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- Best Practice in Systemic Therapy for Head and Neck Squamous Cell Carcinoma
- Overview of Head and Neck Tumors
- 2019, Number 3
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Head and neck cancer accounts for nearly A mean of The variables analyzed included: age, gender, occupation, skin color, tobacco and alcohol consumption, primary site of the tumor, clinical staging, degree of histological differentiation and outcome. The data was analyzed by descriptive and exploratory statistics.
Best Practice in Systemic Therapy for Head and Neck Squamous Cell Carcinoma
Treating head and neck cancer patients with systemic therapy is challenging because of tumor related, patient related and treatment related factors. In this review, we aim to summarize the current standard of care in the curative and palliative setting, and to describe best practice with regard to structural requirements, procedures, and monitoring outcome.
Treatment advice for individual head and neck cancer patients is best discussed within a multidisciplinary team. Cisplatin is the drug of choice for concomitant chemoradiotherapy in the primary and postoperative setting, and also a main component of induction chemotherapy.
However, acute and late toxicity is often significant. Checkpoint inhibitors have recently been proven to be active in the metastatic setting which has resulted in a shift of paradigm.
Detailed knowledge, institution of preventive measures, early recognition, and prompt treatment of adverse events during systemic therapy is of paramount importance. Documentation of patient characteristics, tumor characteristics, treatment details, and clinical and patient reported outcome is essential for monitoring the quality of care. Participation in initiatives for accreditation and registries for benchmarking institutional results are powerful incentives for implementation of best practice procedures.
Patients with advanced hypopharyngeal and laryngeal carcinomas can present with airway obstruction, or develop airway obstruction early during treatment and may require a tracheostomy. Patient related factors that can complicate systemic treatment are tobacco and alcohol addiction, co-morbidity and lack of a social network. In the curative setting, high-dose cisplatin concurrent with radiotherapy is the standard of care, either as primary treatment or after surgery.
Chemoradiotherapy induces high rates of acute and late or long term adverse events. Here, we summarize standard systemic treatment regimens, and describe best practice for administering systemic treatment with regards to structural requirements, procedures and monitoring outcome. In Table 1 , treatment regimens based on at least one phase III study are summarized.
In oropharyngeal cancer patients accelerated fractionation radiotherapy over 6 weeks with two cycles of high-dose cisplatin resulted in similar outcome as conventional fractionation radiotherapy over 7 weeks with three cycles of high-dose cisplatin Alternative concomitant systemic therapy regimens that improve overall survival compared to radiotherapy alone are carboplatin with infusional 5-fluorouracil 5FU 13 or cetuximab Similarly, elderly patients do not benefit in the same way as younger patients from the addition of cetuximab to radiotherapy This is paralleled by an increase in non-cancer related deaths in elderly patients.
Proper selection of fit elderly patients with geriatric assessment might identify a subgroup that derives the same benefit as younger patients, but prospective data to support this is currently lacking. Treatment of elderly head and neck cancer patients has recently been extensively reviewed Hypoxia modification with nimorazole during radiotherapy has been shown to improve locoregional control compared to radiotherapy alone 31 and is used in some countries as a standard of care.
Patients with locoregionally advanced human papilloma virus HPV associated oropharyngeal cancer have significantly better outcome than patients with non-HPV related HNSCC, and treatment de-intensification strategies are under investigation. However, two randomized studies recently demonstrated that radiotherapy with cetuximab results in inferior overall survival compared to CRT with high-dose cisplatin, which therefore remains the standard of care 11 , Outcome in these patients is improved by the addition of concomitant high-dose cisplatin to postoperative radiotherapy 15 , 16 , Results of studies with high-dose and low-dose concurrent cisplatin were recently summarized Of the two randomized trials that have been reported, one study was not evaluable for efficacy due poor accrual Locoregional control at 2 years was inferior in the low-dose arm It remains unclear to what extend the lower cumulative dose of the weekly regimen is responsible for inferior efficacy.
Induction chemotherapy followed by either radiotherapy alone, or radiotherapy with cetuximab, or CRT with weekly carboplatin, can be used as an organ preservation strategy. However, its benefit over CRT alone is not clear at this stage with conflicting phase III studies and heterogenous patient populations on these trials and the role of induction chemotherapy is therefore debated 36 , If induction chemotherapy is chosen, docetaxel with cisplatin and 5FU TPF is the preferred combination 7 — 9.
For patients with metastatic HNSCC, or recurrent disease that is not amenable to curative intent treatment, the EXTREME regimen consisting of cisplatin or carboplatin with 5FU and cetuximab followed by cetuximab maintenance has been the standard first-line treatment for the last decade Based upon a lower level of evidence, other chemotherapy combinations or single-agent treatment options can be considered 2.
In patients who progress after platinum containing chemotherapy, treatment with an anti-programmed death 1 PD1 antibody improves overall survival and induces durable responses in a subgroup of patients with a lower rate of grade 3—4 adverse events compared to investigator's choice systemic therapy 21 , 22 , 38 , Nivolumab was shown to improve overall survival irrespective of HPV status or programmed death ligand 1 PD-L1 expression with better preservation of quality of life compared to the control arm 38 , Pembrolizumab also improved overall survival, in the entire cohort and in the subgroups of patients with PD-L1 positive tumors The first requirement for effective delivery of systemic therapy to HNSCC patients is identification of patients in whom systemic treatment is indicated.
The best way of doing this is discussing every newly diagnosed patient, every patient with recurrent disease and every patient who requires a change in treatment plan, during a multidisciplinary team MDT conference. An MDT approach is associated with improved tumor staging, better adherence to quality indicators, more concomitant CRT, shorter time between surgery and adjuvant therapy, higher completion rate of adjuvant treatment, and most important: improved disease specific and overall survival 42 — This list closely resembles the core team defined in the Canadian guidelines 48 , The minimum recommended volume for medical oncologists who care for head and neck cancer patients is 25 per year, although scientific evidence to support this number is lacking 48 — In the Netherlands, the minimum required volume for immunotherapy in a hospital is 20 patients per year, but this may include different cancer types.
This enables quick communication between health care professionals and prompt admission to address adverse events, which helps to keep treatment breaks to a minimum. Specific information about treatment schedules, potential side effects, instructions on when to contact the oncology nurse or medical oncologist along with contact details, is of importance for patients. This can be digital or on paper. After discussing a patient within the MDT, it is recommended to file a report in the patient's records which accessible for every team member and contains tumor characteristics including TNM stage, patient characteristics such as co-morbidity, medical history, tobacco and alcohol consumption, treatment intent curative or palliative , and treatment plan If the treatment advice deviates from the guidelines, it is preferable to specify the reason for it.
A longer waiting time between histopathological diagnosis and start of primary treatment is independently associated with worse overall survival in patients with HNSCC The median tumor volume doubling time was shown to be 99 days in a Danish cohort, but in the half with the fastest growing tumors this was 30 days Therefore, starting treatment as quickly as possible will improve patient outcome.
If systemic therapy is recommended by the MDT, the patient is referred to the medical oncologist who will carefully evaluate if systemic treatment is feasible through assessing the performance status, co-morbidity, previous medical history, organ function, and current medication.
Vulnerability according to the G8 was found to be independently associated with worse overall survival and persistent lower quality of life in HNSCC patients who received curative intent chemo radiotherapy Furthermore, blood cell counts, renal function, electrolytes and liver tests need to be adequate, and have to be assessed before each cycle.
The tumor itself can cause problems with chewing, odynophagia, and dysphagia which can result in malnutrition. In addition, tooth extractions are performed in many patients before start of radiotherapy, further limiting the ability to eat normally. Also treatment side effects, especially of concomitant CRT, can cause swallowing problems.
In the acute phase this is mainly related to mucositis, while dry mouth and sticky saliva are prominent long term side effects. In order to secure nutrition during CRT, prophylactic placement of a percutaneous endoscopic gastrostomy PEG tube can be considered. In a randomized study prophylactic PEG tube placement resulted in less malnourished patients, longer enteral feeding and better quality of life at 6 months after treatment without increased risk of long-term dysphagia compared with a control group treated according to clinical practice 55 , However, not all patients need enteral feeding, and selection of patients at high risk for malnutrition based on weight loss before start of treatment, age and radiotherapy dose to the constrictor muscles, can be used to select patients for prophylactic PEG tube placement Nasogastric tube feeding appears to be an effective alternative to maintain body weight and the optimal method for enteral feeding of HNSCC patients has not yet been determined It is recommended to dose chemotherapy on actual body weight or, in the case of carboplatin, on actual stable creatinine clearance.
Including this information in the prescription, and filing prescriptions in the patient records facilitates personalized treatment modifications. Nausea is a prominent side effect of chemotherapy and cisplatin belongs to the high-emetic-risk antineoplastic agents.
A combination of four drugs consisting of a neurokinin 1 receptor antagonist, a serotonin receptor antagonist, dexamethasone, and olanzapine is recommended for cisplatin Carboplatin belongs to the moderate-emetic-risk category requiring a three-drug antiemetic regimen, and docetaxel, 5FU and cetuximab have a low-emetic-risk, however combinations and multiday regimens should be treated per day for the drug with the highest emetic risk, and for 2 days after the last dose In addition to general chemotherapy side effects, cisplatin can cause renal toxicity, hearing loss, and neuropathy, and it can provoke cardiovascular events.
Therefore, audiometric testing and an electrocardiogram is recommended before start of treatment, and thereafter if clinically indicated.
Adequate intravenous hydration from 2 to 12 h prior until at minimum 6 h after the administration of cisplatin is essential to protect renal function, and forced diuresis with mannitol or diuretics may be required Allergic reactions to platinum compounds can occur. Therefore, it is important to have medication and a protocol for treatment of allergic reactions readily available at the infusion facility.
Variations in the gene encoding DPD result in reduced enzyme activity, increased 5FU exposure and severe mucositis and hematologic toxicity. Prospective genotyping and upfront 5FU dose reduction in patients who carry a variant allele predicting reduced metabolism can prevent potentially lethal toxicity also in patients who undergo chemoradiation with a relatively low 5FU dose 61 , Docetaxel can induce fluid retention and hypersensitivity reactions characterized by generalized erythema and hypotension.
In order to reduce the risk and severity of these side effects, patients can to be treated with dexamethasone for 3 days, starting the night before docetaxel administration A study in Chinese patients with head and neck cancer receiving TPF showed that lower dexamethasone doses than the recommended six doses of 8 mg twice daily did not increase the risk of severe hypersensitivity reactions The risk of alopecia from docetaxel can be reduced by scalp cooling However, because of tumor localization close to the scalp, reduced efficacy as a result of cooling is a concern and therefore scalp cooling is not recommended in HNSCC patients.
For the TPF regimen, antibiotic prophylaxis with ciproflacin mg orally twice daily, from day 5 to 15 for prevention of neutropenic infections was administered in the pivotal trial 8. If patients develop neutropenic fever or neutropenic infection, addition of granulocyte colony stimulating factor G-CSF after the next cycles is recommended In a retrospective analysis, primary prophylactic G-CSF did not reduce the incidence of febrile neutropenia in patients treated with TPF and ciprofloxacin or levofloxacin Like for cisplatin, neuropathy is also a frequent side effect of docetaxel and assessment before each cycle is recommended.
Cetuximab can induce severe infusion-related reactions, including anaphylactic reactions even within minutes of the start of the first infusion. In the registration study, an antihistamine was administered as premedication, followed by a test dose of 20 mg cetuximab in 10 min followed by 30 min of observation Four out of patients discontinued cetuximab because of a hypersentitivity reaction after the test dose or the first dose.
The compendium advises premedication with an antihistamine and a steroid, as well as close monitoring and prompt treatment of allergic reactions A frequent adverse event of EGFR targeting drugs is an acneiform skin rash. Prophylactic treatment with an oral antibiotic such as doxycycline or minocycline can be used to reduce the severity of the rash, although not all trials showed consistent results, however it is recommended to instruct patients about sunlight protection Intravenous supplementation may be required and it may take several weeks or months to resolve.
Nivolumab, pembrolizumab, and other immune checkpoint inhibitors can cause a wide spectrum of immune related adverse events. The most frequently affected organs are the skin, the gastrointestinal tract, the lungs, and endocrine organs including thyroid, pituitary, and adrenal glands. Less commonly the musculoskeletal tract, nervous system, kidneys, eyes, and heart and blood vessels are affected. Some of these side effects are potentially lethal.
Prompt treatment usually results in complete resolution, although endocrinopathies may require lifelong hormonal substitution. For grade 3—4 toxicity, consultation of organ specialists such as a dermatologist, gastroenterologist, endocrinologist, pulmonologist etc. In contrast to chemotherapy and cetuximab, immune checkpoint inhibitors may be continued at first progression provided that the patient has not deteriorated, although the incidence of pseudoprogression appears to be low in HNSCC If there is suspicion of recurrent disease in patients treated with curative intent, imaging and biopsy is required for confirmation.
For evaluation of immunotherapy, a consensus guideline called iRECIST has been developed to capture response patterns such as pseudoprogression that differ from response patterns to cytotoxic agents
Overview of Head and Neck Tumors
Key words:. Int J Cancer ; 8 : Clinical practice guideline: evaluation of the neck mass in adults. Otolaryngol Neck Surg ; 2 Suppl : S Imaging anatomy of deep neck spaces. Otolaryngol Clin North Am ; 45 6 :
Head and neck cancer develops in almost 65, people in the United States each year. Larynx including the supraglottis, glottis, and subglottis. Oral cavity tongue, floor of mouth, hard palate, buccal mucosa, and alveolar ridges. Oropharynx posterior and lateral pharyngeal walls, base of tongue, tonsils, and soft palate. Less common sites include the nasopharynx , nasal cavity and paranasal sinuses , hypopharynx , and salivary glands.
Neck Tumours. IARC Press: Lyon ISBN 5. World Health Organization (WHO). WHO Blue Books on the web: WHO Blue Books in PDF.
2019, Number 3
Skip to Content. This is the first page of Cancer. Use the menu to see other pages. Think of that menu as a roadmap for this complete guide. Cancer begins when healthy cells change and grow out of control, forming a mass called a tumor.
Treating head and neck cancer patients with systemic therapy is challenging because of tumor related, patient related and treatment related factors. In this review, we aim to summarize the current standard of care in the curative and palliative setting, and to describe best practice with regard to structural requirements, procedures, and monitoring outcome. Treatment advice for individual head and neck cancer patients is best discussed within a multidisciplinary team. Cisplatin is the drug of choice for concomitant chemoradiotherapy in the primary and postoperative setting, and also a main component of induction chemotherapy. However, acute and late toxicity is often significant.
The neoplastic pathology of the head and neck is characterized by a wide variety of tumor types and histologic variants. Recent evidence has shown that in addition to physical and chemical carcinogens, viral infections such as EBV, HPV, and Merkel cell polyomavirus MCV , specific translocations play an important etiologic role in some tumors, such as poorly differentiated sinonasal carcinomas [t 15;19 ] and mucoepidermoid carcinomas [t 11;19 ].
Чтобы еще больше усилить впечатление о своей некомпетентности, АНБ подвергло яростным нападкам программы компьютерного кодирования, утверждая, что они мешают правоохранительным службам ловить и предавать суду преступников. Участники движения за гражданские свободы торжествовали и настаивали на том, что АНБ ни при каких обстоятельствах не должно читать их почту. Программы компьютерного кодирования раскупались как горячие пирожки. Никто не сомневался, что АНБ проиграло сражение. Цель была достигнута. Все глобальное электронное сообщество было обведено вокруг пальца… или так только. ГЛАВА 5 Куда все подевались? - думала Сьюзан, идя по пустому помещению шифровалки.
АНБ очень серьезно относилось к дешифровке. Полученный чек превышал его месячное университетское жалованье. Когда он шел к выходу по главному коридору, путь ему преградил охранник с телефонной трубкой в руке. - Мистер Беккер, подождите минутку. - В чем дело? - Беккер не рассчитывал, что все это займет так много времени, и теперь опаздывал на свой обычный субботний теннисный матч. Часовой пожал плечами. - С вами хочет поговорить начальник шифровалки.
Когда церковь получит все останки этого великого человека, она причислит его к лику святых и разместит отдельные части его тела в разных соборах, чтобы все могли проникнуться их величием. - А у вас здесь… - Беккер не сдержал смешка. - Да. Это очень важная часть! - заявил лейтенант. - Это не ребро или палец, как в церквях Галиции.
Теперь Дэвид Беккер стоял в каменной клетке, с трудом переводя дыхание и ощущая жгучую боль в боку. Косые лучи утреннего солнца падали в башню сквозь прорези в стенах. Беккер посмотрел. Человек в очках в тонкой металлической оправе стоял внизу, спиной к Беккеру, и смотрел в направлении площади. Беккер прижал лицо к прорези, чтобы лучше видеть.
Сьюзан, извини. Это кошмар наяву. Я понимаю, ты расстроена из-за Дэвида. Я не хотел, чтобы ты узнала об этом. Я был уверен, что он тебе все рассказал.
Красную, белую и синюю. Автобус тронулся, а Беккер бежал за ним в черном облаке окиси углерода. - Espera! - крикнул он ему вдогонку.
Упав, он устроил замыкание основного электропитания шифровалки. Но еще более страшной ей показалась другая фигура, прятавшаяся в тени, где-то в середине длинной лестницы.
- Мой человек ликвидировал его, но не получил ключ. За секунду до смерти Танкадо успел отдать его какому-то туристу. - Это возмутительно! - взорвался Нуматака.