HISTORICAL ASPECTS
The evolution of head and neck surgery encapsulates the evolution of a specialty. From the confines of general surgery, otolaryngology, plastic and reconstructive surgery and maxillofacial surgery, the specialty has carved out a niche of its own.
The history of development of head and neck surgery also parallels the developments seen in medicine and surgery such as advances in anesthesia, antisepsis, transfusion and hemostasis; this had led to development of major extirpative procedures.
The brief description that follows is neither exhaustive nor all inclusive, but summarizes various key developments in head and neck cancer therapy.
The earliest mention of cancer dates back to the medical documents of the Edwin Smith Papyrus and the Ebers Papyrus. A description of an “eating ulcer on the gums” treated with a mixture of cinnamon, gum, honey and oil seems to be the first treatment described for oral cancer.1
The Greek Physician Hippocrates (460 bc) was the first to use the term carcinoma and describe skin cancers and its treatment with cautery and caustic pastes. Aurelius Cornelius Celsus (30 ad) treated cancer of the face and lip with excision. Galen in 200 ad advocated the humoral theory of disease and neoplasms due to excess black bile that needed to be treated with diet and purging.2
The medieval age was characterized by a general lack of progression of any scientific developments and it was with the Renaissance (1500–1760 ad) that knowledge started to develop with Vesalius’ anatomical studies. As the use of tobacco reached the European and American continents we find the mention of cancer and also its related treatments.
Table 1 summarizes key milestones and developments in the evolution of head and neck cancer.
EVOLUTION OF HEAD AND NECK SURGERY
Oral Cancer Surgery
As a better understanding of the biology and pathways of spread of oral cancer developed, contributions have been made to access and management of these tumors, which form the principles of current practice. In addition various studies demonstrated the involvement of the mandible in oral cancer and founded the principles of mandible resection in oral malignancies.
It is worthwhile mentioning the early pioneering surgeons and their contributions:
- Lip-split approach with a mandibular division developed by von Langenbeck and Billroth
- Wedge excision for tongue tumors with lingual artery control by von Langenbeck
- Roux described the cervical approach to the oral cavity
- Kocher cervical approach for oral cavity and lateral mandibular osteotomies
- Theodore Billroth described bilateral mandibular osteotomies
Neck Dissection
Management of the neck is an integral part of head and neck surgery of any site. Neck dissection itself is an operation that evolved from a radical surgery (as proposed by Crile and Hayes Martin) to selective neck dissection (preserving function); we are now in the era of superselective neck dissection and sentinel lymph node biopsy.
George Crile was the first person to describe the enbloc resection of the cervical lymphatics in 1906.3 Hayes Martin reported his experience at the Memorial Sloan Kettering Cancer Center from 1928 to 1950 describing radical neck dissections. This was the procedure of choice for clinically positive necks with the sacrifice of the internal jugular vein, spinal accessory and sternomastoid muscle along with the clearance of levels I-V.2
He was not a proponent of prophylactic dissection of the clinically negative neck. Starting in 1938 at Memorial Sloan Kettering Cancer Center, the group published their results of 665 radical neck dissections performed in 599 patients in 1959.4 Due to the extensive morbidity of the removal of the nonlymphatic structures Suarez in 1952, described the modified radical neck dissection preserving the nonlymphatic structures.5 Ballantyne from the MD Anderson Cancer Center demonstrated comparable results of modified radical neck dissection with radical neck dissections with removal of only those lymph nodes having the highest risk of metastases.6 The concept of functional neck dissection developed with the work of Bocca and Suarez in the 1960s and 1970s.
The pioneering clinical evidence that changed the radicality of neck dissection toward a selective approach was the work of Byers from MD Anderson in 428 patients7 and the series of 1,081 patients by Shah from the Memorial Sloan Kettering Cancer Center that studied the progression of cervical metastasis from primaries of the oral cavity, oropharynx, larynx and hypopharynx.8
Thyroid Surgery
Thyroid surgery advances classically reflect the development of our specialty. Initially in the domain of the general surgeon, advances in understanding the anatomy of the parathyroids, the recurrent and external laryngeal nerve, techniques of intraoperative nerve monitoring, imaging and histology acquisition, with high-quality ultrasound, surgery has moved into the head and neck surgeon's armamentarium. From its earliest descriptions in 200 bc for goiter (gutter), with the first surgery being performed in 1646, significant advances and refinements have been made. Kocher, Billroth and Wells made significant contributions in the early century. Rapid strides have been made in the staging system with dynamic risk stratification and personalized approaches in the management of thyroid malignancies.9 Similarly, parathyroid surgery3 made rapid advances with the use of radioimmunometric assays and intraoperative delineation with radionuclide scans.10
Laryngeal Surgery
The initial total laryngectomies were considered highly morbid and thus the role of radiotherapy was envisaged as an excellent alternative. However, radiotherapy had its limitations in advanced cancer. Improvements in the understanding of the anatomy and the lymphatic drainage led Pressman to elaborate the importance of subtotal laryngectomies.11 Open cordectomy, vertical partial laryngectomy, supracricoid laryngectomy and supraglottic laryngectomy were less radical but were able to achieve cure.12,13 With the introduction of the CO2 laser in the 1970 it was demonstrated that oncologic cure rates similar to radiotherapy could be achieved in early lesions. Jako and colleagues from the United States,14 and Kleinsasser and Steiner15 from Germany developed endoscopic laser excision of laryngeal tumors thus creating a paradigm shift in the management approach. Robot-assisted supraglottic laryngectomy with and without CO2 laser has expanded the indication for transoral laryngeal cancer resection.16 Voice restoration after laryngectomy was first described by Singer and Blom in 1980. Tracheoesophageal puncture and valve prosthesis is the standard of care for voice rehabilitation after laryngectomy.17 The future hold exciting scope with the possibility of laryngeal transplantation.
Salivary Gland Surgery
Salivary gland surgery has developed with a better understanding of the anatomy of the facial nerve, intraoperative nerve monitoring, better rehabilitative measures for the paralyzed face (both dynamic and static), histology driven management of the primary and neck, and adjuvant treatment. The role of molecular profiling in recurrent tumors has enabled use of targeted agents. Surgical extirpation of advanced tumors necessitated the use of various lateral skull-base approaches.
Skull-base Surgery
Alfred Ketchum from the National Institute of Health was the first person to describe a craniofacial approach that permitted an enbloc resection of the cribriform plate with the ethmoid complex.18 Subsequently this concept was extended by Terz et al.19 Using the concepts of endoscopic sinus surgery, Kassam, Carrau and Synderman used these to develop transnasal approaches to the management of skull-base tumors.20 Lewis reported innovative techniques with hypotensive anesthesia, high speed drills and repair of the surgical defect reducing operative mortality to 5%.21 Lateral skull-base surgery was advanced by the development of the three Fisch approaches that gave access to lesions in the infratemporal space in relation to the petrous carotid, venous sinuses and the facial nerve.22
Reconstructive Surgery
In the last 40–50 years major strides have been made in reconstructive surgery as this was able to overcome the morbidity associated with extensive ablations, ensure timely commencement of adjuvant therapy and better quality of life and function. From the use of skin grafts, local flaps, diversion conduits, axial pattern flaps, the advent of pedicled flaps such as the deltopectoral and pectoralis major was a major hallmark in head and neck reconstruction.23,24 By the 1970s reconstructive microsurgery had developed as a specialty and was evident in the application of various free flaps in head and neck reconstruction.25-27 Currently, the reconstructive armamentarium is so extensive that one can choose from a reconstructive elevator rather than a reconstructive ladder.
Prosthodontics and Implantology
As the reconstructive armamentarium improved to include free flaps, osseous reconstruction has heralded a new finesse in final outcomes. The use of virtual planning, cutting guides and customized implants has significantly brought in precision, reduced surgical time and enables optimal functional rehabilitation. Primary dental implantation has also been proven to be safe in the settings of adjuvant radiotherapy. Craniofacial implants and obturators are the other aspects of rehabilitation.28
EVOLUTION OF RADIOTHERAPY
This brief description will give insights to the development of radiotherapy in head and neck along with different fractionation schedules and delivery modalities, the details of which will be covered in the relevant sections.
The role of radiation therapy in head and neck cancer emerged in the early 1900s with initially single fraction treatments with subsequent multifraction treatment schedules developed in Europe.29 Advancements were made in the field to incorporate radiation in the postoperative setting in the early 1950s by Fletcher and colleagues at MD Anderson and expanding it to the definitive setting by Million and colleagues (University of Florida) and Wang (Harvard) over the 1960s to 1980s.30 4Fletcher's work defined the indications for postoperative radiotherapy 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 development of protocols enabled its use in organ preservation protocols for tumors of the oropharynx, larynx, hypopharynx and nasopharynx.
The use of radiation was evaluated in different settings in well-designed randomized trials and meta-analysis.
- Altered fractionation: Accelerated repopulation is known to cause locoregional failure in patients experiencing delay in commencement of treatment and in patients with extended overall radiation treatment times. Altered fractionation regimens can be either hyperfractionation or accelerated fractionation. The EORTC trial demonstrated that hyperfractionation in oropharynx improved local control with a strong trend toward improved survival and no difference in late effects.34 Similarly the Danish group (DAHANCA) also reported improved local control at 5 years by 10% for patients treated with 6 fractions per week, but with no difference in overall survival.35 The meta-analysis suggested that altered fractionation regimens delivered without chemotherapy improved locoregional control and survival (6.4% and 3.4%) at 5 years.36
- Concomitant chemoradiation: MACH-NC demonstrated a 5-year 4.5% absolute survival benefit of adding chemotherapy to radiation which was most evident in the concurrent setting, with a 6.5% absolute benefit (HR 0.81, 95% CI 0.78–0.86).37
- Postoperative chemoradiotherapy: Randomized trials conducted by the EORTC and RTOG demonstrated an improvement in local control, disease free survival and overall survival with the addition of cisplatin to postoperative radiotherapy. The presence of positive margins and extranodal extension of tumor were the common indications.38-40
Refinements in Radiation Delivery
From the initial two dimensional clinical and plain radiograph-based findings that would delineate the regions for risk to deliver radiotherapy, progress has been made to three dimensional CT-based conformal approaches. These use parallel opposed fields to deliver radiation.
Era of intensity modulated radiotherapy (IMRT): By modulating the intensity of the beam and allowing it to conform to the shape of the target tissue, it was possible to significantly reduce the dose to critical structures. By using multiple radiation beams from different directions with a steep dose gradient and highly conformal dose distribution it was possible to have better coverage of tumor and high risk target areas.
Inverse planning is used to define the target dose for the tumor. It allows for the delivery of simultaneous integrated boost without treatment field modifications.41,42 Variations have been developed in the delivery of IMRT such as step and shoot fields: Multileaf collimator (MLC) does not move, sliding window fields (MLC moves), volumetric arc therapy (VMAT: gantry and MLC move), tomotherapy (gantry, couch and MLC move).
Brachytherapy: Radioactive sources were placed within the tumor and combined with an external beam to boost the primary to a higher dose while still minimizing exposure to surrounding tissues. This was commonly employed for tumors of the lip, tongue, floor of mouth, recurrent nasopharyngeal cancers and recurrent tumors of the head and neck.43,44 This along with intraoperative radiotherapy (IORT) done with electrons or high dose rate low energy photon source allows steep dose fall-off sparing normal tissues.45
Stereotactic radiosurgery (SRS): A highly conformal form of radiotherapy allowing delivery of high dose radiation to the tumor in small fractions. First described for the palliation of skull-base recurrences, has been proven to be effective and well tolerated in the palliative setting.46 The Cyberknife (Accuracy Inc., Sunnyvale CA) is a smaller 6MV X-band accelerator mounted on a robotic arm allowing greater degrees of movement freedom. It can track implanted fiducial markers and has six degrees of freedom. It is mostly used for reradiation.
Proton therapy: Proton therapy aims at reducing the incidental dose to nontarget structures. This has a direct bearing on outcomes as the toxic effects follow a dose-response relationship. A focused beam created by a particle accelerator allows the protons to travel fast through the body with minimal interactions and then increase the interactions as the velocity is reduced with maximal energy deposited resulting in the “Bragg peak” and no exit dose. The dosimetric advantage can translate to clinical benefits. Treatment can be delivered by using5 passive or active scanning techniques. The active or intensity modulated proton therapy (IMPT) is the most commonly used. Skull-base chordomas, chondrosarcomas, paranasal malignancies are indications for proton therapy post-resection. The use of protons for oropharyngeal and nasopharyngeal cancers can minimize the treatment toxicity. Adenoid cystic carcinoma which are unresectable and periorbital tumors are also indications for proton therapy. Reirradiation is also another avenue for proton treatment. Reported toxicity includes reduced rate of feeding tube dependence, malnutrition, lower mucositis, nausea and dysgeusia though the skin toxicity is higher.47
EVOLUTION OF CHEMOTHERAPY
Dating back to the 1940s the first chemotherapeutic agents were developed from nitrogen mustard. Teropterin was the first folic acid antagonist to be used in advanced nasopharyngeal carcinoma. Gradually the role of platinum-based components came in as a radiosensitizer and predictor of radiosensitivity. The development of chemotherapy has been from a point when it was initially used in the palliative setting with intra-arterial methotrexate to neoadjuvant, concomitant with radiation and in the adjuvant settings. A variety of cytotoxic agents has been used, the common ones being cisplatin, carboplatin, paclitaxel, docetaxel, 5-fluorouracil, methotrexate, ifosfamide, hydroxyurea. Targeted agents that are in vogue are cetuximab [(antiepidermal growth factor receptor (EGFR)], imatinib, gefitinib and erlotinib, though the evidence of benefit for the latter two is lacking. The concept of metronomic chemotherapy is gaining significance in the recurrent and metastatic setting.48
Refinements in Chemotherapy
Platinum-based chemotherapeutic regimens are the cornerstone in the concomitant and adjuvant settings. Multiple phase 3 trials of induction chemotherapy followed by locoregional treatment compared to locoregional treatment alone have shown variable results with regards to survival and decreasing distant metastasis. A meta-analysis showed that induction chemotherapy conferred a nonsignificant survival improvement of 2% at 5 years (HR, 0.95 95% CI 0.88–1.01, p = 0.10).49 The addition of a taxane to cisplatin plus 5-flurouracil-based induction regimen has been shown to improve survival.50,51
Organ Preservation Therapy
The use of organ preservation therapy in head and neck cancer was introduced because of poor functional outcomes with surgery. Surgical organ preservation protocols use transoral robotic surgery (TORS) or transoral laser microsurgery (TLMS) or open partial laryngeal surgeries. However, this discussion would primarily be on nonsurgical options. Curative chemoradiotherapy has been established as the standard of care which showed an absolute decrease in 5-year mortality of 6.5% with decreased locoregional failures.37,52 RTOG 91-11 established concurrent chemoradiotherapy for locoregional control and organ preservation in patients with resectable Stage III or IV glottic or supraglottic disease.31,32 This modality is preferred in advanced laryngeal or hypopharyngeal cancers without cartilage involvement. High dose cisplatin (100 mg per square meter of body surface area) given intravenously every 21 days for 3 cycles concurrent with radiotherapy is the standard of care.37 Patients with poor performance status may have carboplatin substituted for cisplatin though it is less effective as definitive therapy.53
Bonner in 2006 showed that cetuximab with radiotherapy provided better locoregional control and overall survival compared to radiotherapy alone, however there was no comparison with cisplatin radiotherapy regimen. This has been borne out by the data from recent randomized trials.54-56
Induction Chemotherapy
The role of induction chemotherapy remains controversial and is recommended by the guidelines in a clinical trial setting. Taxane-based chemotherapy in the TAX 324 and EORTC TAX 323 trials showed improved survival but with higher toxic effects and treatment delays.50,51 However, there is significant heterogeneity in trial design which needs to be cautiously interpreted before it can be used before definitive chemoradiation. Toxic effects from induction chemotherapy can prevent 20–30% patients from completing definitive chemoradiation.57 Various single institution trials have looked at the role of induction chemotherapy in advanced oral cancer with borderline resectability, as a bioselection tool to guide treatment decision.
FUTURE AVENUES
Personalized Therapy
The treatment modalities of head and neck cancer include surgery, radiation, chemotherapy, and targeted therapy (most recently the checkpoint inhibitors). A common denominator for all these modalities is the toxicity profile. Biomarker driven treatment strategies are an exciting avenue of clinical research. Existing markers are for human papilloma virus (HPV)6 in oropharyngeal carcinoma, and Epstein-Barr virus (EBV) in nasopharyngeal carcinoma, in addition pathways and markers associated with EGFR downstream signaling abnormalities (PI3K/MTOR pathway and PTEN pathway) and immune checkpoint-related markers. Advances in digital genomic technologies, detection of circulating DNA from clinical specimens offer potential predictive biomarkers in head and neck squamous cell carcinoma (HNSCC) therapy.58 With both pembrolizumab and nivolumab getting accelerated approval by the FDA the future is likely drugs that are biomarker based, have a high clinical efficacy and durable response rate. With increased access to next-generation sequencing and with the TCGA tumor type agnostic therapy is a reality in clinical development and practice.
Vaccinations
Patient specific vaccinations will soon become a reality. With the availability of next generation sequencing, many neoantigens have been identified. The neoantigen with highest affinity are formulated into a peptide or dendritic cell vaccine and delivered as a patient specific vaccine to promote an antitumor response. The presence of neoantigen specific T cells in the blood are used to monitor response. Currently phase I clinical trials are ongoing for vaccines for glioblastoma, melanoma, colon cancer and breast cancer. Viral protein-based vaccines are used in HPV associated HNSCC namely the bivalent HPV 16/18 and the quadrivalent HPV 6/11/16/18.
Robotic Surgery
Transoral robotic surgery for head and neck cancer needs appropriate patient selection with outcomes similar to organ sparing techniques having been reported. It has widespread applications as in treatment of the unknown primary, oropharyngeal cancer (allowing for possible deintensification of treatment and better functional outcomes), supraglottic laryngectomy (with outcomes similar to patients treated by radiotherapy) and advanced applications in nasopharyngeal and parapharyngeal tumors.
Composite Tissue Allotransplantation and Tissue Engineering
There are various groups involved in research of tissue engineered regenerative medicine (TERM) using stem cells to develop bone regenerates. Similarly work is ongoing in the field of stem cell-based tissue engineered larynx and airway constructs and also complex face transplants have been performed.
CONCLUSION
Head and neck oncology has developed over the century with tremendous strides in surgical and nonsurgical modalities of care. From multiple worldwide associations to international cooperative and collaborative groups, the specialty has fostered dedicated training and also integration of multiple disciplines. The future holds exciting prospects in terms of personalized medicine, endoscopic and robotic surgeries and the expanding scope of regenerative medicine, all carving out a distinct niche for themselves in the specialty.
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