Case Approach in Oncology - Reviews in Internal...
Transcript of Case Approach in Oncology - Reviews in Internal...
Case Approach in Oncology
& Paraneoplastic Syndrome
THITIYA SIRISINHA DEJTHEVAPORN
RAMATHIBODI HOSPITAL
BERLIN TUTORIAL 2018
Common cases you should know
Lung cancer (NSCLC, SCLC)
Germ cell tumor
Unknown primary carcinoma
แตผู่ป่้วยทีน่ ำมำสอบมกัไม่ตรงไปตรงมำเสมอ
ม ีcomplication จำกโรคทีต่อ้ง approach ใหไ้ด ้
Cord compression, SVC obstruction, leptomeningeal carcinomatosis
Paraneoplastic manifestation/ genetic syndrome that will lead to diagnosis of cancer
อำจมมีำกกวำ่หน่ึงโรค (มะเรง็ + อืน่ๆ)
อย่ำกงัวลเร ือ่งยำรกัษำมะเรง็มำกนัก เนน้กำร approach มำกกวำ่
รู ้basic principle ก็พอ ถำ้ตอบไดล้กึเป็น bonus
Paraneoplastic Syndrome
Definition : disorder occurring at sites remote from the primary tumor and its metastasis
Excessive production of substances (hormones)
Host response to tumor (immune-process)
Appears in 10-15% of cancer patients, May be the first manifestation of an occult cancer
Some are specific for particular tumor types
LEMS, SIADH
Some occur with many tumor types
HCM, DIC, cachexia
Not all syndrome parallels the activity of underlying malignancy
Yes Endocrinologic
Unpredictable Immune/neurologic
หญงิ 64 ปี heavy smoker, HTN, DLP
กย. 57 ไอเรือ้รงั ไม่มเีลอืดปน น้้ำหนักลด
CXR มีก้อนในปอด
พย. 57 เหนื่อยมำกขึน้ ส่งปรกึษำทำ้
bronchoscopy
review system พบวำ่มีขำออ่นแรง ลุกจำกโถ
ส้วมลำ้บำกขึน้ หวีผมได ้ไม่ชำ ไม่ปวดหลงั/ ปวด
หัว กลั้นอจุจำระปัสสำวะได้
Rt. Lt.
deltoid gr. IV IVbicep / tricep IV / IV IV / IV
wrist F/E V Vfinger F/E V Vhand grip V V
hip F/E III+ / IV III+ / IVknee F/E IV / IV IV / IV
ankle dorsiflex V V
plantarflex V V
Tone : normalSensory : normalCN : ptosis gr I DTR :BBK : plantar response
3+ 3+
3+3+2+
1+
2+
1+
0 0
Imp :
1. Chronic cough with lung mass
2. Proximal muscle weakness
Hyporeflexia (LE), mild ptosis
DDx :
What else you want to look for in history,
exam and initial labs?
Additional information
อำกำรออ่นแรงเป็นๆหำยๆ สว่นใหญ่ขยบัขำ
สกัพกัเหมอืนจะแรงดขีึน้ ไม่มผีืน่
ปฎเิสธยำตำ่งๆ /ยำลกูกลอน
PE เพิม่เตมิ : no rash, lymphadenopathy,
clear lungs
Na 136, K 4
Normal TFT, CK
จะตรวจรำ่งกำยอะไรเพิม่เตมิอกีหรอืไม่
Prox weakness,
Hyporeflexia
Mild ptosis
Additional information
PE:
Diagnosis : Lambert-Eaton
myasthenic syndrome
What do you expect from a TBBx?
Prox weakness,
Hyporeflexia
Mild ptosis
Proximal Muscle Weakness and Cancer
LEMS : Small cell lung cancer
Many interesting paraneoplastic syndrome
MG : thymoma
Dermatomyositis
Lung, GI (gastric/colon), ovary, NPC
Cushing syndrome : ectopic ACTH
SCLC, Neuroendocrine tumor : thymic/
bronchial carcinoid, pancreatic NET
Lambert-Eaton Myasthenia Syndrome
Paraneoplastic in 50-60% Small cell CA
but only 5% of SCLC have LEMS
clinical point : decreased DTR which improves after repetitive movement
can be ass. with autonomic disturbance : impotence, dry mouth, constipation, abnormal sweating
Occ. with CN signs : ptosis, diplopia, dysarthria (less common than MG)
Electrodiagnostic : Decrement of action potential with low frequency stimulation, increment w/ high frequency stm.
Lambert-Eaton
Myasthenia Syndrome
Antibody against P/Q type voltage gated Ca
channel (VGCC) (pre-synaptic) prevent
entry of calcium into the cell (necessary for
release of Ach)
Can be detected in both paraneoplastic and
autoimmune LEMS
Usually respond to Rx of cancer
Respond well to IVIG or plasma exchange or
immunosuppression
Myasthenia Gravis
Paraneoplastic in 10-15% of cases
Thymoma : most common tumor with MG
Slow growing tumor
May be rarely ass. with other CA : SCLC, breast, lymphoma
CN involvement more common than in LEMS (ptosis,bulbar)
EMG: decremental compound muscle action potential w/ repetitive stimulation then stabilizes or increasing afterwards
Myasthenia Gravis Anti-AchR +/- other muscle protein Ab,
Not diagnostic for paraneoplastic disease
Thymoma with MG : Better outcome c/w those without MG
MG activity not always correlate with thymoma status
other paraneoplastic syndrome in thymoma
PRCA, pernicious anemia, nephrotic syndrome, thyroiditis, hypogammaglobulinemia
Rx : thymectomy, +/- immunomodulatory Rx
chemoRx in metastatic disease
Neurologic Paraneoplastic Syndrome
Relatively rare, 1% of cancer patients
Most are immune-mediated (autoimmune)
Antigens common to the tumors and nerve cells
Usually precedes the identification of cancer (2/3)… most CA are found within 1 year
Common cancer with neurologic paraneoplastic syndrome Small cell lung cancer > NSCLC Breast cancer, ovarian cancer Lymphoma
Most follow a subacute course, progressing over several weeks- months and then stabilizing
Most neurologic syndrome do not parallels cancer response
Neurologic Paraneoplastic Syndrome
PNS involvement More common than CNS involvement Ex. MG, LEMS, AIDP Could be responsive to immunomodulatory Rx : LEMS, MG,
AIDP
CNS involvement Example: cerebellar degeneration, limbic encephalitis, opsoclonus-
myoclonus
Subacute progression over weeks to months Can render a previously fit patient bedbound
Usually resistant to immunomodulatory Rx (exception : antiNMDA, limbic encephalitis)
Prognosis is poor CSF : Early inflammatory (pleocytosis, high protein) decline with time
Brain imaging : usually unremarkable except limbic encephalitis
Estimated Likelihood That a Given Neurologic Disorder Is a Paraneoplastic Syndrome
Syndrome % Paraneoplastic Cancer
LEMS 60% Small cell lung CA
MG 15% thymoma
Dermatomyositis 20% NHL, ovary, lung,
NPC, GI
Sub acute sensory
neuropathy
20% Lung, lymphoma,
MM
Limbic
encephalopathy
50% SCLC, germ cell,
breast
Subacute cerebellar
degeneration
50% Ovary, breast, small
cell, Hodgkin's
Opsoclonus-myoclonus 40% Neuroblastoma,
breast, SCLC
ชาย 51 ปีพนกังานธนาคาร
ปรญิญาตรี
CC : จ ำ process กำรท ำงำนไมไ่ด ้1 wk PTA
1 wk PTA ตืน่เชำ้ไปท ำงำนตำมปกติ จะเริม่ท ำงำนแลว้จ ำกระบวนกำรท ำงำนไมไ่ด ้จ ำขัน้ตอนกำรจำ่ยเงนิใหพ้นักงำนไมไ่ด ้ตอ้งหยบิเอกสำรเกำ่ขึน้มำดแูลว้พอนกึออก คอ่ยๆท ำไปจนจบได ้เดนิทำงกลบับำ้นโดยรถไฟฟ้ำ BTS ได ้ท ำกจิวตัรประจ ำวนัอืน่ไดต้ำมปกติ
ปกตเิคยไปบำ้นนอ้งสำวหลำยครัง้แตต่อนนีน้กึรำยละเอยีดในบำ้นไมอ่อก
ไมม่ไีข ้ไมม่ปีวดศรีษะ ไมม่ผีืน่ตำมตวั ไมม่อีอ่นแรง/ชำ ไมม่หีแูวว่หรอืเห็นภำพหลอน
PH : สบูบหุรี่ 20 มวน/วนั x 20+ yrs
alcohol 1-2 bottles/wk, no drugs abuse
HT ไมไ่ดก้นิยำประจ ำ
ชาย 51 ปีพนกังานธนาคาร ปรญิญาตรี
PE : unremarkable
Neuro : alert, orientation √
MMSE : 29/30
Impaired executive function
T2Cor FLAIR
Limbic Encephalitis Clinical :
Short-term memory deficit (80%) with intact cognitive Fn.
+/- partial complex seizure (50%),
confusion (40%), psychiatric symptoms (40%)
Related syndrome : brainstem encephalitis, encephalomyelitis
Frequently preceded Dx of cancer but 40% may occur AFTER cancer diagnosis
One of a few CNS paraneoplastic syndrome that brain image helps : abnormal
signal in hippocampus
DDx: herpes encephalitis, other autoimmune limbic encephalitis, Wernicke encephalopathy, psychiatric disorder
CA : Small cell lung cancer*, testicular CA, breast CA, ovarian teratoma
Ab : Anti-Hu, Anti-Ma1-2, Anti CV2, Anti NMDA, Anti AMPA
Occasionally improved with Rx of primary CA
Paraneoplastic Cerebellar Degeneration
Acute or subacute , pancerebellar syndrome, usually symmetrical :
gait, dysarthria, dysphagia, tremor, N/V, eye movement abnormalities (nystagmus, diplopia), vertigo
Results in severe disability (50-80% bedridden)
Immune- mediated destruction of Purkinje cells
Most precede CA , but 30% may occur AFTER cancer diagnosis
MRI : normal or atrophic cerebellar (late)
DDx: drugs (Dilantin, ARA-C), alcohol, B1/B12 def,
prion dz (CJD), MS/demyelination, ADEM
Most common ass. CA are
Breast CA , ovary (anti-Yo*, Ri)
small cell lung CA (Anti-Hu)
Hodgkin’s disease (Anti-Tr*, Anti-mGluR)
Rarely respond to Rx of cancer
CPK 1587
LDH 590
Dermatomyositis
Proximal muscle weakness
Heliotrope :violaceous color of the eyelids, often with edema
Gottron’s papule : keratotic papules over knuckles
Widespread erythema, often over the elbows and knees, resembling psoriasis
Photosensitivity
Nail cuticle abnormalities, including telangiectases, thickening, roughness, overgrowth, and irregularity.
Dermatomyositis/ Polymyositis• About 20-25% have internal malignancy esp. > 50 years old
– 5-7 –fold increase risk compared to general population
– Excess risk declines with time with peak incidence in first 2 years
• Risk is higher in dermatomyositis (32% w/ CA vs 15% in PMS)
• Common autoAg in tumor and muscle cells
• Associated CA : ovary, breast, lung, pancreas, lymphoma, other GI (stomach,colon), bladder
– Asian : NPC ***
• May occur before, at Dx or after Dx of cancer
• Very high CK, several myositis-specific autoAb (anti-Jo, antisynthetase, antiSRP, etc)
• Anti TIF1 gamma (anti p155), Anti NPX2 : significant association with cancer-ass. myositis
• NPV 95%, PPV 53% ( Arthritis Rheum 2012) may aid in extent of work-up
(Paraneoplastic) Dermatomyositis/ PolymyositisShould cancer be searched for ?
Extensive blind evaluation of patients with dermatomyositis is not warranted
Extent of w/u for CA : depends on age and symptoms
detailed PE, breast, pelvic, PR, ENT exam for NPC
Routine labs : CBC, chem., UA, CXR, FOBT
Age-appropriate cancer screening: MMG, PV, colonoscope
If symptomatic (wt loss, anorexia, localizing symptoms, older age) CT chest / abdomen has higher yield than tumor markers
Tumor markers : no real use..? CA125, PSA, CA19-9
Higher OR of cancer with elevated baseline value
Continued periodic screening for up to 4-5 years
High risk group* : older age>45, cutaneous vasculitis/necrosis, dysphagia, absence of ILD, absence of muscle-specific Ab, anti TIF1/ NPX2 +ve
Treatment : Some improve w/ Rx of CA, but usually immuno Rx needed
Prednisone, azathioprine, MTX most do not recover completely*Lu X. Plos One
ชำย อำยุ 31 นักธรุกจิ
6 เดอืนกอ่น พฤตกิรรมกำ้วรำ้วขึน้ ท ำรำ้ยลกูนอ้ง flights of idea
ญำตสิงัเกตวำ่อว้นขึน้ สวิขึน้ ผวิคล ำ้ลง ดลูกุจำกเกำ้อี ้
ล ำบำก
ตรวจพบ HbA1C 9.2, BP สงู insulin
ระยะหลงัเร ิม่ม ีhallucination
PE : acne @ chest, purplish striae,
hyperpigmented inner lips, areolar
proximal muscle weakness
K 2.1, HCO3 36, FBS 245
Ectopic ACTH Syndrome
Clinical Presentation Cushinoid features
Muscle wasting
Hypokalemia with metabolic alkalosis, hyperglycemia
HTN
Hyperpigmentation (ACTH, MSH)
Less prominent : wt loss, centripetal fat distribution
Cushinoid features are usually less prominent than that seen in Cushing’s disease due to shorter time of exposure to cortisol (aggressive nature of the tumor SCLC)
Ectopic ACTH Syndrome
Most are associated with lung cancer (50%): small cell > NSCLC
Pancreatic neuroendocrine tumor
Thymic carcinoid / bronchial carcinoid
Ectopic ACTH Syndrome : Investigation
Confirmation of excess ACTH
Urine free cortisol levels fluctuate but are typically greater than 2 to 4 times normal
plasma ACTH level is usually >200 pg/mL
No suppression by high dose dexa (in contrast to ACTH-producing pituitary tumor)…. But overlaps do occur not definitive
Seeking the etiology
Majority have primary lung/ thymictumor CXR, CT chest
If negative: think of pancreatic neuroendocrine tumor CT abdomen
CT adrenal : bilat adrenal
hyperplasia
MRI brain : pituitary
microadenoma
BIPSS : no gradient of central
and peripheral ACTH
6678 mcg
281 pg/ml
Low and high
dose dexa.
non-suppressible
Biopsy mass :
neuroendocrine carcinoma
Stage ?
Ectopic ACTH Syndrome :
Prognosis
Depends on tumor type and disease stage
Small cell lung CA : highly aggressive, most die within 1-2 years,
Carcinoid tumor: can be indolent
Pancreatic NET : can be indolent
Shorter survival than those without Cushing (Higher incidence of infection)
Ectopic ACTH : Treatment of Cancer
Tumor Rx• Small cell lung CA
– Cis or carboplatin + etoposide +/- RT
– Rapid response
• Carcinoid tumor/ pancreatic Neuroendocrine– Resection if feasible– Embolization of liver mets– chemoRx of limited use– targeted Rx : sunitinib,
everolimus
– High risk of infection if hypercortisolism not controlled
Rx of excess cortisol
• Adrenalectomy
• Ketoconazole 400-1200 mg/d (rec. dose < 800 mg)
– Closely follow LFT (dose dependent)
– N/V/rash/diarrhea
• Aminogluthetimide/ metyrapone (not available in Thailand)
• Etomidate IV : IPD only
• Mitotane : adrenolytic (not available in Thailand)
หญงิ 38 ปี แข็งแรง
2 m PTA : จกุแสบแน่นทอ้ง เรอบอ่ย ถำ่ยเหลวขึน้ 5-8 /วนั ไมม่ไีข ้ไมม่ี
คลืน่ไสอ้ำเจยีน / ถำ่ยด ำ/ถำ่ยมกูเลอืด ได ้AIR-x, omeprazole,
domperidone อำกำรดขีึน้บำ้ง
1 m PTA อำกำรกลบัเป็นซ ้ำ ถำ่ยเป็นน ้ำ ครัง้ละครึง่แกว้ 10-18 ครัง้ตอ่วนั
ตอ้งลกุถำ่ยกลำงคนื ได ้omeprazole 40 mg/d ปวดทอ้งดขีึน้แตย่ังถำ่ยเหลว น ้ำหนักลดเล็กนอ้ย
ไมม่ปีระวตักินิของดบิๆสกุๆ อำกำรไมส่มัพันธก์บัชนดิอำหำร ไมซ่ือ้ยำกนิเองไมส่บูบหุรีไ่มก่นิเหลำ้
PE : mild epigastric discomfort
Stool exam x 5 d : no O&P, no WBC/RBC
Stool weight (NPO) > 1000g/d
CBC, TFT, 8AM cortisol : WNL
Albumin 3.2
Imp : dyspepsia with GERD and chronic diarrhea
DDx Etiology: functional vs organic
IBS-diarrhea
Infection: parasites, C.difficile, OI in HIV
IBD
Malabsorption syndrome: lactose intolerance, celiac, chr. pancreatitis, bacteria overgrowth
Drugs/diet: antibiotic, metformin, gliptins, Mg, colchicine,
sorbitol, caffeine, Cancer Rx (5FU, EGFR TKI, anti-VEGF)
Metabolic: Hyperthyroidism, hypoPTH, Addison’s
Tumors : neuroendocrine tumor (PNET (VIPOMA), carcinoid, gastrinoma), medullary thyroid CA, villous adenoma/colon CA, mastocytosis, etc
Physical signs to look for in chronic diarrhea
Findings Implication
Muscle wasting, edema Malnutrition
Mastocytosis
Amyloidosis
Addison’s disease
Celiac disease
Carcinoid syndrome (NET)
Cancer, HIV
Fecal incontinence
Chronic mesenteric ischemia
Schiller et al. Clin Gastroenterol and Hepatol 2017
Back to the case
• Colonoscopy : normal• EGD : multiple clean based small ulcers in
stomach and 1st -3rd part duodenum• Bx : gastroduodinitis, H pylori negative
• Fasting serum gastrin = 1500 pg/ml (NL < 200)
Gastrinoma (Zollinger Ellison Syndrome)
Gastric hypersecretion, diarrhea, malabsorption/ steatorrhea,
abdominal pain & wt loss
EGD : diffuse peptic ulcers in ususual location post-bulbar
duodenum/jejunum
Extremely high fasting serum gastrin level (x3d)
Frequently misdiagnosed
Gastrinoma is neuroendocrine tumor
Normal state : gastrin released from G cell in gastric antrum
Most tumor in the pancreas (non-beta cells) and duodenum
60% malignant with nodal or distant mets
25% associated with MEN 1
hyperPTH, pituitary adenoma, NET
ZES Investigation
Check fasting serum gastrin (48-hr without acid suppressant Rx)
> 1000 : definitive, 200-<1000 : confirmatory test
Basal acid output(> 15mEq/hr), gastric output volume(> 140 cc), pH<2
?secretin stimulation test
Imaging : CT (misses small tumor), EUS,
Somatostatin receptor scintigraphy (SRS)
Treatment of Gastrinoma
Medical control of acid hypersecretion :
PPI : high dose required
Frequent use of PPI makes Dx even more difficult less dramatic presentation delayed Dx
Gastrectomy in uncontrolled case
Somatostatin analog : inhibit gastrin secretion from the tumor
Tumor removal could be curative : pancreatic enucleation, duodenal resection
Metastatic disease : targeted Rx, IFN, chemoRx, radioactive Rx
Screen for MEN1 phenotype : family history , serum calcium*, prolactin
ชำย อำยุ 20 ปี
เหนือ่ยงำ่ย ใจสัน่ นน.ลด 8 กกใน 4 สปัดำห,์
2 สปัดำห์ มไีอ บำงครัง้มเีลอืดปน
No TB contact
PE : T 38, PR 150 irregular, BP 140/60, RR 24
No exophthalmos, no thyromegaly, flat neck vein
Lungs : few crackles both bases
Hyperreflexia, tremulousness
Work-up: FT4 = 40 pmol/L, TSH 0.022 mU/L
What else you want
to look for in
• physical exam
• labs
20 yo male
• Hyperthyroid
• Hemoptysis
Additional information
Paraneoplastic Hyperthyroidism
Uncommon 3.5% in advanced germ cell tumor
Male : Non-seminoma with choriocarcinoma component
Female : Gestational trophoblastic disease
Structural similarity of α- subunit of HCG, TSH and LH
Considerable homology between the beta-subunits of hCG and TSH hCG has weak thyroid-stimulating activity
Can also binds to LH receptor on Leydig cell testosterone and estrogen production
Usually seen with b-HCG > 50,000 (prevalence 50%)
Associated with widespread metastasis and poor prognosis (high risk GCT)
Responsive to combination chemoRx : BEP regimen
Important Cancer You Should Know
Histologic Classification of
Lung Cancer
AdenoCA
Squamous
Large
cell
Small
cell
Frequent cause of
paraneoplastic
syndrome
• SIADH• Cushing’s syndrome :
Ectopic ACTH• Lambert-Eaton
myasthenia• Cerebellar degeneration, • Limbic encephalitis• Vision loss : Anti
recoverin
Small Cell Lung Cancer
Smoking related disease
Rapid tumor growth, more aggressive clinical course than
NSCLC : don’t wait too long to refer!!
Most are central in location
almost always a systemic disease 2/3 have metastasis @ Dx
sites of metastasis :
LN, liver, bone, bone marrow, brain
Staging of SCLC Does not use TNM not a surgical disease (No role of
surgery in general)
staging based on anatomy
1. Limited stage : lesions confined within one hemothorax, one port of RT possible
2. Extensive stage : multiple sites (malignant pleural effusion, distant organ)
Stage Survival
Untreated Treated
Limited 12 wks 12-20 mos30-40%
Extensive 5-6 wks 7-11 mos
Treatment of SCLC
Limited disease
ChemoRx + radiation
Cisplatin or carboplatin + VP16
Response > 70%
If no residual dz prophylactic brain RT improves survival
2 yr-survival 15-40%
Extensive disease
ChemoRx alone (RT optional)
Cis/carbo + VP16
Response 50%
2 yr survival : rare
Median survival 6-8 months
• Chemosensitive, radiosensitive• but recurrence rate is high even in early stage
Early data of modest benefit of ImmunoRX adding to chemoRx
6 April 2559
Na 11616 May 2559, post C2
Na 136
25 Dec 2559, post C6 / RT
Na 140
26 Jan 2560
Expired 9 m from Dx
Treatment of NSCLC
A Shift in Concept
AdenoCA
Squamous
Large
cell
Past Histology doesn’t
matter
Same Rx
Same prognosis
Present• Histology matter
• Molecular classification
• Prognosis depends on
subtype
• Rx adapted according
to histology/ molecular
profile
Molecular alterations in AdenoCA
Johnson, et al. ASCO 2013 Sun, et al. J Clin Oncol 2010; Barlesi, et al. ASCO 2013
• Squamous cell CA : Molecular characteristic less
well-defined than adenoCA
Adenocarcinoma,
never smokers
RET, ROS, MET
Braf, etc
Features of mEGFR and ALK+ve NSCLC“Oncogenic Addiction”
EGFR Mutation
uncontrolled cell growth (driver mutation): Exon 19 deletion & L858R
Test : Mutation analysis from tumor* or blood
Clinical features suggestive of EGFR mutation (not absolute)
adenoCA , female, Asian decent, non-smoker
Specific inhibitors available :
1st G gefitinib, erlotinib, afatinib
2nd G : osimertinib
Acquired resistance occurs after exposure to 1st line inhibitors
EML4/ALK (ALK+ve)
ALK gene fused with EML4 gene : transform cells
Less common than mEGFR
Test : IHC* or FISH for ALK break-apart
Mutually exclusive with EGFR or K-Ras
Profile : Non-smoker or light smoker, adenoCA with signet ring or acinar histology, younger age of onset
High incidence of brain mets
Highly sensitive to ALK inhibitors : crizotinib, certitinib, alectinib
Treatment Principle of Advanced NSCLC(Metastasis & Malig. Effusion)
All patients : Supportive Rx (symptomatic Rx)
Medications
Local RT: bone / brain mets/ airway obstruction
Intervention: chest drain, airway stent,etc
Cancer-specific Rx : improves survival
1. ChemoRx : any histology
Platinum-doublet regimen : carboplatin/cisplatin + any agents (paclitaxel, docetaxel, gemcitabine, VP-16, pemetrexed)
Response rate 20-40%
2. Molecular targeted Rx: 2 important driver mutations
EGFR inhibitor in mutation +ve cases (preferred)
ALK inhibitor if ALK+ve
3. ImmunoRx : mainly benefit no-targetable tumor
In search for “right” biomarkers
Molecular targeted therapy:
it is making a difference
BSC:
2–5
months1
Med
ian
su
rviv
al
(mo
nth
s)
1980s 1990s 2000s 2013
Platinum-
doublets:
8–10
months3,4
Single-
agent
platinum:
6–8
months2
Targeted
therapies:
>18
months5
0
2
4
6
8
10
12
1. Ganz, et al. Cancer 1989; 2. Bunn, et al. Clin Cancer Res 1998
3. Schiller, et al. NEJM 2002; 4. Scagliotti, et al. J Clin Oncol 2008; 5. Rosell, et al. Lancet Oncol 2012
immunoRx
> 24 m
2018
Treatment Options in NSCLC : 1st Line Rx
NSCLC
AdenoCA Squamous cell CA other
EGFR mutation ALK IHC+ve
• EGFR TKI (preferred)- 1st gen : afatinib, erlotinib, gefitinib(- 2nd Gen : osimertinib)
• Combination chemoRx• Single agent chemoRx
• ALK inhibitor (preferred)
- crizotinib, ceritinib, alectinib
• Combination chemoRx• Single agent chemoRx
• Combination chemoRx
• Single agent chemoRx
Emerging benefit: • Immune checkpoint inh
(ICI) +/- chemoRx- atezolizumab, nivolumab,
pembrolizumab. ……
ImmunoRx not recommended in this group
No targets
EGFR, ALK, (ROS, BRAF, HER2)
Overview of Rx SequencemEGFR
First Line
1st Gen EGFR TKI
Afatinib, erlotinib, gefitinib
Combination ChemoRx4-6 cycles
2nd Line
Combination ChemoRx
2nd Gen EGFR
TKI : osimertinib
1st Gen EGFR TKI
i
3rd Line
Combination/ single
ChemoRx
Single agent chemoRx
2nd Gen EGFR TKI :
osimertinib
ImmunoRx not recommended
T790M+
-
T790M
-
+
NSCLC Treated with EGFR-TKI
EGFR exon 19 mutation
Overview of Rx SequenceALK+ve
First Line
1st G ALK inhibitors
• crizotinib
Combination ChemoRx4-6 cycles
2nd Line
Combination ChemoRx
2nd Gen ALKiceritinib, alectinib
1st Gen ALKi
3rd Line
Combination/ single
ChemoRx
2nd Gen ALKi or Single agent
chemoRx
2nd Gen EGFR TKI or Single agent
chemoRx
ImmunoRx not recommended
Overview of Rx Sequenceother NSCLC without Targetable Mutation
First Line
Combination ChemoRx4-6 cycles
+/- immunoRx
2nd Line
ImmunoRx
3rd Line• Single agent
chemoRx• Docetaxel• Pemetrexed
(non-sq only
ImmunoRxIf PD-L1>50%
Combination ChemoRx4-6 cycles
ImmunoRx
• Single agent chemoRx
• Docetaxel• Pemetrexed
(non-sq only
PPD-L1 ?
8 m
Unselected: chemoRx alone mEGFR only, 1L TKI
G :32m
O: 38 m
ALK+ve, 1L ALK inh
Median NR
PDL1>50%, 1L immunoRx
CT 13 m
Im.Rx 30 m
45 yo male , pain in right shoulder for months, unrelated to activity
Now noted numbness in right hand and weight loss
Not related to neck movement
Superior Sulcus Tumor (Pancoast’s Tumor)
Referred pain to scapula and shoulder
Pain in C8-T1 distributionshoulder-arm medially (lower brachial plexus)
Weakness & atrophy of hand muscles
Thenar m, impairment of adduct/abductn
Horner’s syndrome sympathetic chain/stellate gg.
Respiratory symptoms not common (peripheral location of tumor)
Look for other clinical signs of distant mets
Bone pain, liver mets, brain mets
Treatment of Locally Advance NSCLC(Disease confined to thorax, no distant metastasis)
Mediastinal LN/ SPC involvement, invasion into mediastinal structure including SVC syndrome, invasion of vertebra/ nerves
Most patients die from distant metastasis
Esophagitis is the main side effects
Pancoast tumor : if responds well to CCRT resectableimproves outcome
Role of targeted drug in this stage is not clear yet but immunoRx is coming
Treatment Median survival(months)
Radiation alone 8-9
Sequential chemoRx and radiation 12-14
Concurrent chemoRx and radiation 20-29and radiation (> 36 m with immunoRx+)
A 42year-old female
Known case breast cancer stage 3, LN 15+ve
ER neg, PR neg, HER2 1+
Just completed adjuvant chemoRx 2 months
ago
Presented with severe headache for 3 days
and unsteadiness
Neuro exam
Well oriented
Papilledema bilat
EOM full
Mild Rt. facial palsy LMN
Motor : UE normal tone/ strength
LE : flaccid tone, grade 4 weakness bilat
– Absent DTR both knees / ankles
Cerebellar :impaired FTN
Sensory : decreases PPS L3-5,S1 & perianalsensation
Locate the lesion ?
Investigation ?
Leptomeningeal Metastasis Solid or hematologic malignancy
Etiology
Breast (TNBC, HER2) & NSCLC (adenoCA, mEGFR, ALK) : most common
Melanoma in westerners
Lymphoma / leukemia
Others : small cell lung , gastric, ovarian, RCC, bladder CA, etc
Dismal prognosis in general
60-80% have progressive, refractory systemic disease at time of Dx
Untreated : survival 4-6 weeks
Treated : survival 12-16 weeks (may be longer in breast CA & lung CA with mEGFR, ALK)
Leptomeningeal MetastasisSigns-symptoms
Cerebral involvement / obstruction of CSF flow
Headache, memory loss, lethargy, seizure, behavioral changes, papilledema, gait disturbance
CN involvement Common : 3,4,6,7,8
“numb chin” syndrome
Spinal cord and roots Nuchal rigidity, neck/back pain, incontinence
Weakness, sensory loss
Clinical hallmarks is multifocal neurological symptoms and signs
Imaging : linear and/or nodular enhancement of the leptomeninges, cranial nerves and spinal nerve roots, especially the cauda equine
Hydrocephalus +/-
T1 post Gadolinium
Leptomeningeal Metastasis
Diagnosis- MRI
Leptomeningeal Metastasis
CSF : Gold Standard
OP increased in 50%
Pleocytosis (L)50%
Eosinophils in lymphoma
Protein typically increased due to disruption of BBB
Glucose < 40 (25-30%)
MRI brain should be done before LP (co-existing brain mets
CSF cytology (10ml)
1stLP 55%
2ndLP 80%
Each subsequent LP (3-7) +2%
Persistently negative: autopsy proven 20%
Ventricular or cistern 5%
Standard Treatment
Relief ICP : LP, shunt
Intrathecal chemoRx
MTX (works mostly in breast CA)
Ara-C, liposomal ara-C, thiotepa, topotecan (hemato only)
Given 2-3 times/week x 3-4 weeks weekly x 4, then monthly
Radiation
Focal to sites of visible bulky dz and sites of CSF obstruction
Craniospinal area
Systemic (chemo) Rx: BBB problem … few exception
NSCLC : EGFR TKI, ALK inhibitor
Breast HER2+ve : lapatinib, T-DM1 Good CSF penetration
Carcinomatosis peritonii
Ascites, palpable abdominal mass/omental cake, sister Mary Joseph nodule, clinically small bowel obstruction
Mostly are adenocarcinoma
Morphology helps sometimes:
Papillary adenoCA ovarian CA in female, pancreatic/NSCLC possible
Signet ring, poorly diffentiated, mucin producing favor GI tract primary (colorectal, gastric, cholangioCA / pancreatic CA)
Female Male
- 55% Gyne
- 25% GI, hepatobiliary
- 25% unknown, others (lung,
breast)
- 55% GI (incl. pancreas)
- 25% GI
- 25% GI, others (lung)
Carcinomatosis PeritoniiSymptom-Directed Investigation
CT abdomen/ pelvis : look for primary, extent of abdominal mets
Endoscopy if :
Fe-def. anemia, GI symptoms not explained by ascites
Mucin producing adenoCA/ signet ring (from cytology)
Abnormal findings in CT
Male
Tumor markers : may not be very helpful or sometimes confusing, useful for follow-up Rx response
CA 125 (female) : a marker for peritoneal disease (not just CA ovary) BUT high levels and adenoCA +/- pelvic mass is suggestive of ovarian in origin
CEA/ CA19-9 : very non specific, can be elevated in ovarian as well
Pathology review / special stain is vital
GI tract marker : CK 20, CDX 1, etc
Treatment of Carcinomatosis
Peritonii
Known primary : Rx per standard of each cancer
Colorectal : 5FU + oxaliplatin or irinotecan +/-targeted Rx
Gastric : 5FU based
Ovarian CA : paclitaxel/carboplatin +/- PARP inhibitors
Breast
ER+ve : endocrine Rx / chemoRx,
HER2+ve : trastuzumab + chemoRx
triple negative: chemoRx
Treatment of Carcinomatosis
Peritonii
Unknown primary : select chemoRx to treat the most responsive/treatable tumor
In female : Rx as ovary very Rx responsive
Platinum + taxane : survival 2 years, RR 40-60%
Surgery : TAH/BSO/omentectomy if possible
In male : use GI CA drug : mainly 5FU-based
Cancer Medical Rx
NSCLC See previous
Breast CA 1 ER+ve : endocrine Rx (aromatase inhibitor, tamoxifen)
2.Her2+ve : trastuzumab + chemoRx (paclitaxel, docetaxel,
capecitabine)
3. Triple negative: chemoRx (Adriamycin, paclitaxel, docetaxel,
capecitabine)
Colorectum 5FU-based +oxaliplatin or irinotecan(ex : FOLFOX, FOLFIRI,
capecitabine)
Targeted Rx : bevacizumab or cetuximab
Germ cell
tumor
BEP (bleomycin, etoposide, cisplatin)
Prostate CA Androgen suppression (orchidectomy, LHRH agnonist +/-
antiandrogen)
cholangioCA Gemcitabine +cisplatin
NPC RT + cisplatin cisplatin+5FU
Summary of Drugs in Common Cancers
Thank You for Your Attention !!
Imp : Proximal muscle weakness
DDx :
NMJ disorder, myositis
Metabolic : thyroid, cushing, hypokalemia
What else you want to look for in history, exam and
initial labs
Fluctuation, other neuro deficit
Drug list : lipid-lowering drugs, steroids, colchicine
Skin signs , Cushingoid appearance
Symptoms of rheumatologic disorder
Elyte, CPK, TFT, glucose
Additional information
Enhanced ptosis +ve,
Knee jerk reflex 3+ after sustained contraction
Diagnosis : Lambert-Eaton
myasthenic syndrome
What do you expect from a TBBx?
Prox weakness,
Hyporeflexia
Mild ptosis
Biopsy mass :
neuroendocrine carcinoma
Sputum mAFB : nocardia
Stage :
Physical signs to look for in chronic diarrhea
Findings Implication
Muscle wasting, edema Malnutrition
Urticaria pigmentosa, dermatographism(flushing, abd pain)
Mastocytosis
purpura, macroglossia Amyloidosis
Hyperpigmentation Addison’s disease
Dermatitis herpetiformis Celiac disease
Flushing, murmur, wheezing Carcinoid syndrome (NET)
Lymphadenopathy Cancer, HIV
Anal sphincter weakness Fecal incontinence
Abdominal bruit, A. Fib Chronic mesenteric ischemia
Schiller et al. Clin Gastroenterol and Hepatol 2017
Additional information
A left testicular mass 3 cm
Mild gynecomastia
Lab:
B-HCG : 750,000
AFP : 2
LDH : 1431