Побочные эффекты лучевой терапии при опухолях головы и шеи, D. Fliss
The International Federation of Head and Neck Oncologic Societies Current Concepts in Head and Neck Surgery and Oncology 2012Побочные эффекты лучевой терапии при опухолях головы и шеи Дэн Флисс
Острые vs. поздние • Острые (ранние) осложнения: – В течении и после нескольких недель после облучения – Ткани с высокой степенью деление клеток (слизистая, кожа) – Обычно проходящие – Ткани с высоким α/β соотношением2012 – Фракционная доза не влияет
Острые vs. поздние • Поздние лучевые реакции: – Месяцы и годы после ЛТ – Ткани с медленным клеточным делением (low α/β ratio) – Обычно стойкие и прогрессирующие – Размер фракции имеет значение2012 (BED)
Поздние лучевые реакции по полости рта и глотке:• Стойкая ксеростомия• Ожоги и боли• Мукозиты• Дисфагия• Остеорадионекроз• Прогрессирующий кариес / зубные болезни 2012 Head and Neck Cancer: Multimodality Management By Jacques Bernier
Поздние осложнения как последствие ранних • Выраженная ранняя реакция может быть предшествующей позднему осложнению • Обе фазы манифестация процесса начатого сразу после облучения • Аутокринные, паракринные, и эндокринные влияния которые приводят к дисрегуляции окружения тканей2012
Диагностирование поздней токсичности - сложности • Поздние осложнения – недостаточно подсчитаны и описаны • Определение клинического исхода, разрешения • Стандартное определение степени осложнения • Мультимодальная терапия • Опухоль и местные факторы могут 2012 взаимодействовать с лечением
Система стадирования• The US NCI Common Terminology Criteria for Adverse Events• SOMA scale (Subjective, Objective, Management, Analytic procedures) 2012
Mucositis • Dose-limiting toxicity of H&N RT • Severe pain, dysphagia, weight loss • Psychological distress, isolation, depression • The most common cause of treatment interruptions à possible negative2012 impact on treatment efficacy
Mucositis • Concurrent CRT is associated with increased rates and more severe grades of mucositis compared with radiotherapy alone • The mucositis also occurs earlier2012 during treatment and lasts longer
Mucositis • ~2/3 of patients have severe mucositis during concurrent CRT • ~1/3 of patients in earlier trials were unable to complete their2012 planned treatment d/t toxicity
Mucositis • Usually begins ~2 weeks after starting RT • Symptoms continue for 4-5 weeks after completion of therapy2012
WHO s Oral Toxicity Scale World Health Organization s Oral Toxicity Scale Severe Mucositis Grade 1 Grade 2 Grade 3 Grade 4 Ulcers with Erythema, Mucositis extensive to the extent ulcers; erythema; Soreness that patient can patient ± erythema cannot alimentation swallow is not solid food swallow possible food2012
Mucositis • Wide variation in the methods of capturing, grading and reporting (NCI- CTC, WHO criteria, RTOG scale) • The reported rates of mucositis vary considerably among studies (25% to higher than 80%) • Physician-reported vs. patient-reported symptoms2012
Mucositis – Risk factors • Patient-related: – Poor nutritional status – Poor dental condition, poorly fitting dentures or oral appliances • Pre-treatment dental evaluation and treatment is beneficial in reducing severity of mucositis and ORN – Habits (Alcohol, smoking, tobacco chewing)2012 – Reduced/impaired salivary function – Previous cancer treatment
Mucositis – Risk factors • Treatment related: – Concurrent chemotherapy, agent (5-FU, MTX) and dose – Radiation dose, fractionation, treatment site – More sensitive: lips, pharyngeal wall, soft2012 palate, tonsillar pillars, buccal mucosa, lateral tongue, floor of mouth
Mucositis – Prevention and Treatment • No evidence-based guidelines!!! • Self-care regimens for oral hygiene • Avoidance of : – Chemical irritants (tobacco, alcohol, spicy food, citrus fruits and juices) – Physical irritants (extremes of hot and cold foods, hard or coarse foods) • Dietary changes as needed (pureed or liquid diet)2012
Mucositis – Treatment• Pain medications• Antibacterial or antifungal treatment as needed – Candida Albicans is the most common infection in pts receiving H&N RT à2012
Salivary Hypofunction Xerostomia• Proportional to the surface of salivary glands receiving > 3000- 3500 Gy• Effect is not reversible• Low salivary output, viscous, sticky saliva 2012
Dose-Volume Data Complication probability curves as a function of the mean parotid dose2012
Salivary Hypofunction Xerostomia • Dryness typically not relieved by sipping water • Impaired speech • Burning • Pain2012 • Difficulty in chewing and swallowing
Salivary Hypofunction Xerostomia • Taste disturbances aggravated by lack of normal salivary function • Chapped lips • Major effect on nutrition, social function, QOL2012
Salivary Hypofunction Xerostomia• In the long term major effects on dental health• Normal protective effects of saliva are not available• Caries, periodontal inflammation• Lifelong increased risk for ORN!! 2012
IMRT • Reduced dose to the noninvolved oral cavity • Reduced and limited extent of acute mucositis • Sparing of minor salivary glands2012 may further improve xerostomia
Xerostomia • Common late toxicity with a huge impact on QoL • Leads to multiple problems: – Difficulty speaking – Difficulty chewing and swallowing – Halitosis – Altered taste – Complaint of burning mouth, lips, or tongue – Dental problems, a propensity to oral infections2012 – Sleep disturbances
Sparing of the parotid glands only may not be sufficient!2012
RT Skin Effects • RT-induced damage to the basal layer of the epidermis; cells shed more rapidly • Inflammatory response à edema and erythema • Melanin rises to the surface à characteristic hyperpigmentation of2012 irradiated skin
RT Skin Effects • Begins 2-3 weeks after starting RT, continues for 3-4 weeks after completion of therapy • The effect is cumulative • Mild erythema àhyperpigmentation à dry desquamation (dryness,2012 pruritus) à moist desquamation
Other Oral-Oropharyngeal Side-Effects • Trismus: Limitations in mouth opening and jaw movements caused by fibrosis of irradiated muscles – Pain – Impaired chewing – Impaired oral hygiene procedures – Problems in dental treatment • More severe in patients who also have 2012 surgery involving mandible
Other Oral-Oropharyngeal Side-Effects • Taste alterations • Loss of taste, loss of appetite – Transient but may become persistent – Major effect on choice of food, malnutrition, weight loss 2012
Dysphagia • Field length greater than 82 mm at second phase of Rx • Concurrent chemotherapy • Site • Increasing age2012 • All increase risk for long term dysphagia
Survival Vs QOL • EORTC QLQC-30, EORTC H&N 30 peak complaints at 2-3 months from start of treatment • Major problems: – Nutrition – Pain2012 Head and Neck Cancer: – Psychiatric disorders Multimodality Management By Jacques Bernier
Esophageal Pathology in Patients After Treatment for Head and Neck Cancer • 100 patients, Mean age 64 (± 10) years; 75% were male. • Mean time between the end of treatment and endoscopy 40 (± 51) months. • 81% of HNCA was advanced stage (3 or 4). • Oropharynx (38%), larynx (33%), oral cavity (17%), unknown primary (10%), hypopharynx (1%), and nasopharynx (1%). 2012 Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.
Esophageal Pathology in Patients After Treatment for Head and Neck Cancer • Treatment modalities included – Surgery alone (15%) – Surgery with radiation (34%) – Radiation alone (6%) – Chemoradiation alone (24%) – Chemoradiation with surgery 2012 (20%) Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.
Esophageal Pathology in Patients After Treatment for Head and Neck Cancer • The findings on esophagoscopy included – Peptic esophagitis (63%) – Stricture (23%) – Candidiasis (9%) – Barrett metaplasia (8%) – Gastritis (4%) – Carcinoma (4%) 2012 – Only 13% had a normal esophagoscopy Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.
Esophageal Pathology in Patients After Treatment for Head and Neck Cancer • Esophageal changes after treatment for HNCA are likely multifactorial and related to: – Changes in bacterial flora – Mucosal injury from chemoradiation therapy – Fibrosis Xerostomia and its resultant change in pH – Use of a PPI was not associated with the endoscopic diagnosis of esophagitis in this cohort (P > 0.05)It is unclear if the severity of the esophagitis would have 2012 been worse had they not been on the PPI Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.
Severe acute mucositis is a surrogate risk index for long- term dysphagia 2012
Osteoradionecrosis • Bone within the radiation field becomes devitalized and exposed through the overlying skin or mucosa, persisting as a non- healing wound for three2012 months or more
Evolution of the concept of ORN • 1983, Marx suggested etiopathology • Endarteritis • Tissue hypoxia • Hypocellularity • Hypo-vascularity2012 • Tissue breakdown and chronic non- healing wounds
Evolution of the Concept of ORN • Suppression of osteoclast related bone turnover is the initial event in development of ORN2012 Ruggiero SL et al J Oral Maxillofac Surg 2004;62:527–34.
Evolution of the Concept of ORN • Fibro-Atrophic Theory : – fibroblast populations undergo total cellular depletion but also show a reduced ability to produce and secrete collagen; free radical formation, endothelial dysfunction, inflammation, microvascular thrombosis, fibrosis and remodeling, and finally bone and2012 tissue necrosis Delanian S, Lefaix JL. Radiother Oncol 2004;73:119–31
Epidemiology of ORN • Most frequently noted in the first few years after completion of treatment (70–94%) • Early onset ORN (<2 ) related to radiation doses > 70 Gy or surgical trauma • Late onset ORN, is thought to arise from trauma in a chronically hypoxic tissue environment2012
Mandibular Osteoradionecrosis in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: Incidence and Risk Factors • 73 patients treated for stage I - IV SCC of the oral cavity and oropharynx 2000 - 2007 • Treatment modalities included both RT with curative intent and adjuvant RT 2012 following tumor surgery. Monnier Y et al. Otolaryngol Head Neck Surg. 2011
Mandibular Osteoradionecrosis in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: Incidence and Risk Factors • Results The incidence of mandibular ORN was 40% at 5 years. • Conclusions: – Mandibular ORN is a frequent long-term complication of RT for oral cavity and oropharynx cancers. 2012 – Mandibular surgery before irradiation is the only independent risk factor.
Factors Predictive of Severity of Osteoradionecrosis of the Mandible • METHODS: Retrospective analysis, • 46 patients 2002 – 2009 • 93% had mandibular ORN, staged 0-III (Store and Boysen). • RESULTS: Advanced age, stage IV, RT dose, post-RT extractions, and lack of pre-RT dental extractions appeared predictive of severe2012 mandibular ORN Chopra S, et al. Head Neck. 2011 Epub ahead of print
Additional Risk Factors Drugs: • Abuse of alcohol and tobacco is clearly identified as risk factor for ORN. • 89% of patients with ORN generally continue smoking.2012 B.R. Goldwaser, S.K. Chuang, L.B. Kaban and M. August, Risk factor assessment for the development of osteoradionecrosis, J Oral Maxillofac Surg 65 (11) (2007):2311–2316
Additional modalities • COMPLETE RESTORATION OF REFRACTORY MANDIBULAR OSTEORADIONECROSIS BY PROLONGED TREATMENT WITH A PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE COMBINATION (PENTOCLO): A PHASE II TRIAL • Conclusion: • Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement.2012 DELANIAN S et al.Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 832–839, 2011
ORN After IMRT • RTOG-0022 study reported an incidence of 6% ORN in oropharynx cancer patients treated at fraction size of 2.2–66 Gy without chemotherapy.2012
ORN After IMRT • The University of Michigan reported on 176 patients treated with IMRT. • At a median follow-up of 34 months, no cases of ORN developed (attribute to conformality of IMRT, meticulous dental hygiene as well as salivary gland sparing ) • Similarly Studer reported a 1.3% incidence of2012 ORN after parotid sparing IMRT
HBO in Treatment of ORN of Jaws??? A systematic review in 2008 did not show value of hyperbaric oxygen therapy for osteoradionecrosisPitak-Arnnop P et al: Management of osteoradionecrosis of the jaws: An analysis of evidence. Eur J Surg Oncol 34:1123, 20082012 Pitak-Arnnop P et al. J Oral Maxillofac Surg. 2010;68(10):2644-5.
Radiotherapy Effects on Larynx • Dysphonia and laryngeal edema are potential long-term complications of radiotherapy for HNCa • The impact of dysphonia can result in severe distress and potential financial loss from sick leave • Irradiation of the neck results in dryness of the submucosal laryngeal glands, abnormal vocal cord vibration, and in severe case laryngeal edema2012 with resulting chronic dysphonia G. Sanguineti, et al. Int J Radiat Oncol Biol Phys, 68 (3) (2007), pp. 741–749 Nguyen et al. Oral Oncol. 2011 Sep;47(9):900-4. Epub 2011 Jul 2.
Radiotherapy Effects on Larynx • Laryngeal edema severity correlates with the radiation dose delivered to the larynx • Significant when mean dose > 43.5 Gy • For laryngeal and hypopharyngeal cancers, high doses to the larynx are unavoidable frequently resulting in long-term vocal cord edema.2012 G. Sanguineti, et al. Int J Radiat Oncol Biol Phys, 68 (3) (2007), pp. 741–749
Laryngeal sparingeffect ofTomoTherapy in apatient with locallyadvancednasopharyngealcancer: despite thepresence of a leftcervical node (yellowcircle) adjacent tothe larynx (red)treated to 70 Gy,and the area at riskfor extracapsularextension (lightgreen) treated to63 Gy, meanlaryngeal dose wasonly 17.8 Gy. 2012
Radiotherapy Effects on Larynx • 96 patients, median age was 55 years, 82% men. • Primary site of cancer was – Oropharynx 43 – Hypopharynx/larynx 17 – Oral cavity 13 – Nasopharynx 11 – Maxillary sinus 2 – Unknown primary 102012 Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8
Radiotherapy Effects on Larynx • 85% underwent definitive RT and 15% postoperative RT. • 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, • 59 received concurrent chemotherapy • 9 patients underwent RT alone. • The median follow-up was 102012 months. Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8.
Radiotherapy Effects on Larynx • 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. • the volume of the larynx receiving >or=50 Gy and volume of the inferior constrictor receiving >or=50 Gy were significantly associated with both2012 aspiration and stricture. Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8.
Quality of Life in Patients Treated for Advanced Hypopharyngeal or Laryngeal Cancer • A retrospective 2-center study included 100 patients in remission from squamous cell carcinoma, treated between 1998 and 2009. • 70 (24 hypopharynx, 46 larynx) treated by total (pharyngo-) laryngectomy followed by external radiation therapy, • 30 (13 hypopharynx, 17 larynx) underwent an organ- conservation protocol with concurrent radiochemotherapy or with induction chemotherapy using platin-5FU or taxan-platin-5FU followed by radiation therapy. • All patients responded to the quality of life questionnaires2012 (EORTC QLQ-C30 and QLQ-H&N35). M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.
Quality of Life in Patients Treated for Advanced Hypopharyngeal or Laryngeal Cancer • Advanced tumor stages IVa and IVb were significantly more frequent in the surgery groups • In pharyngeal cancer, the only significant difference between surgical treatment and laryngeal conservation was for sensory disorder (taste and odor), with better results in case of laryngeal conservation (p < 0.0001). • For the other items, there was a trend for quality of life to appear better in patients with laryngeal2012 conservation (p = NS). M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.
Quality of Life in Patients Treated for Advanced Hypopharyngeal or Laryngeal Cancer • In laryngeal cancer, the only significant difference was for dry mouth , which was significantly less invalidating with surgical treatment (p < 0.001). • The impairment of the other quality of life items did not differ between surgical and conservative treatment.2012 M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.
Complications After Radiation Treatment Base of Skull • Endocrinopathy • Cranial neuropathy • Visual deficits • The exposure of the optic apparatus, pituitary stalk, and brainstem must be considered during planning to2012 minimize complications. Hauptman et al. Int J Radiat Oncol Biol Phys. 2011 in press
Complications After Radiation Treatment Base of Skull • If the optic apparatus is included in the 80% isodose line, it might be best to fractionate therapy • Exposure of the pituitary stalk should be kept to <30 Gy to minimize endocrine dysfunction. • Brainstem exposure should be limited to <60 Gy in fractions.2012 Hauptman et al. Int J Radiat Oncol Biol Phys. 2011 in press