Systemic therapy of Thymic Malignancies

Tim Benepal

Consultant Medical Oncologist

St Georges Hospital

October 2018

What is it ?

2

What does it do ?

3

+ve

Selection

-ve

Selection

AIREImmature

T-Cells

Mature

T-Cells

Cell 2016 166, 582-595DOI: (10.1016/j.cell.2016.06.024)

Copyright © 2016 The Authors Terms and Conditions

Problem 1

5

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 6

Engels, Eric A.

Journal of Thoracic Oncology. 5(10):S260-S265, October 2010.

doi: 10.1097/JTO.0b013e3181f1f62d

What exactly does the word Thymoma mean ?

Table 1

TABLE 1. World Health Organization (WHO) Pathologic Classification of Thymoma

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 8

The Management of Thymoma: A Systematic Review and Practice Guideline

Falkson, Conrad B.; Bezjak, Andrea; Darling, Gail; Gregg, Richard; Malthaner, Richard; Maziak, Donna E.; Yu, Edward; Smith, Christopher A.; McNair, Sheila; Ung, Yee C.; Evans, William K.; the Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based CareJournal of Thoracic Oncology. 4(7):911-919, July 2009.doi: 10.1097/JTO.0b013e3181a4b8e0

◆Increasing proportion of lymphocytes with increasing pathological Subtype

◆Thymic carcinoma no lymphocytes , but invasive epithelial cells

9

Is there a staging system ?

Clinical Presentation ?

The Rule of Thirds?

13

Figure 1

FIGURE 1. Fifty-seven-year-old previously healthy man imaged with a chest radiograph after a motor vehicle accident. Posterior-anterior (A) chest radiograph demonstrates a mass (curved arrow) abutting and inseparable from the heart confirmed to be in the anterior mediastinum (black arrows) on the lateral chest radiograph (B). Contrast-enhanced chest computed tomography (CT) (C) revealed a 12 cm mass (T) compressing the lateral wall of the right ventricle. Biopsy confirmed this to be a thymoma. H, heart.

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 14

Imaging Thymoma

Marom, Edith M.

Journal of Thoracic Oncology. 5(10):S296-S303, October 2010.

doi: 10.1097/JTO.0b013e3181f209ca

Figure 3

FIGURE 3. Sixty-one-year-old woman imaged for staging of a newly discovered early breast cancer. Posterior-anterior chest radiograph (A) shows thickening of the anterior junction line (black arrowheads) confirmed on the lateral chest radiograph (B) to represent an anterior mediastinal mass (curved white arrow) anterior to but separate from the ascending aorta (black arrowhead). Contrast-enhanced chest computed tomography (CT) (C) confirmed the presence of a well-demarcated lobulated anterior mediastinal mass (straight white arrow) confirmed at surgery to represent an invasive thymoma (stage II).

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 15

Imaging Thymoma

Marom, Edith M.

Journal of Thoracic Oncology. 5(10):S296-S303, October 2010.

doi: 10.1097/JTO.0b013e3181f209ca

Thymoma Associated Myasthenia Gravis

◆ 1/3 Patients with Thymomas

◆ Never occurs in thymic carcinomas

◆ Is predominantly associated with Ab to Ach receptors

◆Increases with pathological subtype

16Thomas C, JCO Vol 17, No 7 (July), 1999: pp 2280-2289

Immune DysfunctionAcute Pericarditis

Addisons Disease

Agranulocytosis

Alopecia Areata

Cushings

Haemolytic Anaemia

Limbic Encephalitis

Myocarditis

Neuromyotonia

Nephrotic Syndrome

Panhypopituitarism

Pernicious Anaemia

Polymyosotis

Rheumatiod Arthritis

Sarcoidosis

Scleroderma

Sensorimotor Radiculopathy

Stiff persons Syndrome

Thyroiditis

Ulcerative Colitis

17Thomas C, JCO Vol 17, No 7 (July), 1999: pp 2280-2289

Problem 2

18

The Role of Surgery?

19

The Role of DXT?

20

What about the traditional poisons?

THYMOMA

THYMIC CARCINOMA

24

Carbo/Taxol in Thymic Malignancy

S

T

R

A

T

I

F

Y

Thymoma

Thymic

Carcinoma

Carboplatin AUC 6

Paclitaxel 225 mg/m2

Q21 x 646 patients 7 years

PFS/OS

Signal Transduction Pathways Controlled by the Activation of EGFR

Ciardiello F, Tortora G. N Engl J Med 2008;358:1160-1174

Table 1

TABLE 1. Studies Reporting EGFR Expression by Immunohistochemistry in Thymic Malignancies

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 27

Thymic Tumors: Relevant Molecular Data in the Clinic

Girard, Nicolas

Journal of Thoracic Oncology. 5(10):S291-S295, October 2010.

doi: 10.1097/JTO.0b013e3181f209b9

EGFR Mutations in Thymic Malignancies

• Nearly 200 tumours analysed in the literature

• 3 patients mutations

• 1 reponse to gefitinib

28

EGFR

Mutation

Exon

Thymoma1 L858R Exon 21

Thymoma1 G863D Exon 21

Thymic 2*

Carcinoma* Gefitinib

G719A

L858R

Exon 18

Exon 21

1 Yoh K, Lung Cancer 2008;19:1361-1362

2 Yamaguchi H, Lung Cancer 2006;52:261-262

Rare Cancer

Becomes Front

Page News

C-KIT Expression in Thymic tumours

TABLE 2. Studies Reporting KIT Expression in Thymic Tumors

Copyright © 2011 Journal of Thoracic Oncology. Published by Lippincott Williams & Wilkins. 30

Thymic Tumors: Relevant Molecular Data in the Clinic

Girard, Nicolas

Journal of Thoracic Oncology. 5(10):S291-S295, October 2010.

doi: 10.1097/JTO.0b013e3181f209b9

Sunitinib in thymic tumoursThomas et al, The Lancet Oncology, VOLUME 16, ISSUE 2, P177-186, FEBRUARY 01, 2015

Figure 2. Survival in patients with

thymoma and thymic carcinoma

(A)Progression-free survival and (B)

overall survival.

41 patients

26 Thymic Carcinoma RR 26%

16 Thymoma RR 6%

Lung Cancer. 2016 Jul;97:99-104. doi:

10.1016/j.lungcan.2016.04.024. Epub 2016 May 3.

Sunitinib in patients with advanced thymic

malignancies: Cohort from the French RYTHMIC

network.

Remon J1, Girard N2, Mazieres J3, Dansin E4, Pichon

E5, Greillier L6, Dubos C7, Lindsay CR1, Besse B8.

28 patients

RR 22%

Clinical responses to Sunitinib

Rajan ASCO 2017

PD-1 Expression in Thymic TumoursFig 1. CD8 semiquantitative scoring scheme: Scoring for each specimen took into account the heterogeneity of TIL densities throughout the entire section of each tumor, here showing representative images of 1+ (A), 2+ (B) and 3+ (C) scores for CD8 representing numbers of immuno-labeled TILs per 40X microscopic field in

the range of 1–30, 31–100, and >100, respectively.

Arbour KC, Naidoo J, Steele KE, Ni A, Moreira AL, et al. (2017) Expression of PD-L1 and other immunotherapeutic targets in thymic

epithelial tumors. PLOS ONE 12(8): e0182665. https://doi.org/10.1371/journal.pone.0182665

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182665

Arbour KC, Naidoo J, Steele KE, Ni A, Moreira AL, et al. (2017) Expression of PD-L1 and other immunotherapeutic targets in thymic

epithelial tumors. PLOS ONE 12(8): e0182665. https://doi.org/10.1371/journal.pone.0182665

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182665

Arbour KC, Naidoo J, Steele KE, Ni A, Moreira AL, et al. (2017) Expression of PD-L1 and other immunotherapeutic targets in thymic

epithelial tumors. PLOS ONE 12(8): e0182665. https://doi.org/10.1371/journal.pone.0182665

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182665

Rajan ASCO 2017

Rajan ASCO 2017

Rajan ASCO 2017

Pembrolizumab in Thymic Carcinoma

Giaconne et al The Lancet Oncology VOLUME 19,

ISSUE 3, P347-355, MARCH 01, 2018

Conclusions

• Rare

• Chemo sensitive- Pt/Anthracycline/Carbo Taxol

• Sunitinib active in Thymic Carcinomas

• Role of Immunotherapy

• Surgery when indicated

• PORT more valuable than we think

• DATABASE

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