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