misc /NTT Normal Tissue Tolerances: /QUANTEC Esophagus V35 < 50% V50 < 40% V70 < 20% Mean dose < 34 Gy /TD5/5 (/Emami IJROBP 1991, "0360-3016191") Organ TD5/5 for 3/3 Lens 10 Retina 45 Brain 45-60 (necrosis in 6-8 mos) (partial 60Gy, whole 50Gy) Brain Stem 50 (54Gy) Spinal Cord 47 @20cm, 50 Gy @10cm (myelitis) (alpha/beta = 2) Optic Chiasm 50 (for pit adenoma, o/w 54 per Fuss) Optic Nerve 50 (54 Fuss) (9-10Gy for RS) Ear, middle 30 serous otitis. Salivary G 32 Parotid: IMRT limit Mean Dose to 26Gy, or <20Gy if possible, or V30 to 50%, or JH says V26 to <50% (D50 < 26Gy) Eisbruch says TD50 = 28.4Gy Thyroid 50 hypothyroid >20Gy or >7.5Gy of TBI => hyper or hypo in 3-5yrs (PerezCh12). Thyroid nodules >10yrs. Monitor FT4,TSH x10yrs. Lung 17.5-45 pneumonitis, alpha/beta = 3 Heart 40-45-60 pericarditis (6mo-1yr), cardiomyopathy over 10-20yrs after 30-36Gy, esp w/ adria. Heart is fx sensitive. Increased MI w/ threshold 1Gy!! 20 Gy for 50% of heart; 45 to 50 Gy produces incidence of 11% of ____?. Alpha/beta is 1 Gy (beta dominates) so this is late responding tissue and fractionation results in sparing Heart,peds 50% can get 30.6Gy heart ventricles <50% >25Gy (AWC) (CAD, CHF) heart V25Gy<5% (Breast tangents) whole heart (pericarditis) whole heart: mean <26Gy, V30<46% for pericarditis (QUANTEC), V25<10% for cardiac mortality. Kidney 23-30-50 nephritis 12Gy NBL, 14.4 WT, 19 RMS Bladder 65-80 bladder contracture Esophagus 55-60 stricture/perforation, <10cm gets 60Gy Stomach 50-60 ulceration/perforation /Liver 30-50 (ascites, radiation hepatitis, RILD, RUQ pain) Newer limits: 30Gy to 1/3- 1/2. Total Liver V30 <60% (Kim, Red 2007, "doi:10.1016/j.ijrobp.2006.08.015") 23.4 peds whole liver Mean 31.5Gy at 150BID (Laura Dawson or Russell, Red 1993;27(1):117-12) Small Bowel 40-50 (45) obstruct/perf/fistula Colon 45-55 obstruct/perf/fistula Rectum 60 (70 for brachy) proctitis/fistula Femoral head 52 ---- /Rubin 1989 Rubin P. Law and order of radiation sensitivity: absolute versus relative. In: Vaeth JM, Meyer JL, eds. Frontiers of radiation therapy and oncology. Basel: Karger; 1989:7–40 Testes 1-2 (azospermia) (oligospermia @ 44 cGy, chromo abnl @ 40 cGy) Ovary 6 Lens 6-10 Lung 20 Kidney 20 Skin 30 Salivary 30 Liver 35 Thyroid 30 Heart 40 Lymphoid 40 /Bone Marrow 40 (/Mell, Red 06: BM V10<90, V20<75 (old, too generous?) important for acute BM toxicity, V30-50 for chronic) GI 50 connective tissue 50 spinal cord 50 peripheral nerve 65 brain 60 bone/cartilage >70 muscle >70 Rose, 2010, BM sparing IMRT. LOOK THIS UP. FROM OTHER SOURCES: bladder 65-80 uterus 90-100 cervix 200 Gy!!!! vagina 140Gy - 80Gy. LDR (fistula formation, more critical at lower vagina, we don't care about upper) upper 90 mid 80 lower 70 uterus limit for peds to preserve childbearing potential: 6 Gy (CM) /ovary ovaries ovarian fertility 2-3Gy (age-dependent, prepubertal may tolerate up to 12Gy) hormonal 5-10Gy A mathematical model predicted 16 gray (Gy) of radiation would deplete the ovarian oocyte pool at age 20 years and 10 Gy of radiation would deplete the ovarian oocyte pool at age 45 years. Treat 20Gy in 10 for primary ovarian hormonal ablation. Ear nerve deafness 55 brachial plexus 60-65 lacrimal gland 41.4 lens 10 retinopathy 45 temporal bone 20Gy for peds 20Gy bone growth for peds 20Gy growth hormone for peds mandible – osteoradionecrosis – 60Gy (ps) (For IMRT, under 15% should receive >70Gy) Use pentoxifyllene and vitamin E: Robard L, et al. Medical treatment of osteoradionecrosis of the mandible by PENTOCLO: Preliminary results. European Annals of Otorhinolaryngology, Head and Neck diseases (2014) http://dx.doi.org/10.1016/j.anorl.2013.11.006 cochlea mean dose 35Gy. 24-30Gy with cisplatin, 40Gy without cisplatin /Ear, /Bhandare, QUANTEC, Red 10 RT leads to sensorineural hearing loss. Contour bony labyrinth on CT, average contour volume 0.13-0.56mL. cochlea mean dose conv fx 35-45Gy (lower if concurrent cisplatin) SRS for VS PD 12-14Gy SRT 21-30Gy in 3-7Gy/fx over 3-10 days /RILD – radiation induced liver disease /VOD- veno-occlusive disease of the liver. Sx: wt gain is the first sign, hepatomegaly, jaundice, encephalopathy. From severely congested sinusoids in central lobular zones, and atrophy of central liver plates. 90 days post-RT, technically a late effect, but clinically & morphologically a subacute effect. /Renal /Kidney tolerance decreases w/ time indicating continuous progression of renal injury! === /Heart /Cardiac http://clincancerres.aacrjournals.org/content/14/1/14.full The most frequently diagnosed cardiac problems during radiotherapy are acute pericarditis, pericardial effusion, and arrhythmias. Acute radiation damage to pericardial and intimal coronary endocytes eventually leads to myocyte ischemia and fibrosis (85). Constrictive pericarditis is a serious long-term complication that may require pericardectomy. It is more frequently seen in patients who receive mediastinal radiation for Hodgkin's lymphoma than those who receive adjuvant tangential breast irradiation. The incidence of constrictive pericarditis with modern techniques is as yet unknown as the median presentation is 13 years postradiation (86). Radiotherapy damage to coronary endocytes triggers inflammation and eventually leads to atherosclerosis (87). The risk of cardiac disease seems to increase for decades after radiation therapy and has been fully reviewed elsewhere (88). Although an initial metaanalysis of adjuvant breast cancer radiation trials showed that improved disease-free survival was counteracted by excess cardiac mortality (89), a recent metaanalysis that included trials with modern radiation techniques found that increased overall survival was associated with radiotherapy (90). Most cardiac disease has been observed in patients receiving radiation to left chest wall after a left-side mastectomy, but current radiotherapy techniques deliver less radiation to the heart than those of 30 years ago even to patients with left-side tumors (91). Earlier epidemiologic cohort studies observed a higher risk of cardiac death (92) among patients with left-side breast cancer than those with right-side breast cancer, and this risk increased with time since treatment (Table 3 ). However, a Surveillance Epidemiology End Results analysis (93) of patients who received left-side versus right-side irradiation between 1986 and 1993 did not find significant differences in hospitalization for cardiac disease or heart failure. Although these studies were large and adequately powered, right-side breast irradiation does expose the heart to some radiation, especially if internal mammary lymph nodes are also irradiated. Consequently, a more appropriate control group would have been nonirradiated patients. A recent Dutch study (94) compared 4,414 10-year survivors of breast cancer, treated between 1970 and 1986, to the Dutch female population. The authors divided the group into patients treated before and after 1980 when breast-conserving therapy was introduced. Breast irradiation alone did not increase the incidence of cardiovascular disease. Internal left or right mammary chain radiation in the period 1970 to 1979 increased the risk of myocardial infarction and CHF. In the cohort who received internal mammary chain radiation after 1979, the risk of CHF and valvular dysfunction remained elevated but not that of myocardial infarction. Left but not right chest wall irradiation increased the risk of myocardial infarction for the entire treatment period 1979 to 1986. Interestingly patients treated after 1979 who also received adjuvant CMF chemotherapy had an increased risk of CHF compared with those who received radiation alone. Smoking and radiation seemed to have a synergistic effect on increasing the risk of myocardial infarction (94). Patients treated with tangential field irradiation post–left-sided breast conserving surgery had more coronary artery stenosis, especially in the left anterior descending artery than patients with right-sided breast cancer (95). Patients treated with modern techniques that irradiate <5% of heart volume may still develop subtle defects in cardiac perfusion, which could result from irradiation of the left-anterior descending coronary artery causing arteritis (96), but this report was not confirmed in another study (97). Although new techniques, including intensity-modulated radiotherapy (98) combined with free breathing gating (99) and helical tomotherapy (100), may further reduce radiation-induced cardiac toxicities (101), the most important factors in limiting cardiac radiation are associated with the techniques used and the skill of the radiation oncologist. = /plexopathy, brachial For SBRT of apical lung tumors, the risk of brachial plexopathy be reduced by keeping the maximum radiation dose to a brachial plexus below 26 Gy in 3 or 4 fractions. http://emedicine.medscape.com/article/316497-overview#a5 Risk factors: Treatment technique, radiation volume,and concomitant use of chemotherapy are associated with development of radiation injury to the brachial plexus. Surgical lymph node dissection; and underlying comorbidities such as diabetes, hypertension, obesity, and vascular disease all demonstrate significant association with the development of radiation injury to the brachial plexus. The current incidence is 1-2% in patients receiving a typical dose of less than 55 Gy. Most commonly, the plexopathy develops months to years after radiation therapy and demonstrates a relatively stable course over months to years with a gradual worsening of paresthesias and pain. One third of patients deteriorate rapidly and exhibit significant weakness, lymphedema, and pain. Rarely, the disorder presents as a mild and relatively reversible set of symptoms. The average interval range reported is 7.5 months to 6 years; however, symptoms may develop decades after treatment. Sensory symptoms, such as numbness, paresthesia, and dysesthesia, along with swelling and weakness of the arm, are the predominant presenting symptoms. These neurologic symptoms can be progressive and may lead to a weak and edematous arm. Most radiation plexopathies are painless, but when present, pain symptoms usually are limited to the shoulder and proximal arm. Such pain usually is rated as mild to moderate in intensity. Significant pain complaints are more commonly associated with recurrent tumor than with radiation plexopathy. The lymphatic-vascular system may reveal prominent lymphedema of the involved extremity without cyanotic or dusky features. Computed tomography (CT) scanning of the involved brachial plexus may reveal a diffuse infiltration of the tissue planes. Magnetic resonance imaging (MRI) often reveals low signal intensity on T2-weighted images; minimal changes are found with gadolinium.[13, 18, 19] All of these characteristics are in contrast to neoplastic processes, which would be identified by the presence of a focal mass. Treatment: Physical Therapy: Therapeutic modalities should focus on pain reduction, strengthening, preservation of range of motion, and limiting lymphedema. Hyperbaric O2 doesn't help. http://emedicine.medscape.com/article/316259-clinical#a0216 Radiation-induced /brachial plexopathy (RBP) is another relevant topic since it can be confused with Neoplastic Brachial Plexopathy (NBP). As treatment may be different for the two conditions, differentiation between RBP and NBP is important, although it may be difficult. As many as 73% of patients who have undergone radiotherapy at more than 60 Gy develop plexopathy. Overall incidence of brachial plexopathy is approximately 1.8% of treated patients; however, several factors play a role in development of the condition, including dose (incidence is higher with doses more than 50 Gy), volume irradiated, and treatment technique, as well as whether chemotherapy is administered concurrently. Emami reports 5% incidence of NBP at 5 years when the patient has been treated at doses of 60 Gy to the entire plexus; however, up to one third of patients with RBP find that the deterioration may stop after several years. Some historical findings suggestive of NBP include the following: Onset of limb pain less than 6 months following radiation Rapid progression Horner syndrome (in two thirds of patients with Pancoast syndrome) Severe pain predominant Other metastases Focal mass or neoplasm on biopsy The most reliable feature of NBP (in 80% of patients) is early severe unrelenting pain. Fewer than 20% of RBP patients present with pain, and approximately 33% have minimal or no pain throughout the course of the disease. Two thirds of patients with RBP show severe neurologic deficit progression over several years, while in one third of patients, progression spontaneously ceases after 1-3 years.[5] More common findings in RBP include the following: Slowly progressive course, duration greater than 4 years Predominant paresthesias Median sensory amplitude decreased early Involvement of the upper trunk or C5-C6 portions of the plexus Conduction block on supraclavicular stimulation Myokymia on needle examination == /lumbar plexus /sciatic nerve http://accessphysiotherapy.mhmedical.com/data/Multimedia/grandRounds/lumbar/media/lumbar_print.html = = = /PDD Photon Depth Dose Curves. /Surface Dose (/Sfc), /Dmax, /D50% Dose. Sfc Dmax @10cm D50 (cm) 125kVp 0 5 Co-60 0.5 56% 12 4 MV 1 13 6 MV 25% 1.5 67% 15 (15-35%) 10 MV 2 17 18 MV 20% 3.5 80% 24 MV 4 21 6x falloff 3-3.5% per cm. 18x falloff 2% per cm. /Electron Depth Dose Curves E/4 = 90% E/3 = 80% E/2 = absolute range Range of e- in air: 800x tissue. So 2MeV e- will travel 8 meters! I estimated Dmax from the G21 e- curves. E/4 E/3 E/2 Bremsstrahlung (from scattering foil, collimator) Sfc Dmax 90% 80% 50% Rp Range Xray Contamination 6e 77% 1.1 1.7 1.8 2.2 2.9 .5% 9e 80% 2 2.25 3 1.2% 12e 85% 2.7 3.7 4.1 4.8 6.0 4 1.8% 16e 91% 3 4 5.3 2.4% 20e 94% 3? 5 6.7 4.8% /Half-life of Isotopes /T1/2 /HVL Lead Y-90 2.5 days (64hrs) 2.2 MeV Au-198 2.7 days .412 MeV 2.5mm I-131 8 days .364,.6 MeV Cs-131 9.7 days Pd-103 17 days 21 keV .008mm 4%/day I-125 60 days 28 keV .025mm 1%/day Co-60 5.26 yrs 1.17, 1.33 MeV 11mm 1%/month Cs-137 30 yrs .662 MeV 6.5mm 2%/yr (made from fission byproduct) Ir-192 74 days .380 MeV 2.5mm 1%/day Ra-226 1600 yrs .83 MeV(eff) 8-16mm Ra-224 3.6d Rn-222 3.8d .83 MeV(eff) BonePenetration Sr-89 50.6d 1.46 MeV 3-4mm Sr-90 64hrs .546, 2.28 MeV Sm-153 1.9d .29 MeV 1.7mm P-32 14.3d .69,1.7 MeV (for Polycythemia vera) O-15 2 min C-11 20 min F-18/FDG(2 hrs) 110 min /half life, biologic /T biologic: is the elimination from body /half life, effective /Teff 1/Teff = 1/Tphysical + 1/ Tbiologic HVL 6x 5.5cm For electrons, lead cutout to reduce to 5% (4-5 HVLs) is: .5mm per MeV for lead. Cerrobend HVL: multiply lead HVL by 1.2 .6mm per MeV is rule of thumb for Cerrobend /Radiopharmaceuticals /Unsealed Sources Sr-89, Sm-153 Sr-89 for bone pain from met CA. /Unsealed Sources Indications: multiple blastic bone mets who have exhausted EBRT. Contraindications: urinary incont (don’t want to leak everywhere..), impending fx, cord compression, low Hg, poor renal/hepatic fcn (pre- & post- hydration), hypercalcemia, life expectancy < 6 wks. /Samarium-153 /Sm153 – Quadramet. Competes w/ calcium to be taken up by bone. Emits beta and gamma rays. T1/2=46.3 hrs (1.93 d) Average Energy 0.29MeV 1.7mm penetration in bone Pre-Instructions: Minimum WBC: 3-4K Min Plt: 60k-150k Avoid Calcium containing products x 2 wks prior. Dose: 1mCi/kg, inject 25% every 30 sec, over 2 min. Pre-hydrate pt w/ 500cc IVF, Post-hydrate w/ 500cc. Post-Instructions: Drink extra fluids x 12 hrs. Urinate often, flush twice, wash hands. For men: sit to urinate, don't spill. No sex x 12 hrs. Re-check CBC in 1-2 wks Children - Stay 3 feet away x 72 hrs Keep diapers for 2 wks. Toxicities: N/V, Diarrhea, Pain flare in 10-20% of pts lasts 2-4 d, Bleeding (DIC, decreases platelets), decr Hg, decr WBCs, CV (arrhythmias, Mis), infection. Bone pain relief: Partial relief in 37-91%. Onset of relief in 10-20d, maximum 6 wks. Median duration is 12 weeks. Can repeat radionuclide 1 mo later. /Strontium-89 /Sr89 causes more (or same) myelosuppression (nadir 4-8 wks) than samarium. Pure beta. T 1/2 = 50 days SamOncology 11/5/2012 5:26 PM /Incidence (Eng’s rounded) Skin >1,000,000 Lung 200,000 Colon 100,000 Rectal 50,000 Gastric 22,000 Esophagus 15,000 Cervical 10,000 Cervical CIS 65,000 /Incidence (ACS 2010 estimates) Endometrial 43,470 7,950 Cervical 12,200 4200 (increasing) /Incidence (ACS 2007 estimates) 1,400,000 cases incidence mortality Skin >1,000,000 Prostate 219,000 27,000 Breast 180,000 41,000 Lung 213,000 162,000 Colorectal 150,000 52,000 Bladder 67,000 13,000 Melanoma 60,000 8,000 NHL 63,000 19,000 HD 8,000 1,000 Endometrial 41,000 7,350 Renal 38,890 12,840 Leukemia 35,000 22,280 Pancreas 33,730 32,300 Thyroid 30,000 1,500 Stomach 22,000 11,430 Ovarian 20,000 15,300 Esophagus 14,550 13,770 Cervical 9,710 3,700 /Mortality (ACS 2006 est) Lung 162,000 Colorectal 55,000 Breast 41,000 Pancreatic 32,000 Prostate 27,000 Leukemia 22,000 NHL 19,000 Ovarian 15,300 /markers /Tumor markers: /CDX2 is best colorectal marker (large or small intestine). AFP (HCC, Non-seminomatous Germ Cell) AP CEA (Colon) CA19-9 (Pancreatic, stomach, GI) CA 27-29, CA 15-3 (Breast) CA 125 (Ovarian) HCG (Germ cell, chorioCA) LDH (Germ cell) PAP PSA Uric Acid Ki-67, Ki67 - cell proliferation protein, indicates "growth fraction" of a cell population. absent in G0 cells. (6% for adenoCA, 90% for lymphomas) /Anatomy http://www.intute.ac.uk/healthandlifesciences/cgi-bin/browse.pl?gateway=omni&id=109536 C3-4 Hyoid Bone C3-5 Larynx T3 Thoracic Inlet T4 Ao arch, suprasternal notch T5 Carina T6 angle of Louis T11 GE jcn T12 /Celiac trunk L1 SMA, xiphoid tip L2 IMA L3-4 Ao bifurcation L4 iliac crests S2-3 thecal sac /brachial plexus : C5-T1 cribriform plate, posterior orbits - need to include for Lymphoma, Leukemia /CPA - cerebellar pontine angle. DDx: meningioma, acoustic neuroma, /Meckel's cave = trigeminal cave, contains trigeminal (Gasserion) ganglion for CN V /Cavernous Sinus internal carotid a., and CN III, IV, VI, VI (most medial), V1, V2 http://www.geocities.com/afgalaly/cranial_cavity.html Sphenoid has S,R,O foramina: /SOF /Superior orbital fissure III,IV,VI, and V1 foramen rotundum V3 foramen ovale - V3 /CN /Cranial Nerves Muscles of /Mastication by V3: 3M's Munch, Lateral Lowers Masseter, teMporalis, Medial pterygoid Lateral pterygoid Lowers Pupillary Light Reflex (direct, consensual). Consensual is due to parasympathetics to prectectal to Edinger-Westphal Nucleus. Posterior cerebral artery occlusion can cause homonymous hemianopsia. /CN II - optic canal /CN III - Oculomotor n Palsy: Eye Down and Out, Ptosis /CN IV - trochlear n., superior oblique moves the eye Down and Out (the Tramp's muscle), so paralysis will leave you Up and In. CN V: Trigeminal Gasserion ganglion for Trigeminal n (V) is in /Meckel's Cave. /SRO "Standing Room Only" V1 SOF - ophthalmic branch V2 Rotundum - maxillary branch V3 Ovale - mandibular branch CN VI - abducens, has longest intracranial tract CN VII Facial Nerve exits thru stylomastoid foramen. Branches: To Zanzibar By Motor Car (Temporal, Zygomatic, Buccal, Marginal Mandibular, Cervical) CN IX-XII - jugular foramen CN XII - hypoglossal canal foramen lacerum - carotid & cancer /PPF = /pterygopalatine fossa communicates (tumor) between orbit, NC, infratemporal fossa contains maxillary nerve and maxillary artery. also, infraorbital nerve, greater palatine nerve. Diaphragm structures: I 8 10 Eggs AT 12: IVC @T8 Esoph @T10 Aorta & Thoracic Duct at T12 /NF /neurofibromatosis /NF1 - chr17, most common 90%, cafe au lait Lisch nodules (pigmented iris hamartomas) /Optic nerve glioma 45-50Gy (usually grade 1 pilocytic astrocytomas, mostly bilateral and or chiasm or hypothalamus, more indolent. if NF1, RT only if progresses. No evid that early intervention changes outcomes. Observation w/ serial exams. Next, carbo / vcr. If progress, then RT. If adults do RT first. 5-10% have malignant transformation to MPNST (peripheral n sheath tumors) ON lesions: LT OS 90-100%, PFS 60-90% Chiasm/Optic Tract: LT OS 50-80%, LC 40-60% posterior mediastinal neurogenic tumors /NF2 - chr22 B acoustic neuromas (schwannomas) Meningiomas /CN IX Glossopharyngeal (can't really test CN IX well on physical exam) posterior 1/3 of tongue (taste and touch) carotid sinus & body stylopharyngeus (the only somatic motor!) /CN X Vagus - all palato muscles voluntary muscles of pharynx, larynx. and palatoglossus. visceral motor to gut (acid production) visceral sensory from Aortic arch (baro and chemo receptors) all -glossus muscles enervated by hypoglossal, except palatoglossus. all palat- muscles enervated by vagus n., except tensor veli palatini, who was too tense. nucleus /solitarius - CN VII, IX, X - taste, carotid sinus/body, vagus sensory nucleus /ambiguus - CN IX, X - speech & swallow. Denonvillier's fascia - anterior to rectum //Paraneoplastic syndromes: /HPO - Hypertrophic pulmonary osteoarthropathy (adenoCA) (triad of clubbing, symmetric distal arthropathy, “railroad track” on bone scan in tubular bones) Hypercoagulable /RACES in SCLC: Retinopathy (retinopathy (SCLC, gyn, breast)) ACTH (Cushing's) (SCLC, MTC) Cerebellar Ataxia Eaton-Lambert SIADH -> hyponatremia /PLE paraneoplastic limbic encephalitis (SCLC) (Alzheimer-like memory deficits) Metabolic - lactic acidosis Endocrine Hypercalcemia - PTH-rP (NSCLC-SCC), lytic mets, calcitriol production osteoclast activating factor (MM) Hypocalcemia - calcitonin from MTC Hyponatremia - SIADH (SCLC) Hypoglycemia - insulin-like GF in HCC, mesothelioma Polycythemia - RCC or HCC Hyperthyroid - TSH-like substance by hydatidiform moles, chorioCA, lung Neuro /LEMS - Lambert Eaton Myasthenia Syndrome (SCLC) (prox muscle weakness, dry mouth, metallic taste, ptosis, diplopia) (improves on repetitive nerve stimulation - FACILITATION) peripheral neuropathy (SCLC) Vascular Hypercoagulable (Lung AdenoCA) /acanthosis nigricans brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds,[1] such as the posterior and lateral folds of theneck, the armpits, groin, navel, forehead, and other areas. Associated w/ gastrointestinal adenocarcinomas, as well as genitourinary cancers such as those of the prostate, breast, and ovary. Other cancers, such as those of the lung, stomach, and lymphoma, are occasionally associated with acanthosis nigricans /Carcinogens alkylating agents, benzene -> leukemia smoked foods -> gastric /Arsenic -> skin CA, sarcoma, Bowen’s disease /aniline dyes, aromatic amines, beta-naphtylamine - bladder CA, maxillary sinus tumors /vinyl, polyvinyl chloride -> hepatic hemangiosarcoma, sarcoma /thorotrast -> angiosarcoma of liver, cholangiocarcinoma, HCC, maxillary sinus tumors /Proto-oncogene (is normal gene before damage), c-onc /oncogenes: dominant, gain of function e.g., ras/raf, sis, myc, bcr-abl, bcl2, egfr, her2/neu, mdm2 (ubiquitinizes p53), src /ras codes for p21, binds to G proteins (GTP) on plasma membrane. point mutation. Farnesyl transferase inhibitors affect ras. 30% of all human cancers. Radioresistance: ras, myc /tumor /suppressor genes: loss of function e.g., p53, p21, RB, APC, DCC, FAP, BRCA1/2, PTEN, VHL, NF1/2, WT1, TGF-beta, /PTEN is a tumor suppressor gene. Lesions in PTEN are found in more than half of advanced brain and prostate cancers and a third of thyroid and endometrial cancers. /LEERRMMONS-P - small round blue cell tumors Lymphoma Ependymoma Ewing's RMS Rb Medullo Melanoma Osteosarcoma Nbl SCLC Pineoblastoma //chemotherapy /procarbazine - 5-10% leukemia risk, esp. w/ RT 5FU & Platinum: good radiation sensitizers, but watch for increased skin toxicities w/ XRT CM: Be careful w/ concurrent radiation w/ Gemzar (or lower dose) (gemcitabine), Adriamycin (doxorubicin), IT methotrexate (MTX) (sequencing. don't give RT first.), ... others?? Concave UP: antibiotics and taxanes Oxic toxic: bleo Hypoxic toxic: mitoC /crosslinkers: both platinum and alkylating agents /Alkylating Agents – Non cell cycle specific. Substitutes alkyl groups for hydrogen atoms in DNA. crosslinks DNA. dv01504.htm Can cause myelosuppression. Alkylating agents + RT for HD can cause secondary lung cancer, but PROTECTS against Breast CA!!! 5 classes of alkylating agents: 1. Nitrogen Mustard Gas derivatives: /cyclophosphamide (/Cytoxan), hemorrhagic cystitis, severe mucosal reaction w/ RT, bladder CA, lung toxicity, anti-diuretic, N/V. /ifosfamide (/Ifex) - hemorrhagic cystitis chlorambucil /Melphalan 2. thiotepa 3. /busulfan 4. /Dacarbazine (DTIC) IV. alkylating agent. 5. /Nitrosoureas BCNU (carmustine), /CCNU (lomustine) Mechlorethamine (from MOPP) (myelosuppression, secondary hematologic malignancies- leukemia) Temozolomide, Temodar, TMZ /Antibiotics /Adriamycin (/Doxorubicin) 350 mg/m2: /anthracycline abx. NOT cell cycle specific. 1. Intercalates DNA. Inhibits DNA & RNA synthesis. 2. Topo II inhibitor. 3. Binds cell membrane lipids. 4. Induces free radical formation. Toxicities: Febrile Neutropenia. Cardiotoxicity: CHF. complete alopecia. Strong radiation RECALL: appearance of normal tissue radiation reaction when drug administered many months after RT. Wait >2wks after doxorubicin before giving RT. /Doxil - liposome-bound doxirubicin /epirubicin (same interactions w/ RT as doxorubicin?) /mitomycin C /mitoC /MMC 10 mg/m2 q4wks - abx. hypoxic cell radiosensitizer! Toxicities: long term BM suppression, thrombocytopenia, HUS /Bleomycin - intercalates DNA, radiomimetic, cuz it causes strand breaks, induces free radicals, needs O2. ChemoRT interactions: pneumonitis, pulmonary fibrosis /AMD /actinomycin-D - inhibits DNA transcription. DON'T GIVE CONCURRENTLY w/ RT. ChemoRT interactions: radiation recall, liver toxicity. /Antimetabolites /5FU: antimetabolite. Suicide inhibitor of thymidylate synthase. 5FU-> fluoro-dTMP disrupts DNA synthesis, redistributes S phase. Side Effects: peripheral neuropathy, myelosuppression (irreversible :( ) 5FU - 500-1000 mg/m2 PostOp Gastric: 400-425mg/m2/d x 5d Anal: 1000mg/m2/d x 4d /MTX /methotrexate, - DHF reductase antagonist, folate antagonist, interferes w/ DNA synthesis/ repair Decreases thymidine. Use w/ leucovorin rescue. Toxicities: leukoencephalopathy, worse w/ ChemoRT. If you take methotrexate while you are being treated with radiation therapy for cancer, methotrexate may increase the risk that the radiation therapy will cause damage to your skin, bones, or other parts of your body. (https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682019.html) Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. (http://www.rxlist.com/trexall-drug.htm) Table 1: radiation recall from MTX https://www.aafp.org/afp/2010/0815/p381.html https://www.healthline.com/health/methotrexate-injectable-solution For people having radiation therapy: This drug can increase your risk of skin and bone problems if you take it while having radiation therapy for cancer. Your doctor will monitor you closely during treatment. If your skin or bone problems get worse, they may have you stop taking this drug /pemetrexed (Alimta) is an antifolate. Doesn't penetrate CNS very well. One report of radiation dermatitis after Alimta for MPM. Leucovorin -> methylene-THF. works together w/ 5FU. Mayo Clinic regimen: 5-FU 425 mg/m2 and leucovorin 20 mg/m2, over 5 days, q5wks Roswell Park regimen: 5-FU 600 mg/m2 with leucovorin 500 mg/m2 weekly for 6 of every 8 weeks /Nucleoside Analogues /abines are S-phase specific /cytarabine /ara-C – inhibits DNA polymerase /HiDAC - high dose ara-C /gemcitabine /Gemzar- nucleoside (cytosine) analogue, inhibits ribonucleotide reductase. Replaces deoxycytadine w/ fluorine. Fluorine-substituted deoxycytadine analogue. causes esoph strictures Strong synergy w/ RT even at low doses. But more trials doing concurrent Gem now. myelosuppression, n/v /Vinca alkaloids - plant alkaloid, binds tubulin, prevents microtubule polymerization / assembly. Toxicities: peripheral neuropathy, myelosuppression, bowel cramping /VCR /vincristine (Oncovin) /vinblastine - /vinorelbine (/Navelbine) /Taxanes: from Yew tree? binds tubulin, prevents microtubule breakdown, depolymerization. works in M phase. Neurotoxicity, skin & nail changes. //Taxol (/paclitaxel) pacliTaxol. neutropenia, complete alopecia, peripheral neurotoxicity. now being given more often concurrently w/ RT in NSCLC, bladder. /Abraxane is protein-bound paclitaxel. Used for refractory Breast CA, ovarian CA, (toxicities: alopecia within 24 hrs) /Taxotere (/docetaxel) Drugs in Cell Cycle colchicine works in M phase /Hydroxyurea - G1/S block /Platinum: atypical alkylating agents. crosslinks DNA, not cell-cycle specific (Despite 6th ed, Fig 27.1 ???), good for squamous cell CA. dv01505.htm Toxicity: neurotoxicity, peripheral neuropathy, acoustic nerve damage, nephrotoxic. /cisplatin /CDDP - atypical alkylator Cisplatin dosing: Can be given in full doses w/ concurrent RT. (Must reduce dose for carbo, gem, paclitaxel) 40mg/m2 weekly for cervical CA 70-100mg/m2 q3wks for bladder-sparing TCC 75mg/m2 wks 1,5,8,11 for esophagus 100mg/m2 q3wks for concurrent CRT for H&N /carboplatin - less renal & neurotoxicity than cisplatin. N/V, neurotoxicity. /oxaliplatin – need to wait >2hrs before XRT. /Topoisomerase inhibitors: Topoisomerases regulate DNA transcription and replication by regulating Supercoiling. Topo I inhibitors cause SS breaks and ligation. Useful in radiation. /Tecans (Topo Iecans Tecan-I) are all Topo I. /Irinotecan (/CPT11) (Camptosar), Camptothecin. /Topotecan http://www.ncbi.nlm.nih.gov/pubmed/11925142 (cervical CA) http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=40&abstractID=32105 http://www.sciencedirect.com/science/article/pii/S0090825800960517 /Topo II inhibitors - cause DS breaks, Inhibits TopoII in G2 phase. Adriamycin, /Etoposide (/VP16) eTopo-II, myelosuppressive, causes LEUKEMIA - Secondary AML. /Amsacrine /chemo toxicities /alopecia: cyclophosphamide, doxorubicin (at doses higher than 50 mg), etoposide, ifosamide, paclitaxel, docetaxel (taxotere) Radiotherapy and "new" drugs-new side effects? Radiation Oncology20116:177 https://doi.org/10.1186/1748-717X-6-177 https://ro-journal.biomedcentral.com/articles/10.1186/1748-717X-6-177 cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin /Targeted agents /biologics: nibs, mibs, mabs targeted agents, interactions w/ radiotherapy http://www.ro-journal.com/content/pdf/1748-717X-6-177.pdf /nibs are /TKI: small molecule (intracellular) Tyrosine Kinase inhibitors /imatinib, /Gleevec, STI 571 (inhibits bcr-abl, Philadelphia chr) Indications: CML GIST if cKIT+. DFSP if PDGF+. Side Effects: peri orbital edema, diarrhea, myalgias, rash, headache, Nausea. Concurrent imatinib w/ RT? Limited data available: http://www.ro-journal.com/content/6/1/177 /sunitinib /Sutent - blocks PDGF & VEGF. Radiosensitizer, be careful w/ RT. for GIST, RCC. Sutent dose: 50mg QD for 4wks on, 2wks off. /pazopanib /Votrient - TKI for RCC, ... /mTor inhibitors: for advanced RCC after failure of sutent or sorafanib. /everolimus /Afinitor - for cancer of kidney, pancreas, breast, and brain Treatment of advanced hormone receptor positive, HER2-negative breast cancer in post menopausal women, after letrozole or anastrozole treatment failure. oral tablet /temsirolimus /Torisel ErbB Family of Receptor Tyrosine Kinases: (see Lung) /egfr /tarceva /iressa /erlotinib /lapatinib –dual TKI that blocks EGFR and Her1-2. oral drug for breast CA after prior treatment w/ herceptin, 35% response rate /tipifarnib – inhibits farnesyl transferase, RAS signaling pathway /sorafenib (/Nexavar) – inhibits raf, PDGF, VEGF. For RCC, HCC, STS, thyroid? Toxicities: rash, n/v, diarrhea, anorexia, hand-foot syndrome /SHARP trial showed sorafenib improved median survival for HCC from 7.9 mos to 10.7 mos. Vatalanib – a TKI and also a VEGF inhibitor! -- /mibs – proteosome inhibitors /Bortezimib (/Velcade) for MM – proteosome inhibitor, blocks NF-KB (pro-survival nuclear factor) (Apparently, there are some trials of concurrent Velcade & RT for H&N, Rectal CA. No reports of increased toxicities yet.) ZOSTER REACTIVATION --- /mabs: monoclonal antibodies, (extracellular) 8 mabs approved by FDA /egfr mabs rituximab (Rituxan) (1997) trastuzumab (Herceptin) (1998, 2/9/00) alemtuzumab (MabCampath) (CLL) (binds CD52) (2001) gemtuzumab (Mylotarg) (AML) (2000) /cetuximab (/Erbitux) /C225, an EGFR monoclonal antibody ((her1) CRC 2004, H&N 2006) (rash) Puts cells in G0 phase. INDICATIONS: H&N first line, H&N recurrent or metastatic, colorectal, lung DOSE: Cetuximab 400 mg loading wk before & 250 mg IV qwk w/ RT COSTART grading of rash: ... To treat cetux Rash: minocycline 50 BID x 2 wks, topical 2.5% HCTZ cream BID. H&N first line: see / Bonner. H&N recurrent / metastatic: see /EXTREME, The EXTREME trial is the first time in 30 years that a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease. Erbitux was granted approval by the European Commission in November 2008 for the treatment of 1st-line recurrent and/or metastatic SCCHN based on the results of the EXTREME study /Vermorken: adding Cetux to 5FU & platinum prolongs PFS, OS in recurrent or metastatic H&N. Cetuximab prolongs survival w/ Irinotecan in CRC. /K-ras /kras #kras - if K-ras mutation, no benefit from any mab, cetux doesn't work. Need to test ras first, only use cetux if wild-type K-ras. KRAS WT. K-ras mutations in 90% of pancreas, but only 50% of CRC. Get K-ras to "confirm" pancreatic primary. SWOG S0342 Cetux + carbo/ taxol (concurrent or sequential) for NSCLC a progression-free survival of 4 months and median survival of 11 months. In a retrospective analysis of patients on the concurrent arm, those whose tumors were EGFR (+) by FISH had improved overall survival compared with FISH (-) patients (median 15 vs. 7 months; P=0.03). RTOG /0324 Cetux Phase II IIIA/B NSCLC Cetux + CRT /Lynch 099 Phase III. Cetux for NSCLC. /FLEX (ASCO 2008, Plenary 3): cis/ vinorelbine +/- Cetuximab. No RT. For pts w/ EGFR-expressing (by IHC) NSCLC (85%). Weekly C improved median OS 11.3 v 10.1 months. Afterwards, 80% got maintenance therapy. No change in PFS. Bigger benefit for Caucasians. Asians all do better. Discussion by Lynch: Toxicities: Worse Febrile Neutropenia 22% v 15% (both too high) Cost of Cetux therapy: $60,000 1.2 months survival benefit: Cost per LY: 500K-650K! Lynch says: Still should use Bev first if you can, since ECOG 4599 showed better HR. Use Cetux for SCC since you can't use Bev. May need to use biomarker analysis instead of IHC for pt selection. Nadler survey study of oncologists: $300,000 threshold for cost-effectiveness. /S0189 - new trial of both cetux and bev for nsclc /panitumomab (human) /Vectibix * radiolabeled mabs * ibritumomab (Zevalin) for NHL (2002) * tositumomab (Bexxar) (approved 6/27/03) /vegf /angiogenesis inhibitors Tumor Angiogenesis: Release of VEGF, GF binding, hyperpermeability, integrins guide vessels toward tumor, endothelial cells form tubular structures, smooth muscle growth. Folkman Hypothesis: all tumor growth is angiogenesis-dependent Pro angiogenesis: bFGF, IL-8 Anti angiogenesis: Heparin, Endostatin, /bevacizumab (/Avastin) (2004) - arterial thromboses Bev is also approved for NSCLC w/ carbo/ taxol (Sandler, NEJM 2006), improves Med Surv by 1-2mos? FDA issued warning that concurrent RT w/ Bev has increased risk of FISTULAS: TE Fistula (7%) in NSCLC/ SCLC/ esophCA, and other GI fistulas. Recommend wait >6wks before starting XRT. Except some are trying IV bev concurrently w/ RT: for GBMs? for NPC? Also risk of CHF when prior anthracycline and/or RT, mostly breast CA pts. Wait 4 wks after Avastin before doing surgery. /CYRAMZA® (/ramucirumab)‎ VEGF2 inhibitor http://www.cyramzahcp.com/ Indications: met NSCLC, met GEJ/gastric, met colorectal. /brentuximab vedotin /Adcetris http://reference.medscape.com/drug/adcetris-brentuximab-vedotin-999680#5 Avoid w/ bleomycin due to pulm toxicities. Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) /Targeted agents w/ concurrent radiation Cetuximab (Bonner trial) Bevacizumab: Some are trying concurrently w/ RT (although thought to be dangerous by some): for GBMs? for NPC? for esophageal: neoadjuav chemoRT w/ bev & erlotinib (Sarah Cannon Research Institute) Erlotinib - phase I trial of concurrent chemoRT for GEJ. Trastuzumab - for esoph, concurrent chemoRT w/ cis, paclitaxel, trastuzumab. (Safran, phase I trial) /CHOP - cytoxan, doxorubicin, vincristine, prednisone. q3wks /CNOP - cytoxan, mitoxantone, vincristine, prednisone. /EPOCH - etoposide + CHOP (used for NLP, ...) /RICE - Rituxan, ifosfamide, carboplatin, etoposide. For relapsed/refractory lymphoma. --- --- AC/ Taxotere for BreastCA For Advanced CRC, IFL: irinotecan, 5FU, leucovorin /FOLFOX regimen: 5FU/ Leukovorin/ oxaliplatin FOLFOX + Avastin Avastin (bevacizumab) /FOLFIRINOX . /Conroy, N Engl J Med. 2011 May 12;364(19):1817-25. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. A regimen combining 5-FU, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) is the first therapy to show clinically significant survival advantage over single agent gemcitabine in a randomized study in treatment of metastatic pancreatic adenocarcinoma Improved OS 6mo v 3mo. /AIM - for RCC AIM [adriamycin, ifosfamide, mesna] --- /Emergencies, RT In general, for SCC, SVC syndrome, if new dx of cancer, require tissue dx before RT. Why? Small chance it’s not cancer (infection, abscess), may be lymphoma (use steroids), . . Request neurosurgery consult. Put on high dose steroids. Per Eng, not true RT emergencies: brain mets, impending path fx. Per Eng, true RT emergencies: SCC w/ new motor/sensory findings, post-obstructive pneumonia. /PostOp /wait After surgery for SC tumor, wait 10d-2wks to start xRT BrainMet, wait 10d-2wks to start xRT GBM, wait longer 3-6wks to start xRT /MRI AWC: T1: orbital FAT is brighter T1 post gad: nasal mucosa, little vessels, are BRIGHT SW: T1: white matter is white, gray matter is gray. /MRI vertebral body mets: hemangioma: bright on T1 and T2. mets: bright on T1, dark on T2, and demonstrates avid enhancement on the fat-suppressed postcontrast images. /MRI FLAIR: This is similar to T2 except the signal from cerebrospinal fluid (CSF) has been suppressed, so we no longer confuse lesions that are T2-bright from CSF which is also T2-bright. These are the best sequences for a quick look for pathology. Bright on T1: less bright on T2: this usually means the lesion is fatty or contains fat. Aging blood http://radiopaedia.org/articles/ageing-blood-on-mri MRI /Gadolinium - need CrCl >30. http://www.radiology.ucsf.edu/patients/gadolinium_policy /NSF - Nephrogenic Systemic Fibrosis /Cranial Nerves /Tongue enervated by Anterior 2/3: V (sensory), VII (taste) Posterior 1/3: IX (sensory/taste) Extreme Posterior: X (sensory/taste) Motor: XII Ear pain /otalgia: V, IX, X. /AJA Superficial/Anterior: Auriculotemporal, branch of (V3) is from ORAL CAVITY (oral tongue), parotid Middle: recurrent n of Jacobsen (IX) OROPHARYNX (not just BOT) Posterior: Arnold (X) from LARYNX /bacteria in CA /H. pylori /Helicobacter pylori /pylori – Gastric AdenoCA, gastric MALT (and other NHL), gallbladder CA If H pylori +, about 1% risk of gastric adenoCA, 0.0007% of MALT. ----- /viruses in CA RNA viruses HTLV1 Adult T-cell lymphoma HTLV2 Hairy Cell (TRAP) leukemia HIV CNS lymphoma, HD, high grade NHL, KS?, Anal SCC HCV HCC DNA viruses HBV HCC /EBV NPC, Burkitt's, mixed cellularity HD, DLBCL, CNS Lymphoma HPV cervical CA, anal CA in homosexuals, is favorable in H&N! /HHV8 KS, DLBCL /translocations /t( t(2;5) Alk translocation, anaplastic large cell lymphoma t(2;6) t(2;13) alveolar RMS t(8;14) c-myc - Burkitt's, cholangio, Ewing's, medullo, EBV? n-myc: neuroblastoma t(9;22) - Philadelphia, bcr-abl, 90% of CML, poor prog factor for ALL t(11;14) - /bcl1 - mantle cell lymphoma t(11;18) - MALT, Marginal Zone Lymphoma t(11;22) - Ewing's P-PNET, Desmoplastic small round cell tumor t(14;18) - /bcl2, bcFl2 - anti-apoptosis gene, Follicular Lymphoma, NSCLC, SCLC. t(14;19) - /bcl3 t(15;17) - AML M3 Two tissues are resistant to cancer invasion: cartilage, elastic tissue Toviaz (Fesoterodine) 12/2009 Patients treated with Toviaz® (fesoterodine fumarate) 8 mg extended release tablets had greater and statistically significant reductions in urge urinary incontinence episodes at week 12 (P=0.017) compared with Detrol® LA (tolterodine tartrate extended release capsules) in a placebo-controlled randomized clinical trial. The primary endpoint of the study was reductions in urge urinary incontinence episodes. This new study, published today in the January issue of BJU International, is the first head-to-head superiority trial specifically designed to compare the two medications. /PSaMMoma bodies - spiral rings of calcifications Papillary thyroid CA Serous Papillary cystadenocarcinoma Meningioma Mesothelioma /trophoblastic tumors /Ames test - test of carcinogenesis, ability to cause mutations /AT /Ataxia Telangectasia /ATM – breast CA AT is the disorder MOST associated with radiation sensitivity. AP endonuclease defect, a DNA repair defect, DNA damage not recognized Defective cell cycle checkpoint control. Ataxia-telangiectasia (A-T) is an autosomal recessive, complex, multisystem disorder, sensitive to RT, characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, x-ray hypersensitivity, ocular and cutaneous telangiectasia, and a predisposition to malignancy (mostly breast CA) Chediak-Higashi: rare childhood autosomal recessive disorder characterized by immune deficiency; abnl protein transport; Sx: oculocutaneous albinism; easy bruisability and bleeding as a result of deficient platelet dense bodies; recurrent infections with neutropenia, impaired chemotaxis, and bactericidal activity; and abnormal natural killer (NK) cell function Elephantiasis -> lymphangiosarcoma radiation Nerve damage - from damage to blood supply to nerves- nerve vasorum radiation damage: usually damage to either stem cells blood vessels H&N Orals: Always get Anatomy Skin CA: BCC or SCC of eyelid, lip, ear. PostOp H&N May get a Merkel Cell. Unlikely to do Melanoma. ---- /metachronous - sequential, occurring at 2 different times /synchronous - Osteomyelitis can lead to squamous cell CA. If gross tumor, need >70Gy for 80% chance of cure. ========== titanium hip causes 63% attenuation of megavoltage photon beams. (Eng article) --- /Pain Mgt Opiates: side effects: myoclonus, urinary retention, sweating, dry mouth, decreased testosterone Hydromorphone (Dilaudid) - preferred short acting for breakthru pain, no active metabolites so OK w/ renal or hepatic dysfunction. Meperidine (Demerol) - disadvantage: active metabolite normeperidine builds up, crosses BBB lasts 26 hrs, can cause SEIZURES in 3 days. Negative inotrope. Fentanyl (Duragesic) - patches, lollipop, IV, IT. rapid onset. Hydrocodone - disadv: usually only w/ Tylenol Morphine - has 1 active metabolite morphine 6 glucoronite, long half life. Need to have good renal function. Causes LE edema, CHF. Not as favored for elderly. 30mg IV = 90mg oral Oxycodone - generic long acting not as effective as brand name agonist/antagonist - Stadol (butorphenol): don't give w/ opiates! Ultram - tramadol - risk of sz Wellbutrin+Ultram=SEIZURES! /VHL - Von Hippel Lindau - hemangioblastomas of retina/ cerebellum/ medulla, B RCC, Pancreatic cysts, pheo, Islet cell, epididymal cystadenoma VHL is a tumor suppressor gene - if mutated, can't destroy HIF1-alpha, then overexpression of VEGF, neovascularization, helps tumor growth. /Osler Weber Rendu - AD HHT – hereditary hemorrhagic telangiectasias Sx: nosebleeds, skin telangiectasias, AVMS, bleeding into brain, liver, lungs. Types 1,2,3 Dx: Need 3 of 4: Spontaneous recurrent epistaxis Multiple teleangiectasias on typical locations (see above) Proven visceral AVM (lung, liver, brain, spine) First-degree family member with HHT Oprelvekin (Neumega) - synthetic IL-11. For thrombocytopenia. /IMRT reduces Xerostomia Oncologist 2007, 12:565-568. RCT: Kam MK, Leung SF, Zee B, et al: Impact of intensity-modulated radiotherapy (IMRT) on salivary gland function in early-stage nasopharyngeal carcinoma (NPC) patients: A prospective randomized study. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 23:5501, 2005 (abstr) RCT: Pow, Red 2006, PMID 17145528 IMRT vs Conventional Significantly improved both Xerostomia & QoL for T2N0-1 NPC. Prospective non-randomized(?): Braam, Netherlands, Red 2006, PMID 16965864 IMRT vs conventional Salivary flow better after IMRT Looks like a good review from MSKCC: Lee, Head Neck. 2005, Dec 15;29(4):387-400, PMID 16358297, DOI 10.1002/hed.20332 Chao, WashU, Red 2001: "PII S0360-3016(00)01441-3" Salivary sparing in IMRT vs 3DCRT. Improved xerostomia and QoL. Stimulated salivary flow reduced 4% per Gy. Wolden, ASCO 2002, abstract # 956 MSKCC: IMRT vs Conventional for NPC Retrospective, historical study. Improved LRC 97% vs 78% @2yrs Eisbruch, 1999, UMich: IMRT for H&N 88pts Cannulated Stenson’s duct, and measured salivary flow rates before RT and at 1,3,6,12 mos after. Calculated NTCP. Findings: Need to keep mean parotid dose below threshold of 24-26Gy to reduce xerostomia. From NTCP, found that TD50=28.4Gy. IMRT target volume delineation variability: Logue JP, Sharrock CL, Cowan RA, Read G, Marrs J, Mott D. Clinical variability of target volume description in conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 1998;41:929–931. /Nausea Decadron Emend – substance-P Ativan Marinol 5mg PO ___ /Statistics /clinical trials /trials Pilot study - feasibility Phase I: max tolerable dose, toxicity Phase II: efficacy Phase III: compare to standard treatment Phase IV: postmarket surveillance, look for rare side effects /Dosimetry Autocontour Thresholds for lung (800,4096), contrast (1150, 4096) /Wedge angle defined as the angle b/w isodose line and line perpendicular to central axis Wedge angle = 90 – (Hinge Angle)/2 /stp - temperature-pressure correction factor Ctp=(760/P)(273+T)/(273+22) ----- /KPS /Karnovsky /Karnofsky 100% - normal, no complaints, no signs of disease 90% - capable of normal activity, few symptoms or signs of disease 80% - normal activity with some difficulty, some symptoms or signs 70% - caring for self, not capable of normal activity or work 60% - requiring some help, can take care of most personal requirements 50% - requires help often, requires frequent medical care 40% - disabled, requires special care and help 30% - severely disabled, hospital admission indicated but no risk of death 20% - very ill, urgently requiring admission, requires supportive measures or treatment 10% - moribund, rapidly progressive fatal disease processes 0% - death. /ECOG Performance Status 0 - Asymptomatic 1 - Symptomatic but completely ambulant 2 - Symptomatic, <50% in bed during the day 3 - Symptomatic, >50% in bed, but not bedbound 4 - Bedbound 5 - Death CT /Hounsfield units /HU -1000 lung -100 fat 0 is water or muscle 1000 bone Wedges, compensators need to be at least 20cm from skin. Radiochromic film not sensitive to low doses D. Total body irradiation to doses of 1 Gy or more can lead to abnormalities in T cell immunity. E. There is evidence that the apoptotic index among T lymphocytes after irradiation can be used as a predictor of subsequent tissue injury. siRNA, miRNA bind to and inhibit specific genes. You get 5% of dose at 2cm from field edge. (pacemaker problem) Dynamic wedge: use MLCs, less beam hardening, larger field size. Flying wedge: use a 60 deg wedge for a fraction of treatment time. Opposed Parallel Max thickness of patient to achieve less than 5% or 10% non-uniformity: 5% 10% 6x 18cm 23cm 18x 25cm 31cm For parallel opposed w/ 6x photons, If sep is >24cm, max dose is 110% of midline. If sep is 16cm, max dose is 102% of midline. (But this is field size dependent) endonucleases: found in bacteria & cleave at specific DNA sequences (4-8 nucleotides long) “palindrome” – reads the same forwards and backwards exonucleases: remove nucleotides from the ends of a DNA molecule /SBRT Lung, Fuss 4D CT Define a minIP volume and allow higher max dose in this region. /ITV (red): Use MIP MinIP ITV (brown): Use MinIP PTV (orange): 5mm margin around ITV Limit Ring: 10mm beyond PTV 10-12 beams, of which 3 are non-coplanar Prescribe 1200 x 5 to the PTV. Normalization: 100% of dose cover 90% of target volume. Plan Objectives: PTV: At least 95% receives 6000cGy (100% of PD) At least 99% receives 5700cGy (95% of PD) MinIP: At least 50% receives 7800cGy (130% of PD) Cord, Esophagus At most 50% receives 1250cGy At most 10% receives 2000cGy Optimization Objectives (Priority): PTV At least 95% receives 6000cGy (100% of PD) (800) At least 99% receives 5700cGy (95% of PD) (600) MinIP: At least 50% receives 7800cGy (130% of PD) (600) Limit Ring: At most 50% receives 3000 cGy (50% of PD) (600) Cord, Esophagus: At most 50% receives 750cGy (500) At most 5% receives 1000cGy (500) Adrenal met (MF) 12 Gy x 3, using 10 coplanar beams. 5mm margin around ITV HCC Gerber, Kurt: HCC s/p RFA to 2 R lobe lesions, new 3.75cm L medial lesion s/p TACE. /Polypoid (with a stem) /sessile (attached by a base without a stalk) /papillary (leaf-like, finger-like projections) /pedunculated - with a stalk /IVC allergy, premedication for: Prednisone 50mg (or Decadron 8mg), Take 13hrs, 7hrs, and 1hr before CT. Benadryl 50mg, take 1hr before CT. Zantac 150mg, 1 the night before, and 1 on the morning of the procedure. /metformin /glucophage: The recommendation of the American College of Radiology (ACR) is to withold the Metformin the day the contrast is administered and for 48 hours post administration, re-starting the dose only after renal function has been evaluated and found baseline (pre-administration levels). PARQ – procedures, alternatives, risks, questions KP: Here are 3 more questions I remembered 3. Pt with lung cancer. What would be the difference in dosing to the tumor if an uncorrected plan now has inhomogeneity corrections? have less dose to tumor. /anti-emetics /nausea The first-generation 5-HT3 receptor antagonists (ondansetron (Zofran), dolasetron (Anzemet), granisetron (Kytril), and tropisetron (Navoban)). Palonosetron has a longer half life (40h). Emend (aprepitant) /splenomegaly from myeloproliferative disorder McFarland, "Am J Clin Oncol (CCT) 26(2): 178–183, 2003." BIW 50cGy x 2, 75 cGy x 2, 100cGy x 2. Check CBC prior to each fraction. Hold for "worrisome counts". Risks: cytopenia. Prolonged cytopenia in 26% Increased risk of post-operative bleeding if subsequent splenectomy. 22 of 25 courses of RT resulted in decreased pain and sx. 3 of 4 pts showed improvement in thrombocytopenia. /Thrombocytopenia, Secondary Immune /Calverly, Splenic RT for Steroid-resistant immune thrombocytopenia, "1992;116(i2 pt 1):977-981" 100cGy BIW x 6 = 6Gy Included 11 ITP and 8 secondary immune thrombocytopenia (SIT) (dt leukemia, lymphoma,..) Results: 8 of 11 ITP pts responded 2 of 8 SIT pts responded /Guiney, Splenic RT for CLL, Red 1989 Jan;16(1):225-9, PMID 2912945 8 of 10 had at least partial relief of pain. 2 of 14 had improvement in thrombocytopenia, (9 got worse). 4 of 16 had improvement in Hg. Toxicities: leukopenia, thrombocytopenia. /AYA: 15-39yo Issues: delay in diagnosis, access to care, psychosocial issues, insurance Bleyer, Nature Reviews Cancer, April 2008: Distinct Biology of AYA cancers. /Brain complications after RT: Early <1mo: acute encephalopathy from disruption of BBB. Rx: Steroids Early Delayed complications (1-4mos): somnolence syndrome in children, vasogenic edema, demyelination. Rx: Steroids Leukoencephalopathy in PCNSL after MTX. Late complications (6 mos to 2yrs): brain necrosis, diffuse cerebral atrophy Affects white matter > gray matter. /necrosis, Brain necrosis after RT: Imaging: Brain FDG-PET: COLD spots (hypometabolism) indicate necrosis. MRI: MRS, MR Spectroscopy: Necrosis high LACTATE, v choline, v creatine, low NAA. Gliomas: high Choline/Creatine ratio, low NAA. normal cells have high NAA. Need brain biopsy to confirm. TREATMENT: If incidental finding on FU imaging and asymptomatic, OBSERVE. Options: Resection, steroids, Avastin. For osteoradionecrosis: hyperbaric O2, anticoagulants, pentoxifyllene, vitamin E. /pentoxifylline (Trental), vitamin E, for radiation necrosis, osteoradionecrosis, and maybe for fibrosis Chiao, Role of Pentoxifylline and Vitamin E in Attenuation of Radiation-Induced Fibrosis 8 February 2005, www.theannals.com, DOI 10.1345/aph.1E186. The Annals of Pharmacotherapy: Vol. 39, No. 3, pp. 516-522. DOI 10.1345/aph.1E186 phenylephrine suppositories for hemorrhoidal swelling/itching/burning Appetite stimulants /Megace (megestrol) 40mg/cc, 20 cc (4 teaspoons) (800mg) PO QD, Dispense 240cc bottle. progestational agent, (increased risk of thrombosis) /Marinol 5 BID /Candidiasis, Oral Nystatin 100,000 U/mL 4-6cc PO S&S QID x 14 days Disp: 60cc /BMTs Purposes: to allow myeloablative doses of chemo, to clear the marrow, to ... for liquid tumors, better to get someone else's allogeneic, cuz if there's even 1 cell remaining, it could recur. for solid tumors, better to keep your own (autologous) BMT. ----------------- /MAGLA: Supratentorial Ring Enhancing Lesion: Metastases Anaplastic Astrocytoma GBM Lymphoma Abcess --------------- Parag's Notes: Biologic Markers for Medulloblastoma Favorable – Aneuploidy, Expression of TrkC Unfavorable – 17 p deletion, c-Myc amplification, ErbB-2/erbB-4 expression, Gain of 1p /8q Incidence of cerebellar mutism syndrome – 24% and atleast moderate severity in 40% Overall XRT treatment time is a prognostic factor in outcomes < 50 days 5 y PFS: 67% 10 y PFS: 42% 5 y Post Fossa Control: 70% 10 y Post Fossa Control: 70% >50 days - 5 y PFS: 42% - 10 y PFS: 39% - 5 y Post Fossa Control: 46% - 10 y Post Fossa Control: 33% Late Toxicity: Endocrine: @ 4 y GHD – 93% TSH – 23% ACTH – 38% Primary HypoThyroidism – 65% Neurocognitive: Gluathione S transferase gene implicated Loss of Bone growth: Dependent on age @ irradiation May not be apparent till puberty Can decrease impact by decreasing CSI dose, HPA dose, GH replacement, protons Hearing Loss CISPLATIN Reduction in CSI doses have come with increased doses of Cisplatin IMRT to reduce cochlear dose Keep Mean dose < 30 - 35 Gy St. Jude MedulloBlastoma (SJMB – 96) trial Standard risk pts 23.4 CSI and 32.4 conformal tumor bed boost 4 cycles high dose cyclophosphamide based chemotherapy with stem cell rescue 5 y OS – 85% 5 y EFS – 83% PF failure rate – 5% ( can use this in oral boards to justify involved field boost instead of PF boost even outside a trial setting – used by multiple examinees in previous boards – but you HAVE to quote the specific trial and failure rate) EPENDYMOMA Highest prevalence in 4th ventricle, CPA No role for chemotherapy at this time (investigational) Prognostic Factors: extent of disease, extent of resection, tumor grade, tumore location and radiation dose Histology Grade 1 – Myxopapillary Grade 2 – Well Differentiated Grade 3 – anaplastic (focal vs. diffuse) Grade 4 – Ependymoblastoma St. JUDE RT-1 3 y EFS 75% GTR and IF RT ACNS0121 current COG trial Supratentorial, GTR, differentiated histology  Observation (Do NOT offer observation outside of trial) LGG 15% of NF-1 patients have optic pathway gliomas Neurocognitive effects related more to age than dose Hearing loss < 5% at 5 years Vasculopathy 5% at 7 years RHABDOMYOSARCOMA (Karen Marcus) Para Meningeal Sites Mastoid, Middle ear, Infratemporal fossa, paranasal sinuses, nasopharynx Paratesticular Tumors Surgery with inguinal orchiectomy and resection of the spermatic cord Para-aortic LN involvement 20-30% RPLND is recommended even for Group I adolescent pts. CURRENT RISK STRATIFICATION (This is post IRS V) LOW RISK EMBRYONAL RMS ONLY Subset 1 Stage 1 or 2, Gr I or II and Stage I, Group III (N0) orbit only Subset 2 Stage 1, Gr III (non-orbit) Stage 3, Gr I or II N0 Upfront VAC Chemotherapy RT @ wk 13 if needed with VA Followed by VA chemotherapy RT doses 36 Gy for node neg, microscopic disease 45 Gy for Group III orbital RT dose adjusted after second look for Group III pts 50.4 Gy for gross residual disease INTERMEDIATE RISK PATIENTS ALVEOLAR HISTOLOGY Stage 1 – 3, Group I – III EMBRYONAL, BOYTROID, SPINDLE CELL HISTOLOGY Stage 2 -3, Group III NO STAGE 4 patients RT Early RT @ week 4 (instead of week 13 on IRS V) No RT dose reductions HIGH RISK Stage 4 RT @ week 20 with concurrent Irinotecan ------------ /MINSKY 2009 04 14 ESOPHAGUS Treat SCV? Yes, still treat SCV, all to 50.4. APPA (this has least lung) to 39.6, then obliques (supplement 1 side w/ e's (cuz blocking cord). What about Lung V20? I don't think he looks at this. Dose escalate for cervical esophagus? He doesn't, but knows this is controversial. Dose for definitive esophagus? R Komaki likes higher doses, but Minsky doesn't. Is upfront esophagectomy still acceptable standard of care? Still yes, essentially same survival Surg vs CRT. There are 6 RCTs, 2 of which are positive (but Tepper study is small) suggesting that PreOp CRT probably improves OS by 5-10%. PostOp don't try to cover the cervical anastomosis, field is too big. What if TE fistula? stent? lower dose? Minsky says some say don't treat them, high mortality. Historically this was a contraindication to chemoRT (most of these were excluded in the RCTs), but some treat them. Minsky does treat these. For SCC, if Post Op mid thoracic T3N1, esophagectomy alone. (per NCCN) But if AdenoCA, then chemoRT. GASTRIC Unresectable: Start w/ chemo only, then re-stage (laparoscopy to look for omental dz), CRT to 50.4. If preop ECF given, do you give postop chemoRT? No, only if M+. Don't make up new regimens. What about doing preop chemoRT? Yes, Minsky recommends this, esp for T3 or N+, if surgeon willing, extrapolating from other sites. PANCREATIC Resectable: "There were 2 poor RCTs: GITSG (positive trial, but small study), ESPAC (negative trial but poor quality), but I look at the large body of single institution non-RCT data that show benefit to CRT." (He seems to de-emphasize the RTOG 9704 trial.) Unresectable: chemo first, then restage (laparoscopy (Crane says no)), then chemoRT? 2% will be cured(!). Remember gem is toxic w/ RT, don't give w/ RT. RECTAL For PreOp T4 w/ sacral involvement, boost to 54 instead of 50? NO, he never goes above 50.4 for anything pre-op. M may give intra op, but don't say this if you don't have it at your institution. Include sacrum in Boost field? YES. uT3N0 @ 10cm? Minsky says yes to preop CRT, because per GRCT, 20% will be pN+, and if you don't, they will need post op CRT. :( The flip side is that we may be overtreating 20% that turn out to be pT1-2N0. Guillem, JCO 2008 Unlike Colon, Rectal still has late failures after 5yrs, so still need 7yr follow-up data. Proctitis: steroids for simple cases. For more complex, "I'd work closely w/ a gastroenterologist to manage..." What's the standard postOp Chemo after PreOp CRT & LAR-TME? "5FU-based x 4 cycles (4 months)" Minsky says standard adjuv chemo is now FOLFOX. Adjuv chemo is the most important part! There is a 10-15% survival benefit w/ adjuvant 5FU-based chemo. If you have to do post-op CRT: PostOp Rectal sequencing: chemo first, then CRT, chemo. Do you treat PostOp pT2N1 and pT3N0? If post op pT3N0 after TME, benefit of RT is small amount LC, so can skip RT if >12 nodes sampled, only 2-3% LC benefit, not worth toxicities, unless <12 nodes examined. (Despite Gunderson pooled analysis.) If post op pT2N1 after TME, Minsky still treats w/ RT (he gives postop RT for any N+), but he knows he's in minority. He goes by Dutch TME trial that showed that even after TME, the subset w/ N+ had high LF 21%. T1-2N0 w/ WLE, had late >5yr recurrences. Don't do WLE except for T1's. Long term data show up to 10% LR now (U Minnesota data (look this up)). If you did happen to do a WLE and found a T2Nx, first choice is re-excision w/ TME (and only add RT if N+), second choice is post op CRT. Problem w/ 5x5 is can't give chemo, and chemo is what improves survival. Would a resected colon cancer with its anastomosis below the peritoneal reflection be treated like a rectal ca? If low sigmoid CA (T4) stuck to something, treat like rectum. Only diff between rectal and colon CA is harder to get good surgical margins in the pelvis. Distance from AV Minsky uses 12cm (peritoneal reflection) w/ straight scope as his cutoff for giving RT. Guillem found no diff in ypN+ rate for prox vs distal tumors. ANAL Impotence rate for pelvic chemoRT for rectal, anal, APR? Dose for positive inguinal nodes? How to treat anal margin tumors? WLE vs RT alone: nodes? If >5cm away from AV, then WLE. IF < 5cm, then chemoRT. M never does perineal e- boost. M always treats full fields, except maybe start at bottom of SI joint. How to treat anal adenoCA (15%)? Always salvage APR? Yes. Always go by histology: For SCC always treat like Anal. For adeno, treat like rectal w/ surgery. FU: exam q6wks w/ no bx, just keep following as long as getting smaller, after CR then q3mo. If doesn't get smaller, then bx, then APR. Distant spread for anal is rare. Anal doses T1-2: 45Gy T3-4: 50.4Gy !!!! /MoyaMoya- vascular occlusion Anesthesia /ASA Classs 1 A normal healthy patient. 2 A patient with mild systemic disease. 3 A patient with severe systemic disease. 4 A patient with severe systemic disease that is a constant threat to life. 5 A moribund patient who is not expected to survive without the operation. ---- Pediatric Outcomes 5yrOS 95% optic n glioma 80-90% JPA Germinoma Craniopharyngioma 70-80% Medullo, Standard Risk 40-80% Medullo, High Risk optic chiasm glioma ependymoma NGGCT supraPNET 15% ATRT Brainstem Glioma GBM AIDS-defining cancers: cervical CA, KS, HD? /IMRT Use of IMRT survey, Mell LK, Mundt, Cancer 2005, ARS 2005 /ICRU 58 - Dose Volume reporting for INTERSTITIAL /Purdy, SRO 2004, "doi:10.1053/j.semradonc.2003.12.002" Review of ICRU 50 & 62 definitions. /ICRU 50 Hot Spots: Volume outside PTV receiving >100% PD with diameter >15mm /ICRU 62 Added ITV (Internal Target Volume) = CTV + organ motion PTV: adds margin for Organ Motion and Setup Uncertainties Maui 2010 Rad Onc Conference Kavanaugh - Intro to SBRT Here is a study for starting up an SBRT program. For Li? Amount of increased work for Physics Services. The Abt Study www.aapm.org/pubs/reports/ABTIIIReport.pdf --- /Kavanaugh, SBRT for Lung CA Why does SBRT work better? Current theory: higher doses of >8-10Gy effects tumor endothelial cell apoptosis. Sibley, Red 40:149, 1998. Duke Experience for mediaclly inoperable NSCLC 141 pts Covnentiona RT 64Gy, 42% LF rate. Survival similar to SEER. Zhao, Red, 68:103, 2007, U Mich Dose escalation trial 66Gy up to 102.9Gy Higher dose for larger tumors? ----------- Kavanaugh: SBRT for spine For single fx brain: V12Gy<10cc ----------- Kavanaugh: SBRT for oligomets Why? UChicago: immune modulation High dose RT may alter tumor immunogenicity Theory of Oligometastases Hellman & Weichselbaum, JCO,1995;13(1):8-10 ?An intermediate state between early stage and widely metastatic Norton-Simon Hypothesis Gompertzian growth kinetics in host Ultimately can progress to lethal burden of disease So if we reduce systemic burden of disease, can delay time until overwhelming burden of disease. Lee, Red 97: Overall tumor burden (by PET, autosegmented) predicts survival in NSCLC. (Obviously) Halsted "contiguous" theory - cancer progresses in an orderly fashion from primary tumor to regional lymphatics, to the rest of the body. vs Fisher theory - whole host is at risk from the beginning, everybody has micromets, just can't detect it McCammon,,,Kavanaugh, IJROBP 73(1):112–118, 2009 Dose escalation study for lung mets Better LC if >54Gy (in 3 fx), and >36Gy in 3 fx. So BK doing 20Gy x 3, even for mets. Rusthoven, Kavanaugh, JCO 2009 SBRT for 1-3 lung mets 20Gy x 3 Lung DVH V15<35%. Chest Wall / Rib toxicities CW DVH constraints: Dunlap, IJROBP 2009 V30<30cc Pettersson, Radiother Oncol 2009 D2cc < ALARA Rusthoven, Kavanaugh, JCO 2009 SBRT for 1-3 liver mets 20Gy x 3 Liver V15<700cc total kidney DVH V15<35%. Watch dose to renal artery to avoid RAS. Didn't find any evid of "serial" function of biliary structure (aka central interlobar bronchial lesion), so OK to treat "central" liver same way, except limited by bowel. Bowel V12.5Gy <30cc predicts late duodenal ulceration (Stanford) Kavanaugh, ASTRO 2010 talk 4 studies on SBRT lung mets (12x4, 20x3, 12.5x3, 15x4) Wuerzburg Asian Med Ctr Kyoto Colorado-Indiana (get the virtual totebag, ASTRO 2010) BK rule of thumb says treat up to 5 - 6 oligomets w/ SBRT. Lung Cancer. 2016 Jul;97:51-8. doi: 10.1016/j.lungcan.2016.04.012. Epub 2016 Apr 26. Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". Rieber DOI: 10.1016/j.lungcan.2016.04.012 OBJECTIVES: The current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. MATERIALS AND METHODS: All German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0-33.0Gy) in a median number of 3 fractions (range 1-13). RESULTS: After a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). CONCLUSION: SBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach. Radiat Oncol. 2017 Feb 1;12(1):35. doi: 10.1186/s13014-017-0773-4. Lung metastases treated with stereotactic body radiotherapy: the RSSearch® patient Registry's experience. Ricco DOI: 10.1186/s13014-017-0773-4 OBJECTIVES: To report overall survival and local control for patients identified in the RSSearch® Patient Registry with metastatic cancer to the lung treated with SBRT. METHODS: Seven hundred two patients were identified with lung metastases in the RSSearch® Registry. Of these patients, 577 patients had SBRT dose and fractionation information available. Patients were excluded if they received prior surgery, radiation, or radiofrequency ablation to the SBRT treated area. Between April 2004-July 2015, 447 patients treated with SBRT at 30 academic and community-based centers were evaluable for overall survival (OS). Three hundred four patients with 327 lesions were evaluable for local control (LC). All doses were converted to Monte Carlo equivalents and subsequent BED Gy10 for dose response analysis. RESULTS: Median age was 69 years (range, 18-93 years). Median Karnofsky performance status (KPS) was 90 (range 25/75% 80-100). 49.2% of patients had prior systemic therapy. Median metastasis volume was 10.58 cc (range 25/75% 3.7-25.54 cc). Site of primary tumor included colorectal (25.7%), lung (16.6%), head and neck (11.4%), breast (9.2%), kidney (8.1%), skin (6.5%) and other (22.1%). Median dose was 50 Gy (range 25/75% 48-54) delivered in 3 fractions (range 25/75% 3-5) with a median BED of 100Gy10 (range 25/75% 81-136). Median OS for the entire group was 26 months, with actuarial 1-, 3-, and 5-year OS of 74.1%, 33.3, and 21.8%, respectively. Patients with head and neck and breast cancers had longer median OS of 37 and 32 months respectively, compared to colorectal (30 months) and lung (26 months) which corresponded to 3-year actuarial OS of 51.8 and 47.9% for head and neck and breast respectively, compared to 35.8% for colorectal and 31.2% for lung. The median LC for all patients was 53 months, with actuarial 1-, 3-, and 5-year LC rates of 80.4, 58.9, and 46.3%, respectively. There was no difference in LC by primary histologic type (p = 0.49). Improved LC was observed for lung metastases that received SBRT doses of BED ≥100Gy10 with 3-year LC rate of 77.1% compared to 45% for lung metastases treated with BED < 100Gy10 (p = 0.01). Smaller tumor volumes (<11 cc) had improved LC compared to tumor volumes > 11 cc. (p = 0.005) Two-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 72.9, 64.2 and 45.6%, respectively. This correlated with improved OS with 2-year OS rates of 62.4, 60.9 and 46.2% for tumor volumes < 11 cc, 11-27 cc and > 27 cc, respectively (p = 0.0023). In a subset of patients who received BED ≥100Gy10, 2-year LC rates for tumor volumes < 11 cc, 11-27 cc and > 27 cc were 82.8, 58.9 and 68.6%, respectively (p = 0.0244), and 2-year OS rates were 66.0, 58.8 and 28.5%, respectively (p = 0.0081). CONCLUSION: Excellent OS and LC is achievable with SBRT utilizing BED ≥100Gy10 for lung metastases according to the RSSearch® Registry data. Patients with small lung metastases (volumes < 11 cc) had better LC and OS when using SBRT doses of BED ≥100Gy10. Further studies to evaluate a difference, if any, between various tumor types will require a larger number of patients. ----- WJK 2010 02 03 EAC: 4 RCTs, none of shown OS benefit of adjuv RT in early stage endomCA. Low Risk: IA, IBG1, IBG2, some IIA Intermed Risk High Risk: extrauterine disease Morrow, GO 1991. All stage I has 92.7% survival, only Grade and MMI are sig risk factors, others not significant WJK uses small pelvic fields if he's going to use it after LANect, don't chase external iliacs, looks like small rectal fields. Rarely uses pelvic EBRT for Stage I, except ICG3. He adds VC boost if risk: LVSI, ... Omit VC boost if high fundal tumor w/ no other risk factors. For other stage I, if good LANect and many negative nodes, doesn't use LVSI, tumor size factors to influence decision for pelvic RT since these are markers for LN risk (not local recurrence risk?). Advanced stage EAC: Consider lower dose pelvic RT if getting chemo Rarely need VC boost. ==== radiation exposures 0.3 mrem PET pts - personnel making aquaplast mask (10min) 2-5 mrem cross country flight 10 mrem CXR 160 mrem dental xray 370 mrem PET 360 mrem average annual radiation exposure Clinical /Trials /RCT PreClinical: in vitro or in vivo (animal) Phase 0: first in human, subtherapeutic doses in 10-15 humans, to measure pharmacodynamics and pharmacokinetics, not for safety or efficacy Phase I: to measure safety, tolerability. Phase II: dosing and efficacy, could be randomized Phase III: RCTs to measure definitive assessment of efficacy against gold standard treatment /BMI <18.5 Underweight 18.5-25 Normal 25-30 Overweight >30 Obese /Dermatitis, Radiation If unusually rapid reaction, test ANA to r/o CTD, test HIV. Dilantin synergy (-> Stevens Johnson syndrome) --------- /pacemakers 1. Confer with Cardiology on pacemaker dependence. 2. Assume a 2 Gy cumulative absorbed dose tolerance. 3. Keep, if possible, a 3 cm. margin from the radiation field edge. 4. Consider TLD or diode measurement on day one of radiation therapy. 5. Do low-level cardiac monitoring if < 2 Gy cumulative dose. 6. Do high-level monitoring if > 2 Gy or pacemaker-dependent patient. 7. If cumulative dose > 10 Gy, consider repositioning the pacemaker == Pain and Neuropathy in Cancer Survivors: Surgery, radiation, and chemotherapy can cause pain; research could improve its detection and treatment Am J Nursing, March 2006 http://www.nursingcenter.com/pdfjournal?AID=630714&an=00000446-200603003-00015&Journal_ID=54030&Issue_ID=630688 /vaccines during radiotherapy /pneumovax If you are about to undergo chemotherapy or radiotherapy, ideally you should be immunised 4-6 weeks before commencing treatment. (http://patient.info/health/pneumococcal-immunisation) /pneumovax II However, it is recommended that this vaccine is given at least two weeks before starting treatment with therapies that suppress the immune system, eg chemotherapy, radiotherapy, long-term high-dose corticosteroids, or immunosuppressants. This is because once the immune system is suppressed by these treatments, sufficient numbers of antibodies may not be produced in response to the vaccine. The vaccine should particularly be avoided during radiotherapy or chemotherapy treatment. The immune response may also still be reduced after chemotherapy or radiotherapy has finished and the vaccine should therefore not be given within three months of finishing such treatment (possibly longer if the treatment was intensive or prolonged). This vaccine must not be given at the same time as the shingles vaccine (Zostavax). This vaccine may be given at the same time as the influenza (flu) vaccine, but different injection sites should be used. Read more: http://www.netdoctor.co.uk/seniors-health/medicines/pneumovax-ii.html#ixzz3jMLRWbK9 /zostavax /zoster /vzv vaccine, /shingles Contraindications to zoster vaccine are: Acquired or primary immune deficiency states, including AIDS Cancer chemotherapy or radiotherapy Leukemia Lymphoma /influenza vaccine Ideally, influenza vaccine should be given at least 10 to 14 days before the start of any immune-suppressing cancer treatment, to allow for sufficient antibody production by the patient. If the patient is actively receiving chemotherapy, the vaccine should be ideally administered when blood counts are near the normal range. If this is not possible, the patient can still be immunized during a course of chemotherapy or radiotherapy, based on individual clinical judgment incorporating a patient's overall clinical situation. http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/infectionsinpeoplewithcancer/should-i-get-a-flu-shot Can I get a flu shot during cancer treatment? Yes, people getting cancer treatment (for instance, radiation or chemotherapy) should get a flu shot. Treatment often causes them to have weak immune systems, which puts them at higher risk of serious and even life-threatening problems if they get the flu. Many people with cancer worry that the flu shot will make them sick or react with other drugs they are taking. Talk to your cancer doctor about this – he or she knows your situation best. /warfarin /coumadin interaction w/ /steroids /dexamethasone /decadron http://www.medscape.com/viewarticle/553030 Steroids can raise INR by a mean of 1.24 units, at an average of 6.7 days after initiation of steroids. /recall, radiation Radiation Recall with Anticancer Agents Burris, THE ONCOLOGIST Express on November 2, 2010. http://theoncologist.alphamedpress.org/content/15/11/1227.full /pain, cancer http://www.oncologypractice.com/view-pdf.html?file=fileadmin/content_pdf/jcso/2015_Articles/JCSO_oct_347_Cipta /dialysis /ESRD Medication dosing in ESRD pts: http://www.promotingexcellence.org/downloads/grantee_tools/bmc16.pdf /DDI /drug-drug interactions /fluconazole /diflucan INTERACTION w/ oxycodone Many drugs, like Nolvadex (tamoxifen) and Diflucan (fluconazole) inhibit CYP3A4, leading to an increased risk of oxycodone toxicity that can result in excessive drowsiness and slowed breathing. - See more at: http://www.aboutlawsuits.com/oxycodone-combined-pose-risk-of-side-effects-5954/#sthash.Wh1juE7I.dpuf /Pacemaker protocol 1. Hurkmans, "Management of radiation oncology patients with a pacemaker or ICD: A new comprehensive practical guideline in The Netherlands", Radation Oncology 2012, 7:198, http://www.ro-journal.com/content/7/1/198 2. Hudson, F, D Coulshed, E D'Souza, and C Baker. "Effect Of Radiation Therapy On The Latest Generation Of Pacemakers And Implantable Cardioverter Defibrillators: A Systematic Review." Journal of medical imaging and radiation oncology 54.1 (2010): 53-61. http://dx.doi.org/10.1111/j.1754-9485.2010.02138.x DVT PE anticoagulants /NOACS riveroxaban Xarelto apixaban Eliquis dabigatran Pradaxa edoxaban Savaysa /skin care UCSF2018 Neutral: topicals moisturizers Recommended against: Aloe Vera, Biafine Recommended For: topical steroids (mometasone 0.1% cream, 1-2x/day) (Ho, 2018) (but doesn't decrease moist desq) Mepitel film - decreases moist desq - place prior to start of RT - replace q7-12days - get online at CVS/Amazon Skintegrity /calendula /miaderm - contains calendula & aloe vera /enhertu is /fam-trastuzumab deruxtecan, an antibody-drug conjugate composed of an anti-HER2 antibody linked to a cytotoxic topoisomerase I inhibitor, /Dental DENTAL From Dr Heidi Hansen, DMD, Prov: I reviewed with the patient the potential acute and chronic oral/dental sequelae of head and neck radiation therapy to include: oral mucositis, dysgeusia, ageusia, dermatitis, trismus, acute and chronic orofacial pain, and hyposalivation / xerostomia. I also discussed with the patient the risk for development of radiation caries, periodontal disease, and osteoradionecrosis. Risk of developing ORN is reported in areas of the bone receiving > 50-60 Gy (Wahl MJ. Osteoradionecrosis prevention myths. Int J Radiat Oncol Biol Phys 2006.) The risk of osteoradionecrosis in all sites is 5.4% with RT alone and 6.3% with chemoRT(MASCC/ISOO 2011). The importance of maintaining a healthy dentition and practicing excellent oral hygiene including the use of a fluoride dentifrice, as well as the impact of sugar consumption on caries development, were explained to the patient. Prevalence of dental caries in patients treated with cancer therapies have been reported as 37.3% for chemotherapy alone, 24% post-radiotherapy, and 21.4% post chemotherapy and radiotherapy (Hong CHL. A systematic review of dental disease in patients undergoing cancer therapy. Supportive Care Cancer 2010). In addition, the patient was instructed to limit sugar consumption between meals, and made aware that henceforth, it is essential to undergo frequent (recommended three times a year) dental/oral examination and prophylaxis. The patient's questions were answered and an understanding was expressed.