Oropharyngeal cancer of the human papillomavirus-orifal ( HPV OPC ) is an oropharyngeal cell carcinoma subtype (OSCC), associated with human 16-cell papillomavirus virus (HPV16). Historically, throat cancer oropharynx (throat) was associated with alcohol and tobacco use, but most cases are now associated with HPV virus. HPV OPC differs in some respects from OPCs unrelated to HPV (HPV-OPC), and is considered a separate disease. HPV has long been associated with cancer in the anogenital region, but in 2007 it was also recognized as a cause of oropharyngeal cancer. HPV is common among healthy adults and is mostly transmitted through sexual contact, but the use of tobacco increases the risk of cancer.
Detection of tumor suppressor proteins, known as p16, is commonly used to diagnose OPC-related HPV. The extent of the disease is described in standard cancer staging systems, using the AJCC TNM system, based on the T stage (tumor size and level), stage N (regional lymph node involvement level) and stage M (whether there is outbreak spread of disease, and coupled to the overall stage of I-IV. By 2016, separate staging systems are developed for the HPV OPC, different from HPV-OPC.
The OPC's historical treatment is surgical, with an approach through the neck and the separation of the jawbone, resulting in a substantial mortality risk. Then, radiotherapy with or without the addition of chemotherapy, provides a less invasive alternative, and the results in terms of treating cancer, are comparable. Newer, more invasive, minimally invasive surgical techniques have improved results, and surgery is often followed by radiation and/or chemotherapy in high-risk cases. In the absence of high quality evidence, management decisions are often based on technical factors, the possibility of functional loss and patient preference. Some HPV OPCs may first appear in the lymph nodes in the neck, with no obvious source (primary unknown cancer of origin) but removal of the tonsil tissue from the oropharynx will often show hidden disease. The presence of HPV in tumors is associated with better responses to treatment and better outcomes, regardless of the method of treatment used and nearly 60% reduce the risk of dying from cancer. Most recurrences occur locally and within the first year after treatment. Tobacco use reduces the likelihood of survival. While most head and neck cancers have decreased with reduced smoking levels, HPV OPC has increased. Compared with HPV-OPC patients, OPC HPV patients tend to be younger, have higher socioeconomic status and tend to not smoke. In addition they tend to have smaller tumors, but are more likely to have cervical lymph node involvement. In the United States and other countries, the number of oropharyngeal cancer cases continues to increase, with the incidence of OPC HPV rising faster than the decrease in HPV-OPC. This increase is particularly noticeable in young men in developed countries, and the OPC HPV now accounts for the majority of all OPC cases.
Efforts are underway to reduce the incidence of HPV OPC by introducing vaccinations that include HPV types 16 and 18, found in 95% of these cancers, before exposure to the virus. Preliminary data suggest a reduction in infection rates.
Video HPV-positive oropharyngeal cancer
Signs and symptoms
As with other cancers arising in the head and neck areas, HPV OPC may be an incidental, asymptomatic finding of oral abnormalities, by patients or health professionals, present with local symptoms such as speech, swallowing and breathing difficulties as well as pain and infection, or as a swelling in the neck if the cancer has spread to the lymph nodes there. This may be accompanied by more general symptoms such as loss of appetite, weight loss and weakness.
Maps HPV-positive oropharyngeal cancer
Cause
Most head and mucosal squamous cell cancers, including oropharyngeal cancer (OPC), have historically been associated with tobacco and alcohol use. But this pattern has changed a lot since the 1980s. It is recognized that some cancers occur in the absence of these risk factors and the relationship between human papilloma virus (HPV) and various squamous cell cancers, including OPC, was first described in 1983. Since then both molecular and epidemiological evidence has accumulated, with the International Agency for Cancer Research (IARC), which states that HPV types 16 and 18 are high-risk carcinogenic in humans, in 1995, and In 2007 HPV became the cause of oral cancer. The incidence of human papillomavirus (HPV) -Positive (HPV OPC) has increased while the incidence of HPV-negative cancers (HPV-OPC) declines, a trend that is expected to increase in the coming years. Because of the marked differences in clinical presentation and treatment relative to HPV status, OPC HPV is now seen as a distinct biological and clinical condition.
Human HPV has long been involved in the pathogenesis of some anogenital cancers including the anus, vulva, vagina, cervix, and penis. In 2007 it was also involved by molecular and epidemiological evidence on cancers that arise outside the anogenital tract, which is mouth cancer. HPV infection is common among healthy individuals, and is obtained mostly through sexual contact. Although fewer data are available, the prevalence of HPV infection is at least equal in men among women, with 2004 estimates of about 27% among US women aged 14-59 years.
HPV oral infection precedes the development of HPV OPC. Minor injuries in the mucous membranes serve as the entrance gate for HPV, thereby working to the basal layer of the epithelium. People who are positive for HPV 16 infection type (HPV16) have a 14-fold higher risk of developing HPV OPC. Immunosuppression appears to be an increased risk factor for OPC HPV. Individuals with genetic variation TGF-1, especially T869C, are more likely to have HPV16 OPC. TGF-1 plays an important role in controlling the immune system. In 1993 it was noted that patients with human papillomavirus (HPV) -related anogenital cancers had a fourfold increased risk of squamous cell carcinoma tonsil. Although evidence suggests that HPV16 is the leading cause of OPC in humans who are not exposed to secondhand smoke and alcohol, tobacco and/or alcohol use rates may contribute to increased risk of OPC HPV is not always clear but it appears both are smoking and HPV infection is an independent risk factor and additive developing OPC. Human herpesvirus-8 infection can potentiate the HPV-16 effect.
Risk factors included a large number of sexual partners (25% increase & gt; = 6 partners), oral-genital sex history (125% & gt; = 4 partners), or anal-oral sex, female partners with a good history of abnormal Pap smears or cervical dysplasia, chronic periodontitis, and, among men, decreased age at first sexual intercourse and history of genital warts.
Pathology
Oropharynx cancers mainly occur in the lingual and palatine lymphoid lymphoid tissue coated by respiratory squamous mucosal epithelium, which can be invaded in lymphoid tissue. Therefore, the tumor first appears in a hidden basement. OPCs are assessed on the basis of the degree of squamous and keratin differentiation into well-differentiated, moderate or poor (high) classes. Other pathological features include finger-like invasions, perineural invasion, depth of invasion and tumor spacing from margin resection. Phenotypic variants include basaloid squamous carcinoma, high grade form ( see Chung Figure 35-3 (C) and illustrated here). They are most commonly non-keratinized. OPC HPV is also different from HPV-OPC being focused rather than multifocal and unrelated to pre-malignant dysplasia. Therefore, OPC HPV patients are at less risk of developing other malignancies in the head and neck area, unlike other primary and neck primary tumors that may be associated with a second neoplasm, which may occur at the same time (synchronously) or over time (metachronous). ), both inside the head and neck region or further away. This suggests that the oncogenic changes generated by the virus are spatially limited rather than related to field defects.
Anatomy
Oropharyes, at the back of the mouth, form a circle and include the base of the tongue (third posterior) below, the tonsils on each side, and the soft palate above, along with the pharyngeal wall, including the anterior epiglottis, the epiglottic vigalsa and the branchial branches at the base. Oropharynx is one of the three interior divisions of the pharynx based on its relationship to adjacent structures (nasopharynx), oropharynx (oropharynx) and larynx (laryngopharynx - also called the hypopharynx), from top to bottom). Pharynx is a semi-circular fibromuscular that joins the nasal cavity above to the larynx (voice box) and esophagus (throat), below, where the larynx is located in front of the esophagus.
Oropharynx is located between the mouth (the oral cavity) forward, and the laryngopharynx below, which separates it from the larynx. The upper limit of the oropharynx is marked by a soft palate, and its lower border by epiglottis and tongue root. Orofaring communicates with the mouth, up front through what is known as isthmus oropharyngeal, or isthmus fauces. Ismusus (ie connection) is formed on top by the soft palate, below by the posterior third of the tongue, and on the side by the palatoglossal arch. A posterior third of the tongue, or tongue base contains many lymphatic tissue follicles that form the lingual tonsils. Adjacent to the base of the tongue, the epiglottic lingual surface, which is curved forward, attaches to the tongue with median and lateral glossoepiglottic folds. The creases form small troughs known as vallecula epiglottis. The lateral wall is characterized by two vertical pillars on each side, fauces pillar, or palatoglossal arch. More precisely they are separately named after the anterior palatoglossal arch and the posterior palatopharyngeal arch. The anterior arch is named from the palatoglossal muscle inside, running from the soft palate to the tongue (glossus), whereas the posterior arch contains the same palatopharyngeal muscle running from the soft palate to the lateral pharynx. Among the arch lies the triangular space, the tonsils of the fossa where the tonsils of the palatine are located, the other lymphoid organs.
The external pharyngeal wall consisting of four constrictor muscles is part of the swallowing mechanism. Microscopic anatomy consists of four layers, derived from exit lumen, mucosa, submucosa, muscle and fibrous, or fibrous layer. The mucosa consists of stratified squamous epithelium, which is generally not keratinized, except when exposed to chronic irritants such as tobacco smoke. Submucosa contains aggregates of lymphoid tissue.
Mechanism
Virology
HPV-related cancers are caused by high-risk HPV, especially HPV-16 and HPV-18. HPV is a small non-envelope DNA virus from the papillomavirus family. The genome encodes early Oncoproteins (E) E5, E6 and E7 and capsid proteins (L) L1 and L2. The virus gets access to the mucosa through microcions, where it infects the basal layer of cells, which can still multiply. While the virus does not replicate in these cells, early gene expression stimulates the proliferation and lateral expansion of basal cells. As this moves the viral particles into the suprabasal layer above them, slow viral gene expression occurs, allowing circular viral genome replication (see figure ) and structural proteins. Since this is pushed into the most shallow mucosal layer, complete viral particles are assembled and released.
Oncogenesis
Increased risk of OPC HPV was observed over 15 years after exposure to HPV, suggesting slow progression of disease, similar to that seen in cervical cancer. With respect to HPV-OPC, the oncogenic molecular development of OPC HPV is poorly understood. Two major viral oncoproteins of high risk HPV types are E6 and E7. This is consistently expressed in malignant cell lines, and if their expression is inhibited the malignant phenotype of cancer cells is blocked. One of these oncoproteins can capture cell lines, but is more efficient when both are expressed, since the separate molecular role is synergistic. Oncogenes E6 and E7 are integrated into host cell DNA, and their expressed oncoproteins interfere with the dominant antiproliferative cellular regulatory mechanisms. They bind and disable the most recognizable of these mechanisms, p53 tumor suppressor proteins and pRB protein retinoblastoma (pRb) leading to genomic instability and then cell cycle deregulation ( see Chung et al., 2016 Fig. ). Furthermore, not yet available, mechanisms are needed for the final step of malignant transformation of HPV-infected cells.
HPV- and HPV OPC can be differentiated at the molecular level. Natural P53 (wild type) is widely involved in cellular processes, including autophagy, response to DNA damage, cell cycle regulation and aging, apoptosis and adenosine triphosphate (ATP) formation through oxidative phosphorylation. The p53 gene encoding is attenuated by E6 at the protein level and found as wild type in OPC HPV but mutated in HPV-OPC. In HPV OPC p53 protein has accelerated degradation by E6, drastically reducing its level, while in HPV-OPC it has a genetic mutation, which can produce abnormal p53 protein synthesis, which may not only be inactive as a tumor suppressor, but also bind and disabling p53 wild-type non-mutation, with increased oncogenic activity. Although p53 mutations occur in OPC HPV, these mutations are much more common than in HPV-OPC (26% vs. 48%), and do not appear to affect clinical outcomes.
The pRb protein is inactivated by E7 in OPC HPV, but in HPV-OPC it is the p16 tumor suppressor part of the inactive pRb tumor suppressor tissue. Also the pRb path is inactive by E7 rather than Cyclin D1 amplification. CDKN2A is a tumor suppressor gene encoding a tumor suppressor, p16 (cyclin-dependent kinase inhibitor 2A) and inhibits the kinase activity of a cyclic-dependent kinase CDK4 and CDK6, which in turn induce cell cycle capture. The expression of p16 depends on the cell cycle and is expressed only focally about 5-10% of the normal squamous epithelium. Like most HPV cancers, HPV OPC expresses p16 but the latter does not work as a tumor suppressor, because this achieved mechanism, pRb, has been disabled by E7. p16 is regulated (overexpressed) due to loss of pRB associated with E7 with negative feedback reduction, whereas it decreases regulation by up to 90% of HPV-OPC. The spread of excessive expression in these tumor cells provides a diagnostic marker for HPV involvement. Although HPV E6 and E7 reduce tumor suppressor activity, they do so less than the genetic and epigenetic processes in HPV-OPC.
The tonsillar (palatine and lingual) epithelium has noncatinization characteristics similar to those of the cervix, where HPV infection plays a major role in cases of cervical cancer. Also E6 and E7 can make OPC HPV more immunogenic than HPV-OPC, since anti-E6 and E7 antibodies can be detected in these patients. This in turn may limit the malignant behavior of HPV OPC and the presence of antibodies has been associated with better prognosis, while treatment may improve tumor immunogenicity, and therefore increase the response, although to what extent is unclear. Results were also associated with an increase in adaptive immunity.
Diagnosis
Initial diagnosis requires visualization of either the tumor by mouth or endoscopy through the nose using a rhinoscope, illustrated here, followed by a biopsy. OPC HPV is usually diagnosed at a later stage than HPV-OPC, with 75-90% having regional lymph node involvement. The genetic signatures of HPV and HPV-OPC are different. HPV OPC is associated with E6/E7 and P16 mRNA expression levels. Non keratinization squamous cell carcinoma strongly predicts HPV relationship. A histopathologically-characterized case of HPV16 E6/E7-E7 is characterized by a nipple-like or verilous or nipple-like structure and adjacent mucosal coilocytosis. About 15% of HNSCC is caused by HPV16 infection and subsequent constitutive expression of E6 and E7, and some HPV-initiated tumors can lose their original characteristics during tumor development. High-risk HPV types may be associated with oral carcinoma, with dysregulated cell cycle control, contributing to oral carcinogenesis and overexpression of mdm2, p27 and cathepsin B.
HPV OPC is not only characterized by the presence of HPV-16. Only the expression of viral oncogenes in tumor cells plus the presence of serum antibodies E6 or E7 are clearly inconclusive. There is no standard HPV testing method for head and neck cancer, both in-situ hybridization (ISH) and polymerase chain reaction (PCR) are commonly used. Both methods have comparable performance for HPV detection, but it is important to use appropriate sensitivity controls. Immunohistochemical staining (IHC) tissue for p16 is often used as a cost-effective replacement for HPV in OPC, compared with ISH or PCR but there is a small incidence of positive HPV-negative p16-positive disease of about 5% of HPV-OPC.
Staging
Staging is generally by the UICC/AJCC TNM system (Tumor, Node, Metastasis). HPV OPC has been treated similarly to unrelated and match-table and site-compatible tablets, but its unique features, which differentiate head and neck cancers associated with HPV-OPC, in which patients are demographic, comorbid, factor risk, and carcinogenesis are markedly different, suggesting that different staging systems were developed to more accurately represent the severity of the disease and its prognosis. Standard AJCC TNM staging, such as the seventh (2009) temporary edition predictive for HPV-OPC has no prognostic value in HPV OPC. Issue 8 of AJCC TNM Staging Manual (2016) combines this specific staging for HPV OPC. Current treatment guidelines do not take into account the different results observed in OPC HPV. As a result, less intensive (de-intensification) use of radiotherapy or chemotherapy, as well as specific therapies, is being investigated, enrolling HPV OPC in clinical trials to maintain disease control and minimize morbidity in certain groups based on modified TNM stadium and smoking status..
Oropharynx HPV cancer staged as (AJCC 8th ed. 2016): Tumor Stage
- T0 is not identified primary
- T1 2 cm or less in the largest dimension
- T2 2-4Ã, cm
- T3 & gt; 4 cm, or extension to the epiglottic lingual surface
- T4 locally advanced disease, invading the larynx, tongue extrinsic muscle, medial pterygoid, hard palate, or mandible or outside
Nodal stage
- Nx regional lymph nodes can not be assessed
- N0 no regional lymph nodes are involved
- N1 one or more ipsilateral nodes involved, less than 6 cm
- N2 contralateral or bilateral lymph nodes, less than 6 cm
- N3 lymph node (s) greater than 6Ã, cm
Clinical stadium
- Stage I: T0N1, T1-2N0-1
- Stage II: T0N2, T1-3N2, T3N0-2
- Stage III: T0-3N3, T4N0-3
- Stage IV: any metastasis (M1)
However, published literature and ongoing clinical trials use the older seventh edition that does not distinguish between HPV OPC and HPV-OPC - see Oropharyngeal Cancer - Stages. Stage T is essentially the same between AJCC 7 and AJCC 8. with two exceptions. Tis (carcinoma in situ) has been removed and the division of T4 into substages (eg T4a) has been removed. The major changes are in stage N, and hence the overall clinical stage. N0 remains the same, but as in stage T, substages like N2a have been omitted. Invasion by tumors outside the lymph node capsule (extracapsular extension or ECE) has been eliminated as a staging criterion.
This results in OPC HPV tumors given lower levels than if HPV-OPC. For example, a 5 cm tumor with one ipsilateral node involved with a size of 5 cm but ECE would be considered as T3N3bM0 Level IVB if HPV- but T3N1M0 Stage II if HPV.
Prevention
Prevention of OPC HPV involves avoiding or reducing exposure to risk factors whenever possible. Approximately 90% of HPV OPC carries HPV 16, and another 5% type 18. Both of these types are available vaccine targets. HPV vaccine given prior to exposure can prevent persistent genital infections and consequent precancerous conditions. Therefore, they have theoretical potential to prevent oral HPV infection. A 2010 review study found that oral HPV16 infection is rare (1.3%) among the 3,977 healthy subjects analyzed.
Treatment
The goal of treatment is to optimize the survival and control of locoregional disease, and prevent the spread to distant parts of the body (metastasis), while minimizing short-term and long-term morbidity. There is no evidence of high grade I levels of prospective clinical trials in HPV OPC, therefore treatment guidelines should rely on data from OPC treatment in general and from some unplanned retrospective studies from the study, along with data for head and neck cancer generally.. Treatment for OPC has traditionally relied on radiotherapy, chemotherapy and/or other systemic treatments, and surgical resection. Depending on the stage and treatment of other factors may include a combination of modalities. The mainstay is radiotherapy in many cases. analyzes collected from published studies show comparable disease controls between radiation and surgery, but a higher rate of complications for surgery/- radiation. Ideally a single modality approach is preferred, because the three modalities are associated with more toxicity, and multidisciplinary teams in large centers with high patient volumes are encouraged.
The differences in response to treatment between HPV-OPC and HPV OPC may include wide differences and the way in which the mobile growth regulatory pathway is altered in two OPC forms. For example in HPV OPC oncogens HPV E6 and E7 simply make the p53 and pRb paths inactive, letting open the possibility of reactivation of these pathways by decreasing (decreasing) oncogenic expression. This is in contrast to the mutant p53 form found in HPV-OPC that is associated with treatment resistance. Furthermore, it is suggested that the effects of E6 and E7 on these pathways make the tumors more radiosensitive, possibly with impaired mechanisms such as DNA repair, red cell signaling and redistribution of cell cycles. The microenvironment is also important, with radiation increasing the host immune response to the viral antigen expressed on the tumor. Also, there is an association between increased lymphocyte infiltrate tumors and in the circulation of white blood cells in OPC HPV patients and better prognosis. This implies a role for the adaptive immune system in suppressing tumor progression.
Surgery
Historically, surgery provides a single approach to head and neck cancer. OPC surgical management carries a significant morbidity with a transervical approach (via the neck), often involving the mandibulotomy, in which the jawbone (mandible) is split. This is called an open surgical technique. Consequently, surgical approaches decrease in support of radiation. In the United States, the use of operations decreased from 41% of cases in 1998 to 30% in 2009, the year in which the Food and Drug Administration approved the use of newer techniques.
This improvement in surgical technique has enabled many tumors to be resected (removed) by the transoral (oral) (TOS) surgical approach, using transoral endoscopy and neck surgery (HNS). As a result operations are becoming more widely used, rising to 35% of cases in 2012. This approach has proven safety, efficacy and tolerability, and includes two major minimally invasive techniques, transoral robotic surgery (TORS) and transoral transoral (microsmery). There is no direct comparison between these two techniques that have been done, and clinical trials on head and neck cancers such as ECOG 3311 allow both. They are associated with large postoperative morbidity, depending on the resection level but compared with older techniques having shorter hospital stays, faster recovery, less pain, and less need for gastrostomy or tracheostomy, and less long-term effects, which minimal in the absence of postoperative radiation (RT), or chemoradiation (CRT). TORS has the practical advantages that make the telescope tilt and rotate the robotic surgical sleeve providing a better outline. The result of a minimally invasive procedure is also proportional to the more invasive one. In early-stage disease, including neck node involvement, TORS results in a 2-year survival of 80-90%. The same TLM, reportedly has a five-year survival of 78% and a local control rate of 85-97%. In addition to the initial disease, minimally invasive surgery has been used in advanced cases, with local controls of up to 90% and disease-specific survival. Postoperative swallowing is very good at 87%, but long-term dysphagia is associated with greater cancer (T4), especially if involving the base of the tongue.
Details of the surgical approach depend on the location and size of the primary tumor and stage N. Neck dissection to check for dried lymph nodes can be performed simultaneously or as a second staging procedure. For tonsile tumors and lateral pharyngeal walls, and clinically negative nodules (N0), neck dissection usually involves ipsilateral level 2-4 ( see the diagram). When nodes are involved clinically, dissection will depend on the location and size of the node or node. In the case of the basic prelate of the tongue, close to the midline, bilateral dissection is recommended. Pathological Staging
The advantage of the primary surgical approach is the amount of pathological information available, including levels, margin status, and lymph node involvement levels. This may alter the staging, as up to 40% of patients may have different post-operative pathological stages compared to their preoperative clinical stage. In one study, 24% experienced a decrease in stages (downstaged), which could have an impact on subsequent decision making, including decreased intensity and morbidity. In the United Kingdom, the Royal College of Pathologists (1998) has standardized surgical margin reporting, with two categories, "mucosa" and "in", and for each group made based on microscopic distance from invasive cancer to margin, as follows: mm (clear), 1-5 & amp; nbspmm; (close) and less than 1 mm (involved).
Postoperative adjuvant therapy
Data on the use of postoperative radiation therapy (PORT) is largely limited to historical or retrospective studies rather than high-quality randomized clinical trials and is based on the overall population of patients with head and neck cancer, rather than OPC HPV-specific studies, which will form a very small proportion of population studied. Despite surgical excision, in more advanced cases, local and regional recurrence of cancer, along with outbreak and neck spread (metastasis) are common. The risk of subsequent recurrent illnesses is highest in those tumors in which pathology shows tumors in resection margins (positive margins), some of the involved regional lymph nodes and extension of tumors outside the lymph node capsule (extracapsular extension). PORT was introduced in 1950 in an effort to reduce treatment failure from surgery alone. Although never tested in a controlled setting, PORT has been widely adopted for this purpose. In an analysis of surgical failure at the Sloan-Kettering Memorial Cancer Center, surgically treated patients between 1960-1970 had a failure rate of 39 and 73% for those with negative and positive surgical margins. This compared with those who received PORT (with or without chemotherapy) from 1975-1980. The latter group had a lower failure rate of 2% and 11%, respectively. In addition, a randomized study from the 1970s (RTOG 73-03) compares preoperative radiation to PORT, and found a lower failure rate with the latter.
The addition of another treatment modality is referred to as adjuvant therapy (literally helpful), compared to its use as a primary (primary) therapy, also referred to as radical therapy. As a result, many of these patients have been treated with adjuvant radiation, with or without chemotherapy. In a series of reports above minimally invasive surgery, many (30-80%) patients received adjuvant radiation. However, functional outcomes are worse if radiation is added to surgery and worst if radiation and chemotherapy are used. The radiation dose has many follow-derived for all head and neck cancers, in this setting, based on risk. Historically only one randomized clinical trial had discussed optimal dosage, allocated patients to two dose levels, grouped by risk, but did not show differences in cancer control between low and high doses (63 and 68.4 Gy), but the incidence of more complications high at higher doses. As a result, a lower dose of 57.6 Gy is recommended. Since the authors used the 1.8 Gy fractionation scheme per treatment, this dose was not widely adopted, the practitioner preferred a fraction greater than 2 Gy to produce a shorter treatment time, and a slightly higher dose of 60 Gy in 2 Gy fractions (30 daily treatments). However 57.6 Gy in 1.8 Gy fraction is equivalent (iso-effective dose) for only 56 Gy in 2 Gy phrase. 60 Gy according to 63 Gy is used as low dose in high risk group. 60 Gy is also the dose used in RTOG 73-03. Furthermore, there is a tendency to intensify treatment on head and neck cancer, and a number of centers adopt a dose of 66 Gy, at least for patients with adverse tumor features. The effectiveness of PORT in HPV OPC received some support from the cohort study (Level 2b), although the number of patients was low, and the number of incidents (recurrent illness or death) was only 7%. Another retrospective population level study (Level 4) from the SEER database (1998-2011) concluded that there was overall survival but no specific radiation-specific survival effects in 410 patients with single lymph nodes involved, but only using univariate statistics. analysis and does not contain information about HPV status. A much larger study in the same population at the National Cancer Database (2004-2013) of more than 9,000 patients found survival advantage but this was only in HPV-OPC, not in 410 OPC HPV patients.
Deintensification
While fewer studies have completed checking for deintensification in this setting, rather than primary radical radiation for this cancer (see below), this is an active field of investigation. In a single agency study, a decision was made to reduce radiation doses in high-risk patients with HPV OPC from 66 to 60 Gy, according to actual evidence, and follow-up showed no decrease in cancer control. Current trials, both in North America and Europe (such as ECOG 3311 and PATHOS) use 50Ã, Gy as a comparison arm. A comparator of 50 Gy is selected on the basis of (i) excellent OPC HPV sensitivity to radiation, both in vitro and in vivo; ECOG 1308 showed excellent disease control at 54 Gy; and data showing that 50 Gy in 1.43 Gy (the iso-effective dose of 43 Gy in 2.0 Gy is enough to treat the neck electively.Another study evaluates doses as low as 30 Gy in high-risk cases.
Chemotherapy has been used in conjunction with radiation in this setting, as in primary treatment with radical radiation, especially where the pathological features indicate a higher risk of cancer recurrence. a number of studies suggest that this does not improve local control, although it adds toxicity.
Radiotherapy
Concerns over the morbidity associated with open traditional open surgical resection, led to exploring alternative approaches using radiation. Intensified modulated radiation therapy (IMRT) can provide good control of the primary tumor while maintaining excellent levels of control, by reducing the toxicity of salivary and pharyngeal structures relative to previous technologies. HPV OPC has shown increased sensitivity to radiation with faster regression, compared to HPV-OPC. IMRT has a two-year disease-free survival between 82 and 90%, and a special disease-specific survival of two years to 97% for stages I and II.
Reported toxicities include dry mouth (xerostomia) from salivary gland damage, 18% (level 2); difficulty in swallowing (dysphagia) from damage to constrictor muscles, larynx and esophageal sphincter, 15% (level 2); subclinical aspiration up to 50% (incidence reported aspiration pneumonia about 14%); hypothyroidism 28-38% at three years (possibly up to 55% depending on the number of thyroid glands exposed to radiation greater than 45 Gy; esophageal stenosis 5%; 2.5% mandibular osteonecrosis; and the need for gastrostomy tubes to be placed at some point during or up to one year after treatment 4% (up to 16% with longer follow-up). Concerns have been expressed about short-term and long-term toxicities, especially dysphagia and xerostomia, and therefore whether standard doses better expose patients to prognosis being exposed to adverse events excessive and unnecessary side effects.
Dosimetry
The probability of xerostomia in one year increases by 5% for every 1Gy increase in dosage to the parotid gland. Doses above 25-30 Gy are associated with moderate to severe xerostomia. Similar considerations apply to the submandibular glands, but xerostomia is less common if only one parotid gland is included in the radiation area and the contralateral submandibular gland is spared (less than 39 Gy). In the same way, the radiation dose to the muscle of the pharyngeal, laryngeal, and cricopharyngeal inlet constituents determines risk of dysphagia (and hence dependence on gastrostomy tube feed). The threshold for this toxicity depends on the volume of 55-60 Gy, with moderate to severe disturbance, including aspiration, stricture and tube dependence over an average dose of 47 Gy, with the recommended dose for inferior constituents less than 41 Gy Dose -toxicity for the superior and medium borders is very steep, with a 20% increase in the likelihood of dysphagia for every 10 Gy. For late dysphagia, the threshold means total dose of constrictors, to limit levels greater than or equal to grade 2 and 3 under 5% are 58 and 61 Gy respectively. For level 2 dysphagia, this figure increased 3.4% per Gy. Doses above 30 Gy to the thyroid are associated with moderate to severe hypothyroidism. Subjective, patient-reported outcomes of quality of life also correlate with the received radiation dose.
Changes in fractionation schemes, such as RTOG 9003 and RTOG 0129 have not provided additional benefits. Recommended radiation doses were highly empirically determined in clinical studies with some OPC HPV patients, and remained unchanged for half a century, making it difficult to determine the optimal dose for this subgroup. The general approach uses 70 Gy bilaterally and anteriorly, such as RTOG 9003 (1991-1997) and RTOG 0129 (2002-2005). For lateral tonsillar cancer unilateral neck radiation is usually determined, but for primary tongue tongue, bilateral neck radiation is more common, but unilateral radiation can be used in which the tongue base lesion is lateralized.
Deintensification
Concerns have been expressed about short-term and long-term toxicities, especially dysphagia and xerostomia, and therefore whether standard doses expose patients to a better prognosis for overtreatment and unnecessary side effects. The current toxicity has been described as "intolerable", and therefore intense interest in de-escalation.
While comparisons with historical controls have limited scores compared with randomized clinical trials (phase III), phase II studies using lower radiation doses compared to the 70 Gy historical standard have been performed. A study using 54-60 Gy (15-20% reduction, grouped based on response to early induction chemotherapy) showed a level of disease control comparable to a much lower complication rate, when compared with similar studies, using 70 Gy, such as ECOG 2399. The percentage of patients living after 2 years was 95% at higher doses and 98% at lower doses. Similarly for the percentage of disease-free (86 and 92%). Toxicity is greatly reduced from the incidence of grade 3 or greater, dysphagia and mucositis respectively 54 and 53%, to 9%. The lower incidence and severity of dysphagia also means that fewer patients require gastrostomy. A similar comparison can be made with data collected from two RTOG studies using 70 Gy (0129 and 0522).
There are no new guidelines specifically addressing OPC HPV that have been developed, outside of clinical trials. Indirect data show less intense treatment efficacy. An advanced retrospective (N) HPV OPC analysis suggested 96% local 5-year control with radiation-defined from 54 Gy and concurrent cisplatin-based chemotherapy. The conclusion of a similar pair of phase II experiments has been supported by several other phase II trials. A prospective trial (ECOG 1308) showed a locoregional control similar to 54 Gy, and another study, a complete pathological high response rate at 60 Gy. All of these studies were used well below the previous standard dose of 70 Gy. Because long-term toxicity is associated with radiation doses, determining the efficacy of lower radiation doses and therefore less morbid is a priority, as many HPV patients can be expected to have long-term survival.
Radiation is commonly used in combination with chemotherapy, but can also be used as a single modality, especially in the early stages, eg. T1-T2, N0-1, and their use in the later stages are being explored in clinical trials such as RTOG 1333 which compares radiation alone with radiation with reduced chemotherapy, in non-light smokers.
Chemotherapy
Like radiotherapy data, most of the available knowledge on chemotherapy efficacy comes from advanced head and neck cancer treatment rather than OPC HPV-specific studies. Since 1976, many clinical studies have compared CRTs with RT alone in the primary management of local head and neck cancers and have demonstrated advantages to CRT in both survival and locoregional control. Cisplatin is considered a standard agent, and survival benefits are seen for patients receiving concurrent cisplatin radiation. Although no direct trial comparing cisplatin with other agents in this context has been done. Another widely used agent is Cetuximab, a monoclonal antibody directed at the epidermal growth factor receptor (EGFR). The 10% survival advantage over three years was recorded when cetuximab was administered simultaneously with radiation (bioradiation). Cetuximab trial completed before knowing the status of HPV. Its main toxicity is acne rash, but it has not been compared directly with cisplatin in OPC HPV, although RTOG 1016 answers this question. Concurrent chemotherapy is also superior to chemotherapy alone (induction chemotherapy) followed by radiation. Cetuximab showed no benefit when added to cisplatin in combination with radiation. Although chemoradiation became a treatment standard based on clinical trials and in particular, meta-analysis, subsequent population-based studies in patients with OPC, showed no advantage in the addition of chemotherapy to radiation to HPV OPC or HPV-OPC, and significant concerns about additional toxicity.
Chemotherapy also has a role, combined with radiation, in postoperative settings (adjuvant therapy). It is commonly used in which the pathology of the resected specimen shows features associated with a high risk of locoregional recurrence (eg extracapsular extension via involved lymph nodes or very close margins). This has shown increased disease-free survival and locoregional control in two very similar clinical trials in such high-risk patients, EORTC 22931 (1994-2000) and RTOG 9501 (1995-2000). However, for OPC HPV patients, such extracapsular deployment does not appear to be a detrimental factor and the addition of chemotherapy to radiation in this group does not provide any further benefit. Because of the size of the sample to detect large survival advantages, given the small number of events in this group, the study may be less energetic and questions about the usefulness of adding chemotherapy are being discussed in randomized clinical trials (ADEPT) with two year-old locoregional control and disease-free survival endpoint. The addition of chemotherapy to radiation increases acute and advanced toxicity. In the GORTEC trial, chemotherapy with docetaxel provides improved locoregional survival and locongegional control of the local OPC, but is associated with increased mucositis and the need to eat with gastrostomy. Chemotherapy and radiation are associated with a 3-4% mortality risk in this context. It is unclear whether additional toxicity adding chemotherapy to radiation is offset by significant clinical benefits in disease control and survival.
It is estimated that OPC HPV patients benefit better from radiotherapy and concurrent cetuximab treatment than HPV-OPC patients receiving the same treatment, and that radiation and cisplatin induce an immune response to antigenic tumors that increase their effect on cancer cells. Despite the low positive HPV incidence (10-20%), the benefits for OPC HPV are seen in trials of both cetuximab and panitumumab, similar anti-EGFR agents, but not interactions consistent with treatment, although HPV OPC does not seem to be as useful as HPV-OPC for second-line anti-EGFR therapy, probably due to lower EGFR expression in the OPC HPV.
Choice of treatment approach
In the absence of high-quality evidence comparing the primary surgical approach to other modalities, decisions are based on consideration of factors such as adequate surgical exposure and favorable anatomical features for adequate resection, post-treatment function and quality of life. The selection of such patients enables them to avoid additional adjuvant treatment morbidity. In the absence of favorable surgical features, treatment of primary choice remains radiation with or without chemotherapy. Characteristics of tumors supporting non-surgical approaches including invasion on the tongue base to levels requiring resection of 50% or more of the tongue, pterygoid muscle involvement, extension to parapharyngeal fat bordering carotids, mandibular or maxillary involvement or invasion of prevertebral spaces.
Adequacy of surgical resection is a major factor in determining the role of postoperative adjuvant therapy. In the presence of a positive margin on pathological examination, most radiation oncologists recommend radiation to the primary site, and concurrent chemotherapy. Negative margins are more likely to be tracked with lower doses and smaller treatment volumes. Also large tumor removal may allow dose reduction to the unaffected pharyngeal structure and hence less effect on normal swallowing.
Cancer outcomes (local control, regional control, and survival) for transoral resection are followed by adjuvant therapy in proportion to primary chemoradiation, so treatment decisions depend more on treatment-related morbidity, functional outcome, and quality of life. Patient factors also need to be taken into account, including common basic functions, smoking history, anesthesia risk, oropharyngeal function, swallowing and airway protection and potential for rehabilitation. Patient preference is equally important. Many clinical trials are underway with a focus on deintensification, often with risk stratification, eg Low, Medium and High Risk (see see Fundakowski and Lango, Table I ).
Clinical decisions also take into account morbidity, especially if comparable cancer outcomes for surgery for example are associated with a 5-10% bleeding risk, and a 0.3% risk of fatal postoperative bleeding. Surgery can also be complicated by dysphagia, and while most patients can tolerate diet on the first postoperative day, long-term use of the filler tube has been reported as high as 10%. Patients with larger tumors, tongue involvement and requiring postoperative adjuvant therapy are more likely to require long-term filler tubes. Overall, the function and quality of life appear to be relatively similar between surgery to postoperative radiation, and primary chemoradiation, but OPC OPT patients tend to have a better quality of life when diagnosed than HPV-OPC but can sustain a greater loss after treatment.
Anatomical considerations may also determine preferences for surgical or non-surgical approaches. For example, trismus, large tongue, limited extension of the neck, protruding teeth, mandibular mandibes (mandibular bone growth) or limited mandibular width would be a relative contraindication to surgery. Tumor related considerations include mandibular invasion, skull base and extensive laryngeal involvement or more than half of the base of the tongue. Technical considerations in offering operations as a primary modality include the ability to allegedly achieve sufficient margin within the resected specimen and the degree of defect caused, as close or positive margins tend to produce subsequent adjuvant therapy to achieve disease control, with the result of increased morbidity. Costs are difficult to estimate but one US study, based on an estimated 25% of all OPC patients receiving surgery alone and 75% of surgery followed by adjuvant therapy, using the NCCN criteria, found that this approach was cheaper than primary chemoradiation.
Initial disease is associated with relatively favorable outcomes, where single modal therapy is recommended, the choice depends on the location of the tumor and accessibility. For example unilateral tonsils or base tumors of the tongue will generally be treated with transoral resection and selective ipsilateral neck dissection. On the other hand, large midline tongue lesions will require bilateral neck dissection, but in the absence of what is considered an adverse pathology (positive margins, extracapsular extension) is likely to be treated by surgery alone or radiation including ipsilateral or bilateral neck radiation fields, with surgery for examples where possible adjuvant therapy is low.
But many HPV OPCs present with lymph node involvement in the neck, and therefore a higher stage of disease, commonly referred to as advanced local disease. This group was largely treated with multimodality therapy, with the exception of one of the more favorable subgroups with small primary tumors and lymph node involvement confined to a node no larger than 3 cm, which, as recorded, was considered to be an early stage disease. Three main options for locally advanced but operable disease are resection, neck dissection and adjuvant therapy; chemoradiation (with possible rescue operations); induction chemotherapy followed by radiation or chemoradiation. But the last option is not yet supported in a clinical trial that tests it. The main consideration of surgery for advanced local disease is to obtain adequate negative margins and postoperative postoperative reserves of the patient. But this must be balanced against the morbidity and functional loss of extensive resection, especially where the base of the tongue is involved. To avoid such morbidity, primary chemoradiation is preferred. Management of diseases in cervical lymph nodes should be taken into account in treating advanced local disease. The guidelines for all OPCs specify that ectracapsular extension is given postoperative chemoradiation. Where rough cervical disease is proven initially primary chemoradiation is usually given.
Patient preferences
The current guidelines are based on data for OPC as a whole, so patients are generally treated regardless of HPV status, but many doctors and researchers consider deintensification. It is likely that treatment of this condition will continue to evolve in the direction of deintensification, to minimize loss of function but to maintain disease control. In the absence of clinical trials and specific guidelines, patient preferences need to be considered to minimize short-term and long-term toxicities as well as functional loss and optimize quality of life, given the prolonged survival that is often seen. This may involve exploring patient values ​​regarding illness control trade-offs on treatment side-effects. Patients who have received CRT as a primary treatment for OPC place high value on survival, and although agree that deintensification is desirable, are reluctant to trade many survival benefits for lower toxicity, although it is more likely to forget chemotherapy than to receive less radiation.
Unknown primary carcinoma
In some situations OPC HPV may present with cervical lymph nodes but there is no obvious disease of the primary tumor (T0 N1-3) and is therefore classified as an Unknown Primary Carcinoma of Squamous Cell Squamous Cells. Lack of evidence such as primary tumor occurs in 2-4% of patients with metastatic cancer in the cervical nodes. The positive incidence of HPV increases at the same rate as seen in OPC. In such situations, lingual and palatine tonsil resection, along with neck dissection may be diagnostic and is a sufficient intervention, as the recurrence rate is low.
Prognosis
The presence of HPV in tumors has been realized to be an important factor for predicting survival since the 1990s. The HPV Tumor Status is strongly associated with positive and survival therapy response compared to HPV-negative cancers, regardless of the treatment modality chosen and even after adjustment for the stage. While OPC HPV patients have a number of favorable demographic features compared to HPV-OPC patients, the difference is only about ten percent of the apparent survival differences between the two groups. Over 80% response rates reported in HPV and three-year free development survival have been reported as 75-82% and 45-57%, respectively, for HPV and HPV-cancer, and improved with increasing time. It is likely that OPC HPV is inherently less malignant than HPV-OPC, because surgically treated patients have better survival after adjustment for stage. In one study, less than 50% of patients with HPV-OPC were alive after five years, compared with more than 70% with OPC HPV and equivalent stage and disease burden.
In a RTOG 0129 clinical trial, in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis (recursive-partition analysis, or RPA) in three years identified three groups of survival risk (low, medium and high) based on HPV. status, smoking stage, stage T and N ( see Ang et al., Figure 2). HPV status is the main determinant of survival, followed by a history of smoking and staging. 64% were HPV and all were in the low and medium risk group, with all non-smoking HPV patients in the low-risk group. 82% of HPV patients live at three years compared with 57% of HPV patients, a 58% decrease in the risk of death. The locoregional failure was also lower in HPV, to 14% compared with 35% for HPV-. HPV positivity confers a 50-60% lower risk of disease progression and death, but tobacco use is an independent negative prognostic factor. The analysis collected from OPC and HPV-OPC HPV patients with disease progression in RTOG 0129 and 0522 trials showed that although fewer HPV OPC developed disease (23 v. 40%), the median time for disease progression after treatment was similar (8 month). The majority (65%) of recurrences in both groups occurred within the first year after treatment and were locoregional. HPV does not reduce the rate of metastasis (about 45% of patients experience progression), especially to the lungs (70%), although some studies have reported lower rates. with a recurrent 3-year recurrence rate of about 10% for patients treated with primary radiation or chemoradiation. Even if recurrence or metastasis occurs, positive HPV still benefits.
In contrast, the use of tobacco is independently of negative prognostic factors, with a decrease in response to therapy, an increase in disease recurrence rate, and a decrease in life expectancy. Negative effects of smoking, increased by the number of smoking, especially if more than 10 pack-years. For patients such as those treated at RTOG 0129 with primary chemoradiation, detailed nomograms have been derived from the dataset combined with RTOG 0522, allowing predictive results based on a large number of variables. For example, a 71-year-old married and non-smoking high school graduate with a performance status (PS) of 0, and no weight loss or anemia and T3N1 HPV OPC would expect a 92% free survival progression in 2 years and 88 % at 5 years. Unmarried 60-year-old unmarried high school graduates with PS 1, weight loss and anemia and T4N2 HPV OPC will expect to survive 70% at two years and 48% at five years. Insufficient information is available for those who are treated primarily by surgery, for less-available patients, as well as low recurrence rates (7-10%), but features traditionally useful in predicting prognosis in head and neck cancers, appear to be less useful in HPV OPC. These patients are often grouped into three risk groups:
- Low risk: No adverse pathological features
- Medium risk: T3-T4 primary, perineural or lymphovascular invasion, N2 (AJCC 7)
- High risk: Positive margin, ECE
HPV OPC patients are less likely to develop other cancers, compared to other head and neck cancer patients. Possible explanations for the beneficial effects of HPV are "lower likelihood of amplification of the 11q13 gene, considered the underlying factor of faster and more frequent relapse of the disease." The presence of the TP53 mutation, a marker for HPV-OPC, is associated with a poor prognosis. High-level p16 staining was considered better than HPV PCR analysis in predicting radiotherapy response.
Epidemiology
By 2015, squamous cell cancers in the head and neck areas are the fifth most common cancer in addition to skin cancer, globally, with an annual incidence of 600,000 cases and about 60,000 cases per year in the United States and Europe. The global incidence of pharyngeal cancer in 2013 is estimated to be 136,000 cases. For 2008, the global disease burden for OPC in 2008 is estimated to be 85,000 cases, of which 22,000 are caused by HPV, a 26% fraction (PAF) population. Of these, 17,000 are male and 4,400 female, 13,000 (60%) are between 50 and 69 years of age, and most cases (15,000) are in developed areas compared to developing regions (6,400). The age of Incidentized Incidence Rates (ASR) differs greatly by region and country (see i de Martel et al., 2017 Fig. 2b). ASR for 2012 is the highest in Europe (Hungary 3.0) and North America (United States 1.7) but much lower in Africa (<= 0.3), Asia (<= 0.6), Latin America (<= 0.4) and Oceania (< = 0.2)) (other than Australasia, Australia 0.9). Estimates of the average number of cases and ASR for the US in the 2008-2012 period were 15,738 and 4.5 respectively. HPV OPC is much more common in men than women (12,638, 7,6 and 3,100, 1.7). The highest incidence age group is 60-69, and is higher in Caucasian than other races.
OPC HPV patients tend to be younger than HPV patients in general. Clinical presentation also changed from patients with head and neck cancer "common" with old age and the use of key substances. In contrast, patients with younger HPV (4-6 decade) cancer, men (ratio 8: 1) with none or only smoking history, generally Caucasian, achieve higher levels of education, marry, and have higher incomes. Risk factors for HPV-OPC and HPV OPC tend to be independent, with the exception of smoking that has adverse effects on both. The presentation feature also differs between HPV and HPV-OPC. HPV tumors have smaller primary lesions (less than 4 cm) but further nodal disease results in a higher stage of TNM. This in turn may overestimate the severity of disease status.
Trends
There has been a global trend in increasing the incidence of OPC, especially in North America and Northern Europe, but even in Taiwan, which has a very high rate for all cancers in the head and neck region, OPC levels increased faster between 1995 and 2009. than sites other cancers. OPC's global HPV Expenses increased from 22,000 in 2008 to 29,000 in 2012, and PAF from 26% to 31%, and is considered an epidemic. In the United States the estimated number of cases is 12,410 in 2008, 13,930 in 2013 and 17,000 for 2017. Of these cases, HPV cancer has increased compared to HPV cancer, but an increase in OPC HPV exceeds the HPV-OPC decline resulting in an overall increase in OPC. Increased incidence of pharyngeal cancer contrasts with a marginal decrease in head and neck cancer. As a result, the most common head and neck cancer has shifted from the larynx to the oropharynx. A survey of 23 countries between 1983 and 2002 showed an increase in oropharyngeal squamous cell carcinoma especially seen in young men in economically developed countries. In the UK the incidence of oral and oropharyngeal cancer in men increased by 51%, from 7/100 to 11/100,000 between 1989 and 2006. In the US there was a growing incidence of oropharyngeal cancers associated with HPV, In the early 1980s HPV accounted for only 7.5% of cases in the US but by 2016 this is 70%, possibly as a result of changes in sexual behavior, decreased popularity of tonsillectomy, increased radiological and pathological evaluation, and changes in classification. Tonsillar and oropharyngeal cancer increased in male dominance between 1975 and 2004, although there was a decrease in smoking. HPV-OPC declined with a decrease in smoking levels from 1988 to 2004, while HPV OPC increased by nearly 7.5% annually from about 16% of all OPC cases in the early 1980s to nearly 70% in 2004. The decline in smoking may be related with a decrease in the proportion of HPV-negative cancers, while changes in sexual activity may be reflected in an increased proportion of HPV-positive cancers. More recently, in the US, OPC-related HPV accounts for about 60% of OPC cases compared with 40% in the previous decade. In 2007, in the US, general OPC events, including non-HPV related, were 3.2 cases per 100,000 males/year and 1.9 per 100,000 sex/year. This makes HPV OPC one of only five cancers that have increased incidence in the US since 1975. The highest incidence of incidence occurs in patients under 50 years of age.
Increased incidence of OPC-related HPV is also seen in other countries, such as Sweden, with a 2007 incidence of over 80% for cancers in tonsils, Finland, and the Czech Republic. Partners of patients with HPV positive oropharyngeal cancers do not appear to have an increase in oral HPV infection compared with the general population. In Australia, OPC-related HPV-related events were 1.56 cases per 100,000 male/year (2001-2005), up from 19% (1987-90), to 47% (2001-05) and 63.5% (2006 -2010). In Canada the percentage of OPC cases associated with HPV increased from 47% in 2000 to 74% in 2012.
See also
- Cancer
- Head and neck cancer
- Oropharyngeal cancer
- Human papilloma virus
- Awareness and prevention of HPV-related oropharyngeal cancer
Note
References
Bibliography
External links
Source of the article : Wikipedia
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