Overview of treatment for head and neck cancer

INTRODUCTION — Most head and neck cancers begin in the mucosal surfaces of the upper aerodigestive tract, and these are predominantly squamous cell carcinomas.

An overview of treatment for head and neck squamous cell carcinomas will be presented here. An overview of the diagnostic approach and staging of head and neck cancers is presented separately. (See "Overview of the diagnosis and staging of head and neck cancer".)

Malignancies arising in other organs within the head and neck regions are discussed in the relevant site-specific topics.

INTEGRATED APPROACH TO MANAGEMENT — A multidisciplinary approach is required for optimal decision making, treatment planning, and posttreatment response assessment. This should include surgeons, medical oncologists, and radiation oncologists, as well as dentists, speech/swallowing pathologists, dieticians, psychosocial oncology, prosthodontists, and rehabilitation therapists. Specifically, a multidisciplinary tumor board affects diagnostic and treatment decisions in a significant number of patients with newly diagnosed head and neck tumors [1]. Whenever possible, complex cases of head and neck cancer should be treated at high-volume centers of excellence with expertise in these disciplines since most studies suggest improved outcomes with this approach [1-6].

ANATOMIC SUBSITES — Head and neck cancers arise from a variety of sites within the head and neck region, which is divided into five basic areas (figure 1). These are discussed in detail separately. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Anatomic subsites'.)

In brief:

●The oral cavity includes the lips, buccal mucosa, oral tongue, floor of the mouth, hard palate, upper gingiva, lower gingiva, and retromolar trigone (figure 2).

●The pharynx is divided into the oropharynx, the nasopharynx, and the hypopharynx.

•The nasopharynx, the narrow tubular passage behind the nasal cavity, is the upper part of the pharynx.

•The oropharynx, the middle part of the pharynx, includes the tonsillar area, tongue base, soft palate, and posterior pharyngeal wall.

•The hypopharynx, the lower part of the pharynx, includes the pyriform sinuses, the posterior surface of the larynx (postcricoid area), and the inferoposterior and inferolateral pharyngeal walls.

●The larynx contains the vocal cords and epiglottis. It is divided into three anatomic regions: the supraglottic larynx, the glottic larynx (true vocal cords and the anterior and posterior commissures), and the subglottic larynx (figure 3 and figure 4).

●The nasal cavity and the paranasal sinuses include the maxillary, ethmoid, sphenoid, and frontal sinuses (figure 5).

●The major salivary glands (parotid, submandibular, and sublingual (figure 6)) and the minor salivary glands are located throughout the submucosa of the mouth and upper aerodigestive tract, including the oral cavity (especially the palate), paranasal sinuses, larynx, and pharynx.

TNM STAGING SYSTEM — The eight edition Tumor, Node, Metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used to stage cancers of the head and neck [7]. The T classifications indicate the extent of the primary tumor and are site specific; there is considerable overlap in the cervical N classifications.

TNM staging varies depending on the primary tumor site:

●Oral cavity (table 1) - (see "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Clinical presentation and diagnosis')

●Nasopharynx (table 2) - (see "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'STAGING')

●Oropharynx (table 3A-B and table 4A-B) - (see "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'Staging' and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer")

●Hypopharynx (table 5A-B) - (see "Treatment of early (stage I and II) head and neck cancer: The hypopharynx", section on 'Anatomy and staging')

●Larynx (table 6) - (see "Treatment of early (stage I and II) head and neck cancer: The larynx", section on 'Staging and anatomy')

●Nasal cavity and paranasal sinuses (table 7) - (see "Tumors of the nasal cavity" and "Cancer of the nasal vestibule", section on 'Staging' and "Paranasal sinus cancer", section on 'Diagnosis and staging')

●Salivary glands (table 8A-B) - (see "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging", section on 'Staging')

The approach to the diagnosis and staging of head and neck cancer is discussed separately. (See "Overview of the diagnosis and staging of head and neck cancer", section on 'Diagnosis and staging evaluation'.)

MANAGEMENT OF SQUAMOUS CELL CARCINOMAS

Localized (early stage) disease — Approximately 30 to 40 percent of patients with head and neck squamous cell carcinomas present with stage I or II (early stage) disease. In general, these patients are treated with either primary surgery or definitive radiation therapy (RT). Patients with carcinoma in situ usually are managed surgically in the same way as those with T1 disease.

Five-year overall survival in patients with stage I or II disease is typically from 70 to 90 percent. Careful observation and follow-up after initial treatment are required both to detect a potentially curable recurrence and to identify and treat second primary tumors. Particularly in patients with tobacco- and alcohol-related head and neck cancers, there is a substantial increase in the risk of a second head and neck cancer, as well as of a second primary arising in the lung. Smoking cessation should be pursued in smokers. (See "Second primary malignancies in patients with head and neck cancers" and "Overview of smoking cessation management in adults".)

RT and surgery result in similar rates of local control and survival for many sites; the choice of therapy is typically based upon the specific site and its requirements, the surgical accessibility of the tumor, and the functional outcomes and morbidity associated with each modality. Oral cavity cancers are a notable exception and are usually best treated with surgery, based upon generally better cure rates and toxicity profile compared with radiation-based therapy. External beam RT may be an may be an option for oral cavity tumors, especially if surgical expertise is not available.

Traditional surgical approaches through skin incisions to gain access to the primary (ie, wide local excision) are usually used for salivary and thyroid cancers, which are easily accessible. At other sites, minimally invasive techniques, such as transoral laser microsurgery (TOLM) for larynx and hypopharynx cancers and transoral robotic surgery (TORS) for oropharynx cancers, have improved transoral access. These approaches can improve functional outcomes and decrease morbidity compared with standard surgical approaches. Most early stage oral cavity cancers can be treated through a transoral approach.

Definitive RT is administered using external beam RT, and requires a three-dimensional conformal technique. Highly conformal RT techniques, such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), are the standard of care since they have demonstrated reduced morbidity. (See "General principles of radiation therapy for head and neck cancer", section on 'Three-dimensional conformal RT'.)

For patients initially treated with surgery for clinically early stage cancers, postoperative RT, with or without concurrent chemotherapy, is indicated for those that are pathologically locoregionally advanced and have close or positive margins and other factors that increase the risk of local recurrence, including perineural invasion, lymphovascular invasion, and extranodal extension. The finding of multiple lymph nodes on elective lymph node dissection in the clinically N0 patient is likewise an indication for RT. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)

Specific recommendations for pretreatment evaluation and treatment are described according to the head and neck squamous cell carcinoma site:

●(See "Treatment of stage I and II (early) head and neck cancer: The oral cavity".)

●(See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'General principles'.)

●(See "Treatment of early (stage I and II) head and neck cancer: The hypopharynx".)

●(See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

●(See "Treatment of early (stage I and II) head and neck cancer: The larynx".)

Locoregionally advanced disease — Locoregionally advanced (stage III/IV) squamous cell carcinoma of the head and neck is associated with a high risk of both local recurrence and distant metastases. Combined modality approaches (surgery, RT, and/or chemotherapy) are generally required to optimize the chances for long-term disease control [8,9]. These combined modality approaches include primary surgery followed by either postoperative RT or concurrent chemoradiotherapy, induction chemotherapy (the addition of chemotherapy prior to surgery and/or RT), concurrent chemoradiotherapy without surgery, and sequential therapy (induction chemotherapy followed by concurrent chemoradiotherapy) without surgery.

Decisions about the optimal sequencing and selection of surgery, RT, and/or chemotherapy require multidisciplinary input. Key factors to consider include the primary tumor site and disease extent, the individual patient factors (age, comorbidity, preferences regarding treatment type), and the likely functional consequences and morbidity of each treatment approach. The choice of therapy should also take into account the experience and technology available at the patient's medical institution.

●Oral cavity – Surgery is generally preferred for locoregionally advanced oral cavity squamous cell carcinomas since most cases are easily accessible, and simultaneous resection and reconstruction can be accomplished with acceptable functional outcomes. However, oral cavity tumors are aggressive cancers with high rates of locoregional recurrence; thus, postoperative RT, with or without chemotherapy, is generally used.

Definitive RT, concurrent chemoradiotherapy, and sequential therapy are typically reserved for patients who are medically inoperable, who have unresectable disease, or who have resectable disease where surgical resection cannot be accomplished with acceptable long-term functional consequences (eg, total glossectomy that may require total laryngectomy to prevent aspiration).

●Oropharynx, hypopharynx, and larynx – Organ-sparing and, more importantly, function-sparing approaches (TORS, TOLM, chemoradiotherapy) rather than large ablative primary surgery are preferred for most patients with cancers of the oropharynx, hypopharynx, and larynx. Concurrent chemoradiotherapy is often a standard option for functional organ preservation, either as upfront definitive treatment or in a postoperative setting.

Definitive RT alone, often using an altered fractionation schedule, remains a treatment option for older adult patients and those with a poor performance status, as data suggest limited benefit for concurrent chemotherapy in those over age 70 years [9,10]. Further details are discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Chemotherapy plus definitive locoregional therapy'.)

The efficacy, indications, and application of organ-sparing approaches are discussed separately, as are definitive RT and postoperative RT:

●(See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

●(See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)

●(See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)

Specific recommendations for treatment are discussed according to the primary site of disease:

●(See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oral cavity".)

●(See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx".)

●(See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx".)

Management of the neck — Head and neck squamous cell carcinomas frequently metastasize to the cervical lymph nodes, which is associated with a negative prognosis for most patients. Consequently, treatment of the cervical neck nodes, even if involvement is clinically occult, is often part of the treatment strategy.

For patients with head and neck squamous cell carcinomas who have cervical lymph node involvement at presentation and are treated with definitive RT or chemoradiotherapy, residual abnormalities in the neck are managed differently depending on response to initial treatment. For patients with complete regression, as documented clinically and by structural (computed tomography [CT], magnetic resonance imaging [MRI]) and functional (positron emission tomography [PET]) imaging, observation is generally indicated, whereas salvage surgery is indicated in the absence of an adequate response (algorithm 1). (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

The risk of developing nodal metastases varies by primary tumor site and factors such as size, histology, tumor thickness, and perineural invasion. When the probability of occult metastases exceeds 15 to 20 percent, the risk of neck recurrence without elective (prophylactic) treatment is sufficiently high to outweigh the morbidity of neck dissection and/or (chemo)irradiation. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment".)

Reconstruction and rehabilitation — Surgical resection of the mandible, palate, and larynx can lead to problems in airway management, mastication, deglutition, speech, and cosmesis. Function is also impaired by RT and chemoradiotherapy.

●Every effort is made to provide functional reconstruction during the ablative surgery, with the goals of restoration of orofacial functions, including deglutition, control of secretions, mastication, and phonetics, and to aesthetically replace the missing orofacial structures. Primary reconstruction of maxillary, palatal, tongue, and mandibular defects is the current standard of care. Local flaps can be utilized for smaller defects, such as the submental island flap. Free tissue transfer, such as radial forearm free flap or fibula osteocutaneous free flap, can be used for larger or more complex defects. (See "Mandibular and palatal reconstruction in patients with head and neck cancer".)

●Prosthetic rehabilitation of patients who are not healthy surgical candidates can also be considered. For example, hard palate defects or maxillary defects can be covered with a custom-made obturator prosthesis. This requires the skills of a dedicated orofacial prosthodontist. Sometimes, prosthetic appliances augment the primary reconstruction. For example, a palatal drop prosthesis can improve speech and swallow function in patients with glossectomy defects. (See "Management of acquired maxillary and hard palate defects".)

●Speech and swallowing rehabilitation are critical to restoring function and quality of life following both surgery and RT [11,12]. (See "Speech and swallowing rehabilitation of the patient with head and neck cancer" and "Alaryngeal speech rehabilitation".)

Complications — The toxicity associated with treatment for head and neck cancer (whether surgery, RT, and/or chemotherapy) is substantial, and every effort should be made to minimize side effects and treat these complications. Surgery may alter form and function, while acute effects of RT or chemoradiation treatment include skin reaction, mucositis, function alteration and dysphagia, fatigue, and weight loss. Delayed toxicity can have a significant effect on quality of life. Long-term side effects of RT or chemoradiation, such as dry mouth, severe dysphagia, osteoradionecrosis, aspiration pneumonia, or radiation fibrosis syndrome, are directly related to radiation dose [13-15]. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment" and "Health-related quality of life in head and neck cancer".)

Posttreatment evaluation and surveillance — Regular posttreatment follow-up is an essential part of the care of patients after potentially curative treatment of head and neck cancer. Patients should be educated about the possible signs and symptoms of a second primary cancer and locoregional recurrence, including hoarseness, pain, dysphagia, bleeding, and enlarged lymph nodes. Consistent with the standards of the Commission on Cancer for those treated with curative intent, a survivorship care plan and treatment summary should be generated and reviewed in detail with the patient within six months of completion of therapy, and a copy should be shared with the patient and primary care physician. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)

Upon completion of therapy, posttreatment imaging is important to evaluate for residual disease and to establish a baseline.

●For patients who have surgical resection followed by radiation or chemoradiotherapy, a clinical evaluation and baseline imaging with CT or MRI is typically performed approximately four to six weeks after completion of therapy.

●For patients who have undergone nonsurgical treatment as initial strategy, our approach is to conduct a clinical evaluation around four to six weeks following RT or chemoradiotherapy and then a complete evaluation, including imaging (CT or MRI and generally a PET/CT) at 12 weeks to document regression of the primary tumor.

Imaging should not be performed too soon. Obtaining imaging studies, particularly PET/CT, prior to 12 weeks following treatment can lead to an increased frequency of false-positive results. CT or MRI can be carried out at four to six weeks, if needed, as part of the clinical evaluation. This imaging approach can also be used to identify patients with clear residual disease who need surgical intervention. (See "Overview of the diagnosis and staging of head and neck cancer".)

●For patients who have clinically involved cervical lymph node disease prior to RT or chemoradiotherapy, functional imaging (PET) and structural imaging (CT/MRI) are important components of assessment of response to initial therapy (algorithm 1). (See 'Management of the neck' above and "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

Following treatment, the intensity of follow-up is greatest in the first two to four years. Approximately 80 to 90 percent of all recurrences occur during this time frame; the risk of a second primary malignancy is higher than the recurrence risk for most patients after three years, especially those with carcinogen-related (eg, tobacco and alcohol) cancers.

However, lifetime follow-up is required since the morbidity of treatment can worsen over time, and the risk of recurrence and second primary malignancy remains beyond the first five years. Because of the higher risk of recurrence and second primary malignancy, as well as other late toxicities, in those who continue tobacco use, many experts schedule more frequent surveillance visits for these patients.

Locally recurrent disease — Although most patients with recurrent disease have a poor prognosis, those with only locoregionally recurrent disease may benefit from definitive treatment.

All patients with locoregionally recurrent disease should be evaluated for distant metastases prior to initiating retreatment. Those with a good performance status and whose disease is confined to the head and neck may benefit from surgical salvage, and/or radiation or reirradiation, systemic therapy (eg, chemotherapy and immunotherapy), or clinical trial participation, although treatment options are limited by the previous treatment received. (See "Treatment of locally recurrent squamous cell carcinoma of the head and neck" and "Reirradiation for locally recurrent head and neck cancer".)

Metastatic disease — Palliative chemotherapy, immunotherapy, and/or supportive care are the most appropriate options for patients with locally recurrent and/or metastatic disease that is not amenable to definitive therapy, as well as for patients who have widely disseminated disease. Immunotherapy may lead to lengthy remissions in some patients. Palliative RT is sometimes used for patients with pain or symptoms due to tumor compression. (See "Treatment of metastatic and recurrent head and neck cancer".)

SPECIAL CIRCUMSTANCES — Some malignancies arising in the mucosa of the upper aerodigestive tract have unusual histology or biology, which can have important implications for patient management.

These are briefly discussed here, and more detailed discussions are provided in other topics, as noted below. Nonmucosal malignancies (eg, thyroid, base of skull) are discussed in the relevant site-specific topics.

Human papillomavirus associated oropharyngeal cancer — Human papillomavirus (HPV) infection is a causative agent for many head and neck squamous cell carcinomas arising in the oropharynx (tonsils and base of tongue) (table 9). HPV associated cancers have increased dramatically and have substantially altered the epidemiology of oropharyngeal squamous cell carcinoma. These tumors define a distinct subset of patients who have frequent lymph node involvement and an improved prognosis compared with HPV negative, tobacco-driven oropharynx cancers.

A revised classification/staging system has been implemented as of January 2018 for HPV related oropharyngeal cancers in the American Joint Committee on Cancer (AJCC) eighth edition staging manual [16]. This new system recategorizes many of the patients previously staged as IVA to stage I, II, or III with much better prognostic accuracy; the therapeutic approach for patients with HPV associated oropharyngeal cancer has not changed. Because of the better prognosis for patients with HPV associated oropharyngeal cancer, clinical trials that include deintensification of treatment are underway to define the optimal approach for these patients, with the goal of maximizing long-term cure rates while minimizing toxicity. Currently, however, the approach to these patients outside of a clinical trial setting is the same as for patients with oropharyngeal cancer not associated with HPV. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer" and "Treatment of human papillomavirus associated oropharyngeal cancer".)

Nasopharyngeal carcinoma — Nasopharyngeal carcinoma differs from other head and neck cancers in its epidemiology, pathology, natural history, and treatment. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

Radiation therapy (RT) is the mainstay of treatment for locoregional nasopharyngeal cancer, but the integration of chemotherapy has been instrumental in improving survival for most stage II and advanced-stage disease (III and IV). Surgery is not typically used because of the deep anatomical location of the nasopharynx and its close proximity to critical neurovascular structures and the base of skull. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma" and "Treatment of recurrent and metastatic nasopharyngeal carcinoma".)

Nasal vestibule and nasal cavity cancers — Tumors of the nasal vestibule are essentially skin cancers and are treated with surgery and/or RT, depending on the size and location within the nasal vestibule. Cancers of the nasal cavity are similar to those that occur in the paranasal sinuses and have a wide variety of histologies. Both early and moderately advanced tumors of the nasal cavity are treated with surgical resection and postoperative RT. (See "Cancer of the nasal vestibule" and "Tumors of the nasal cavity" and "Paranasal sinus cancer".)

Paranasal sinus cancer — Paranasal sinus cancers encompass multiple histologies, with adenocarcinoma and squamous cell carcinoma being predominant. Surgical resection, which is most often a transnasal endoscopic image-guided resection, remains the mainstay of treatment, but multimodality approaches with surgery, RT, and chemotherapy may be appropriate for certain histologies and for advanced-stage cancers. (See "Paranasal sinus cancer".)

Salivary gland cancers — Salivary gland tumors consist of a wide array of benign and malignant histologies that occur in salivary gland tissue throughout the head and neck. Surgical resection of the salivary gland is important for both diagnosis and treatment. Patients with benign and low-grade tumors are typically treated with surgery alone, whereas patients with high-grade carcinomas and other high-risk features are usually treated with surgery and postoperative RT.

●(See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

●(See "Salivary gland tumors: Treatment of locoregional disease".)

●(See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)

Squamous cell carcinoma of unknown primary — A squamous cell carcinoma (SCC) of unknown primary that involves the upper cervical lymph nodes most likely originate from a head and neck primary. Most head and neck squamous cell carcinomas of unknown primary originate in the oropharynx and are HPV associated tumors [17]. The diagnostic evaluation needed to identify the primary tumor site and the management of a head and neck SCC of unknown primary are discussed separately. (See "Head and neck squamous cell carcinoma of unknown primary".)

By contrast, carcinomas that involve the lower neck may represent distant metastases from an esophagus, lung, gastrointestinal, or genitourinary tract primary.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Throat cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical factors that influence treatment – Treatment for head and neck squamous cell carcinoma requires consideration of tumor site and stage, the functional outcomes and morbidity associated with various treatment approaches, and patient-specific factors, such as performance status, comorbidities, and preference.

●Multidisciplinary management – A multidisciplinary approach including surgeons, medical oncologists, and radiation oncologists, as well as dentists, speech/swallowing pathologists, dieticians, and rehabilitation therapists, all with adequate expertise, is required for planning treatment and managing these patients. (See 'Integrated approach to management' above.)

●Localized (early stage) disease – Patients with localized (stage I and II) head and neck carcinomas are generally managed with either surgery or radiation therapy (RT) alone. However, a combined modality may be required in cases with high-risk features. (See 'Localized (early stage) disease' above.)

●Advanced disease – Patients with more advanced (stage III, IVA, and IVB) disease are typically managed with a multimodality approach including both RT and chemotherapy; functional organ-preservation approaches are generally preferred. (See 'Locoregionally advanced disease' above and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

●Locally recurrent and metastatic disease – Palliative systemic therapy and/or supportive care are appropriate for most patients with locally recurrent and metastatic disease. Immunotherapy may lead to lengthy periods of remission in some patients. However, carefully selected patients with disease confined to the head and neck may benefit from surgical or radiation salvage and/or reirradiation. (See 'Locally recurrent disease' above.)

●Management of the neck – Treatment of the cervical lymph nodes, even if involvement is clinically occult, is often required. (See 'Management of the neck' above.)

●Posttreatment evaluation and surveillance – Survivorship care planning and regular posttreatment follow-up are an essential part of the care of patients after potentially curative treatment of head and neck cancer. (See 'Posttreatment evaluation and surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Benedito Carneiro, MD, MSc, who contributed to earlier versions of this topic review.