland tumors.  Irwin et al. reported on operative monitoring of parathyroid gland hyperfunction and introduced intraoperative monitoring of parathyroid hormone (IOPTH) with immunoradiometric assay. They introduced the concept of not exploring four glands and minimally invasive parathyroidectomy (MIP) in patients with a single adenoma. This report revolutionized surgery for primary hyperparathyroidism and made MIP with IOPTH the standard of care. 
One of the largest reports on salivary gland tumors of 2807 patients over a 35-year experience was published by Spiro in 1986. Outcomes data with reference to the location, stage, histology, grade, and treatment were presented. These data became reference points for future publications in the management of salivary gland neoplasms. These publications on salivary tumors provided benchmark data on the outcomes of surgical management. 
| Radiation Oncology|| |
The role of radiotherapy in the management of squamous cell carcinoma of the supraglottic larynx was reported by Fletcher et al. in 1970 based on the treatment of 267 patients with carcinoma of the supraglottic larynx treated at MD Anderson Hospital. This manuscript defined the indications for postoperative RT and its benefits in improving locoregional control. It also showed differences between aryepiglottic fold lesions and false vocal cord lesions and refined the techniques of radiation delivery, precise data recording and reporting, radiobiology and time-dose factors, and preservation of larynx function.  The results of RTOG 9003 phase III randomized trial of hyperfractionation versus accelerated and standard fractionation were reported by Fu et al. in a series of 1073 patients. Hyperfractionation and accelerated fractionation with concomitant boost had better local-regional control and showed a trend toward improved disease-specific survival, but overall survival was similar for all the four arms. Acute side effects were noted to be higher. 
| Combined Modality Treatments|| |
The last quarter of the past century was an exciting period, where an increasing number of major studies combining various treatment modalities showed significant improvement in outcomes. Chemoradiotherapy versus radiotherapy alone in patients with advanced stage nasopharyngeal carcinoma was reported by Al-Sarraf et al. in a randomized trial (intergroup phase III trial 0099). High-dose cisplatinum was used on day 1, day 22, and day 43, showing 3-year progression-free survival of 69% compared to 24% and an overall survival of 78% versus 47% in the control arm. This study showed that chemoradiotherapy was superior in terms of progression-free survival and overall survival for advanced stage nasopharyngeal carcinoma.  A meta-analysis of 63 clinical trials including 10,741 patients treated between 1965 and 1993 of locoregional treatment with or without chemotherapy was reported by Pignon et al. in 2000. The pooled hazard ratio of death was 0.9, and absolute survival benefit was only 4%. Concomitant chemoradiation was felt to be superior to neoadjuvant chemotherapy. In three larynx preservation trials, the hazard ratio in the chemotherapy arm was 1.19.  The value of epidermal growth factor receptor (EGFR) inhibitor cetuximab was reported in a phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic head and neck cancer by Burtness et al. in 2005. This study showed that the progression-free survival improved to 4.2 months compared to 2.7 months and a median overall survival of 9.2 months versus 8 months. Response rate of 26% was observed compared to 10% in the control arm. This study defined the role of targeted anti-EGFR agent cetuximab in the treatment of head and neck cancer.  A randomized trial of induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) versus cisplatin and fluorouracil (PF) followed by chemoradiation reported by Posner et al. in 2007 studying 501 patients with Stage III and Stage IV head and neck carcinoma showed an overall 3-year survival of 62% versus 42% in the control arm. Median overall survival was 71 months compared to 30 months in the control arm with improved local-regional control. Thus, induction chemotherapy with TPF was felt to be superior to PF.  Platinum-based chemotherapy (cisplatin + 5 fluorouracil [5FU]) plus cetuximab in head and neck cancer was studied in a randomized trial including patients with untreated, recurrent or metastatic carcinoma in a group of 442 patients with head and neck cancer, where a response rate of 36% compared to 20% in the control arm was observed. The overall median survival improved from 7.4 months to 10.1 months. This study highlighted the utility of targeted therapy in recurrent or metastatic head and neck carcinoma. 
| Basic Research|| |
The contributions from basic research in understanding the pathobiology of head and neck cancers are too numerous to cite in this brief presentation. Clearly, numerous important advances have been made in understanding etiology, risk factors, and the biology of progression of squamous cell carcinoma of the head and neck. However, three recent publications have paved the way toward improved understanding of progression of squamous cell carcinoma in the mucosa of the upper aerodigestive tract, introduction of the role of EGFR in squamous cancer, and whole exome sequencing of squamous carcinoma. Califano et al. studied genetic aberrations in a spectrum of lesions, including benign lesions, dysplasia, in situ carcinoma, and compared them to known mutations in invasive carcinoma. Their observations formed a framework for today's understanding of a progression model of genetic abnormalities, leading to invasive carcinoma. These observations have clear implications for field cancerization.  Rubin Grandis et al. reported on the levels of transforming growth factor (TGF) alfa and EGFR protein in head and neck squamous cell carcinoma and patient survival in 1998. They quantified TGF alfa and EGFR in surgical specimens and correlated with outcomes in patients. They showed that expression level of EGFR and TGF alpha is the strongest predictor of disease-free survival and cancer-specific survival. This observation paved the way for targeted therapy by tyrosine kinase inhibitors (TKIs) and EGFR antibodies.  Finally, exome sequencing of head and neck squamous cell carcinoma revealed inactivating mutations in NOTCH 1. This report by Agrawal et al. in 2012 was based on whole exome sequencing of 32 tumors to identify genetic abnormalities in head and neck squamous cell carcinoma. They showed that NOTCH 1 mutations function as tumor suppressor genes and identified Tp53, CDKN2A, PTEN, PIK3CA, HRAS, and FBXW7 mutations and their role in squamous carcinoma. 
| Quality of Life|| |
Quality of life in patients with head and neck cancer was studied and reported by Weymuller et al. in their publication in 2002, indicating lessons learned from 549 prospectively evaluated patients. Following a series of previous studies, this article reports on the global quality of life score versus domain-specific quality of life score, studied in oral cavity, oropharynx, larynx, and hypopharynx cancer patients. This led to the development of the University of Washington Quality of Life Questionnaire and provided tips and advice for future quality of life studies.  Morton studied the quality of life in head and neck cancer patients in a 2-year study comparing cross-sectional, cross-cultural groups in a survey for over 30 years. He did a comparative cross-cultural study between Toronto and New Zealand and compared the quality of life outcomes in relation to treatment and culture. He showed cross-cultural differences in the quality of life. 
| Summary|| |
The past century has been an exciting period during which major advances emerged in every discipline dealing with the etiology, biology, diagnosis, treatment, rehabilitation, and prevention of head and neck cancer. To summarize these major advances, in each of the disciplines, we need to address them by each of the specialty and allied disciplines.
Surgery had been practiced in the treatment of head and neck cancer for nearly two centuries. However, the beginning of the past century ushered in the era of surgery as a definitive means of treating head and neck cancer. By mid-century, radical surgery was introduced due to advances in anesthesia, blood transfusions, and antibiotics. However, over the course of the second half of the past century, quality of life became an important issue and progressively conservative function-sparing surgery became more popular. Over the course of the past two decades, minimally invasive surgical approaches to maximize esthetics and function have played an important role. A vivid example of a transformation from radical surgery to minimally invasive surgical procedure is exemplified in the management of cervical lymph node metastases. We have transitioned from radical neck dissection to selective neck dissections to sentinel node biopsy. Similarly, function-sparing surgery and minimally invasive surgery have led to the development of transoral laser microsurgery, endoscopic endonasal skull base surgery, and transoral robotic surgery. In the arena of reconstruction, we have advanced from delayed staged reconstruction to immediate reconstruction of major surgical defects. Development of microsurgery and free flap surgery with composite tissue transfer has led to the ability to reconstruct virtually any defect in the head and neck area. There has been increasing attention to preservation or restoration of form and function and increased sensitivity to esthetics in planning surgical procedures.
Advances in radiation oncology have been significant over the course of the past century. With the discovery of radium and its application in cancer treatment, a new era was ushered in. The rapid transition from low-voltage superficial X-ray to super voltage linear accelerator with photons and the introduction of electrons, neutrons, protons, and particle therapy continue to improve the outcomes from radiotherapy, with reducing the sequela of treatment. Similarly, there have been significant advances in the development of radiation delivery systems from radium plaques and needles to radon seeds to superficial and deep X-rays using parallel opposing ports to conformal RT and 3 dimensional treatment planning. The past quarter of the century saw the development of intensity-modulated RT, image-guided RT, and the development of protons and intensity-modulated proton therapy, and in the very foreseeable future, we are looking forward to the clinical application of carbon ion particles.
Development of new drugs continues to advance the field of medical oncology over the course of the second half of the past century with the introduction of nitrogen mustard during the Second World War and the subsequent introduction of methotrexate, bleomycin, vincristine, doxorubicin, cisplatinum, 5FU, taxanes, anti-EGFR agents, TKI, and mitogen-activated protein kinase inhibitors and targeted agents as well as immune modulators such as anti-PD1, PDL1, and anti-CTLA 4 agents. Similarly, the drug administration focus has changed from palliative chemotherapy to adjuvant chemotherapy to induction chemotherapy and eventually to concurrent chemotherapy with radiation and administration of targeted agents and immunotherapy. Advances in allied disciplines such as pathology, radiology, nuclear medicine, dental oncology and prosthetics, rehabilitation medicine, quality of life and support services, nursing, social services, patient support groups, and internet-based resources have kept pace with advances in therapeutic modalities for head and neck cancer. The biggest advance during the course of the past century is, however, integration of multiple treatment modalities into the development of multidisciplinary care and precision medicine [Figure 1].
Thus, the past century has been an exciting time which has delivered major strides in the understanding of the biology, etiology, diagnosis, treatment, rehabilitation, and prevention of the head and neck cancer. Clearly, these advances have allowed more patients to live longer with better quality of life.
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Conflicts of interest
There are no conflicts of interest.
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