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Management of UnresectableThymoma/Thymic carcinoma

Dr. Ajay Yadav

Medical Oncology

Epidemiology

• Thymic epithelial tumors-1.3-3.2 per million annually

• 90% of thymus tumors-thymoma

• 10%-thymic carcinoma,carcinoid tumor

Engles E et al. Epidemiology of thymoma and associated malignancies.J Thorac Oncol.2010 Oct

Epidemiology

Journal of Thoracic Oncology 2014

Indian Data

• 62 pts(2006-2011),Tata Memorial Hospital,Mumbai.

• 36M, 26F;

• 22-84yrs, median 51.5 years

• Stage1-22,2-13,3-18,4-9

• Type A-7,AB-14,- B-30 (49%).C-11

• Sx,Sx with adj .,NACT/CTRT,palliative

• 3yrs survival-95%,89%,100%,71%

Rathod S et al.Thymoma:First large Indian experience.Indian Journal of Cancer.2014

Clinical Features

• 1/3rd -Mediastinal mass, local symptoms (chest pains, dyspnea, hemoptysis, dysphonia, Horner syndrome, and superior vena cava compression).

• 1/3rd- paraneoplastic syndrome, such as myasthenia gravis (MG) or pure red cell aplasia (PRCA).

• 1/3rd -mediastinal mass incidentally discovered on radiographic imaging

Paraneoplastic syndrome

• Myasthenia Gravis

• 30%- 50% thymoma develop MG

• 10% MG-thymoma

• Pure Red Cell Aplasia PRCA:

• 5%thymoma-PRCA

• 10% PRCA-thymoma

• Isolated anemia,low Retic count,bone marrow –absence of erythroid precursors.

• Hypogammaglobulinemia –

• In 5% to 1 0 % of patients with thymoma

• 10% hypogammaglobulinemia- thymoma.

• Recurrent sinusitis ( common) red cell hypoplasia.

Devita .Principle and Practice of Oncology.9 th Edition

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Second malignancies

• B cell NHL

• Soft tissue sarcoma

Paraneoplastic syndrome associated with thymoma

Upto Date 21.2

Anterior mediastinal anatomySuspecting anterior med.mass in CXR(Hilum overlay sign)

CT scan showing anterior mass Imaging:CT features

Thymoma Mediastinal germ

cell

Goitre Lymphoma

Encapsulated, Cystic,well defined

margin

Contunity between

cervical and

mediastinal

compartment

Irregular

contour,surface

lobulation

Homogenous,hetero

genous

heterogenous Homogenous,mild

to moderate

enhancement

Calcification

infrequent

Foci of soft

tissue,fat,fluid,calcifi

cation

Calcification rare

Mediastinal LN

No vessel

involvement

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Radiographic appearance:CT

A B1,2,3 Invasive Thymic

Configuration Smooth contour Irregular contour Irregular contour

Calcification More

Attenuation Homogenous Homogenous Heterogenous Heterogenous

Mediastinal

LN,distant

mets,phrenic nerve

palsy

Present

Pleural

Dissemination

Present Present

• MRI:

• Vascular involvement, tumor contour, capsule.

• PET:

• Not recommended to assess thymic masses.

• Standard uptake higher in type B3 thymomasthymic carcinomas,thymic hyperplasia

• Optional in aggressive and advanced stage histology

FNAC or Biopsy

• FNAC-

• Difficult to distinguish by cytology

• Sensitivity< 60%.

• Biopsy:

• Larger samples can be obtained by incisional biopsy (e.g., anterior mediastinotomy or video-assisted thoracoscopy)

• Sensitivity >90% .

• Should not violate the pleural space.

Mehran R, Ghosh R, Maziak D, et al. Surgical treatment of thymoma. Can J Surg 2002;45:25-30.

Murakawa T et al. Results from surgical treatment for thymoma. 43 years of experience. Jpn J Thorac Cardiovasc Surg

IHC in anterior mediastinal masses

Saad et al. Utility of Immunohistochemistry in Separating Thymic Neoplasms From Germ Cell Tumors and Metastatic

Lung Cancer Involving the Anterior Mediastinum. Applied Immunohistochemistry & Molecular Morphology.June 2003

WHO histology

• A,B(morphology of neoplastic cells and their nuclei)

• A-spindle cells,

• B dendritic cells

• AB-Both

• B

• B1-cortex (normal thymus,large number of lymphocyctes),

• B2-less lymphocytes,

• B3 endothelial cell with round or polygonal cells with no mild atypia with minor lymphocytes

• C- Thymic carcinoma

Differences between thymoma and thymiccarcinoma

Thymoma Thymic carcinoma

Histology Organotypic tissue Non Organotypic tissue

Clinical course Less Aggressive More Aggressive

Metastasis Less distant metastasis Distant metastasis

Genomic alteration B1 –similar genomic

features

Thymic Squamous cell ca.- losses of chromosomes 1q,

6q, 13q, and gains of chromosome 1q, 17q, and

18.

Response to RT B1,B2(Lymphocytic)>B3

Recurrence Mixed ,medullay pattern

Survival B1 10 yrs-95% 5 yrs-30-50%

Onuka T et al.J Thor Oncol.2008,Wright CD et al.J Thorac Cardiov Surg 2005

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Histological type of Thymic Carcinoma Masaoka staging

a.Masaoka A et al. Cancer 1981,b.Okumara M.Cancer 2002

Staging Staging grouping

Management Management

• Locally advanced thymoma:

• Is it resectable?

• Does induction therapy make it resectable?

• What are the agents used and their results?CT,RT alone or CTRT

• How do we manage once it is resected?

• Chemotherapy combination used?Which one is superior?

• Thymic carcinoma:

• What are the multimodality approach used?Any role of targeted agents?

• Recurrent thymoma

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NCCN guidelines Resectability in thymoma(Indian data)

• 1989-2009,Retrospective study,

• 150 thymic tumors(5 NEC,145-thymoma)

• Stage1-34,2-39,3-56,4a-16

• 6 invasive thymoma-reconstruction of SVC,and /or brachiocephalic vein.

• All 6 pts adj.RT,CT(6 cycles cyclophosphamide,epirubicin,carboplatin)

• All alive at the end of f/u 18-24mnths

Arvind K et al.Resection and reconstruction of mediastinal great vessels in invasive thymoma.Indian Journal of Cancer.2010

Predicting unresectability in high risk thymoma

• Trial to study modalities for pre-operative treatment,

• Inclusion criteria predicting unresectability

• tumour size >8 cm, or

• size ranging from 5 to 8 cm with one or more of the following criteria: multifocal calcification, heterogeneous appearance, irregular or scalloped borders, great vessel invasion or encirclement.

• tumours <5 cm in greatest diameter, obvious great vessel invasion/encirclement in CT scan

Preoperative Treatment of Patients With High Risk Thymoma Clinicaltrial.gov NCT00387868

Multimodality tt thymoma:CT as induction

Shin DM et al..Annals of Internal Medicine.July 1998

Multimodality tt thymoma:CT as induction

• Median f/u-43mnths

• 9 complete resection DFS rate 7yrs-73%

• 2 pts incomplete resection-recurrence (OS at 7 yrs-100%)

• Major S/E-myelosuppression

• Ki-67 minimum if tumor necrosis >80%

Multimodality tt:CTRT as induction.

• MGH, 1997-2006,Retrospective

• 10 pts,stage3-7,stage4-3

• Cisplatin,etoposide/RT-Sx-cis,etoposie if incomplete resection and high risk of recurrence(close margin)

• R0-8,R1-2(chest wall invasion,pul.artery invasion).

• Median f/u 41mnths

• 1pt- CTRT associated pneumonitis

• 3 pts recurred

• 5 yrs survival was 69%

Wright CD et al. Induction Chemoradiotherapy Followed by Resection for Locally Advanced Masaoka Stage III

and IVA Thymic Tumors.Ann Thor Surg.2008

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Preoperative RT in unresectable thymoma

• 1983-1994,Japan

• 25 thymoma involving

• RT 12-21 Gy 5 fractions per wk -2-3 wks

• Invasive thymoma:12RT-sx-RT

• Median f/u 77.6mnths

• 9 (75%)Complete resection,3 incomplete resection

• 2 pts died of respiratory failure

• OS 5yrs-72.2%,10 yrs-48.2%

Akaogi E et al.Preoperative RT and Surgery to advanced thymoma with invasion to great vessels.Journal of Surgical Oncology 1996

Which is better CT vs CTRT in induction?

• Resectability rate of stage 4a without preoperative therapy:0-42%

• Resectability with induction therapy 57-76%

• Advantages of CTRT as induction:• Young patients

• Smaller stage 3,stage 4a with pleural disease to achieve complete resection

• Limitations:• Increase in toxicity

• Ability to give RT in the adjuvant setting

• Large tumors>15cm might pose more radiation to the lung

• Diagnosis difficulty due to fibrosis

Multimodality tt for thymic carcinoma

• Retrospective,1984-1998,Japan

• 40 thymic carcinoma(29-low grade SCC,11—high grade,small,undiff.,lymphoepithelioma like)

• 27 Sx(6NACT,4 Adj.)

• 13 RT( 10 with CT,3 without CT)

• 20 CT

• Complete resection- 16(59%),incomplete -11

• 27/40 recurrences.Complete resection developed no recurrence.

Ogawa et al.Cancer 2002

Multimodality tt for thymic carcinoma

• 5 yrs OS-38%,10 yrs OS-28%

• Median survival:

• Low grade-29mnths,high-11mnths

• Complete resection:predictor of survival-

• 12/16 (75%) with Complete resection-alive and free of tumor at f/u

• 1/24(4%) with incomplete resection-was alive.

Ogawa et al.Cancer 2002

Chemotherapy for Unresectable thymoma

• Phase 2 trials:• Cisplatin (single agent)

• Ifosfamide(single agent)

• Cisplatin,doxorubicin,cyclophosphamide(PAC)

• Cisplatin Etoposide

• Cisplatin,etoposide,ifosfamide(VIP)

• High dose carboplatin and etoposide

• Octreotide+/-prednisone

• Interleukin 2

• Case reports:• 5 fluorouracil and leucovorin

• Prednisone

Palliative chemotherapy

chemo stage No.pts response TTP Toxicity Median

survival

survival

ECOG Cis-50mg/m2-

3wkly

Advanced/re

current

24 2(

8

%)

PR

8(

33

%)

SD

10

(4

1

%)

P

Nauses,emesis- 76wks 2 yr

(39%)

Highley Ifos.,mesna 5

days,3wkly

Invasive

thymoma

15 5(33

%)C

R

1PR Nausea,emesis,

leucopenia

5yrs

(57%)

Loehere Pemetrexed( 21

prior RT)

Recurrent

thymoma,th

ymic

carcinoma

16,11 2(7%

)CR

2(7%

)PR

Recurrent-

45.4wks,

Thymic CA-

5.1wks

Chahinian Doxo,cis,pred. Invasive,met. 12 2 PR Nausea, emesis,

alopecia

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Chemo. Stage No. of

pts

Response Median

time to t/t

failure

Median

survival

Toxicity survival

Intergroup trial Cis50mg/m2

,doxo50mg/m2,

Cyclophos

500mg/m2

3kly.-8 cycles

Unresectabl

e,advanced

30 3(10

%)

CR,

12(4

0%)

PR

18.4mnths 38mnths 1 FN 5yrs(32+/-

12%)

Fornasiero Doxo,cis,cyclop.,

vcr 4 wkly

3,4 invasive 37 ORR-92%,

CR43%%

15mnths(5-

96mnths)

Lohrer Ifo.,eto,cis(VIP)

(1-6cycles)

3,4 St 3-

6,4a-

13,4b

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No CR,9

(32%)PR

32mnths 2yrs(70%)

E1c99 Carbo,pacli 3 wk

-6cycle

Thymoma,

thymic ca

40 3(8%)CR,5(

37%)PR

(thymoma),

no CR, 5PR

(thymic)

PFS-

19.8mnths,

6.2mnths

15mnths 13 neutropenia

Advanced thymoma:anthracyclines vsnonanthracyclines

Okuma Y et al.Key components of chemotherapy in advanced thymic carcinoma:systematic and pooled review.J Cancer Res

Advanced thymic CA:anthracyclines vs non anthracyclines

Advanced thymic CA:cisplatin vs carboplatin

Can definitive radiation therapy be used alone?

• 7/12 pts,unresectable tumors

• Survival-1 year 8 months to 5 years and 1 month

• Stage 4 A

• 5-year survival of 87% .

Arakawa A et al. Radiation therapy of invasive

thymoma. Int J Radiat Oncol Biol Phys 1990

Ichinose Yet al. Treatment of invasive thymoma with

pleural dissemination. J Surg Oncol 1993

Recurrence

• More in above stage 3 than stage 2

• 10-30% even after complete resection

• Multimodality therapy as in the time of diagnosis

• Performance status

• Chemotherapy

• Response to previous therapy

• Cumulative dose of anthracycline

• Monitoring cardiac toxicity(RT,paraneoplastic myocarditis)

• Targeted agents

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Salvage therapy

• Relapsed thymoma or thymic carcinoma

• 5 pts .Indiana University.

• High-dose carboplatin and etoposide followed by peripheral blood stem cell rescue given in a tandem fashion

• 3 alive beyond 2 yrs

• None remained disease free.

Hanna N et al. High-dose carboplatin with etoposide in patients with recurrent thymoma: the Indiana University

experience. Bone Marrow Transplant 2001;28:435–438.

EGFR mutation

• EGFR overexpressed in 70% of thymomas and 53% of thymiccarcinomas.

• 3 EGFR mutation:L858R-2cases,G863D-1.

• Phase 2, chemorefractory thymic tumors,Gefitinib

• 19 thymomas and 7 thymic carcinomas,

• PR-1,SD-14

KIT mutation

• KIT overexpression thymoma-2%,thymic carcinoma-79%

• KIT mutation in 7% thymic carcinoma

Drug effects in KIT mutation

Sunitinb in chemo-refractory thymoma and thymic ca

• Phase 2 trial

• Chemorefractory thymic epithelial tumors for platinum based chemo.

• Sunitinb 50 mg OD.4 wks treatment ,2 wks off until progression or unacceptable toxic effects.

• Median f/u:17 mnths

• 41 pts(25 thymic ca,16 thymoma)

• 23 thymic carcinoma, 6 PR(26%),15 SD,2 PD.

• 16 thymoma-1 PR(6%),12 SD,3 PD

Thomas A et al.Lancet Oncolgy 2015

Sunitinib…

• Median PFS thymic ca-7.2mnths,thymoma-8.5mnths

• OS at 1 yr,thymic ca-78%,thymoma-86%

• Grade 3 and 4 treatment-related adverse events: lymphocytopenia 8, fatigue 8, and oral mucositis 8 cardiac arrest-1

• Association between circulating tumor cells(CTC) with outcomes

• >10 CTC s per 10 mL peripheral blood before treatment and on day 1 of cycle two had slightly shorter overall survival

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Other agents

• Bevacizumab-VEGF inhibitor

• Belinostat-Histone deacetylase inhibitor

• Aflibercept, a soluble decoy receptor that binds VEGF-A (VEGF trap)

• Sorafenib-Multikinase RAF,VEGFR,PDGFR,cKIT,p38 nhibitor

• IMC-A12Cixutumumab-Insuline like growth factor1 receptor

• PHA-848125-AC:CDK2/Cyclin A complex and TRKA inhibitor

• Saracatinib-Src inhibitor

Management of Myasthenic patients with thymoma

• Thymoma-

• 15-20% of mediastinal tumors,

• 50% of anterior mediastinum

• Thymic carcinoma-10%of all thymoma

• Annual incidence-0.15/100000 US.

• Thymoma with MG- more in Chinese origin(44%)than in the white race.

MG:More mortality,less recurrence

• Thymoma and MG -increased operative mortality,surgical deaths due to MG crisis.

• Recurrence higher in patient without MG .

• Therapy:

• Preoperative use of immunosuppressive drugs variable(4.1%-100%)

• López-Cano et al-66.7%

• Maggi et al.- steroids(81.7%), immunosuppressive drugs(3.1%), and both(60.9%).

Follow up

• Baseline thoracic CT scan should be carried out 3–4 months after surgery .

• Completely resected stage I/II thymomas: CT scan every year for 5 years, then every 2 years.

• Stage III/IV thymomas, thymic carcinoma or after R1–2 resection: CT scan very 6 months for 2 years, then annually .

• Follow-up may be continued for 10–15 years.

ESMO guideline.2015

Prognosis

• Selection bias:

• Use of different histologic classifications

• Retrospective nature.

• Confounding factors:

• Treatment differences

• Extent and expertise of the surgical resection.

3 Factors

• Completeness of resection

• Extent of the disease

• Tumor histology

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Prognosis:completeness of resection Prognosis:Extent of disease

• Significant differences in

the survival rate

between stages II and III

(p = 0.04), and between

stages III and IV (p =

0.008).

• No significant difference

in survival between

stages I and II (p = 0.12).

Kim DJ et al.Prognostic and Clinical Relevance of the World Health Organization Schema for the

Classification of Thymic Epithelial Tumors.March 2005 Chest

Prognosis:subtypes

• Other poor prognostic indicators:

• recurrence,

• unresectable tumor ,

• symptoms at presentation, and

• invasion of great vessels

Future perspectives/Research questions

• Establishing thymoma registries

• No data comparing chemotherapy with chemoradiotherapy in the preoperative setting

• Study on various histology types of thymic carcinoma

Proposed management algorithmThymoma/Thymic

carcinoma

Locally advancedSystemic

Locally

restricted

RescetableNACT

Unrescetable

Multidisciplinary

discussion

Rescetable

RT(optional for

stage 1) ChemotherapyRT/CTRT

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Thank You