thymic carcinoma management at a glance.pptx

Thymic Carcinoma Management

Thymic carcinoma is a rare, aggressive epithelial malignancy of the anterior mediastinum, distinct from thymoma in its biology, behavior, and prognosis. Management requires a multimodal, stage-adapted approach integrating surgery, radiotherapy, and systemic therapy, often tailored to individual patient and disease characteristics.

1. Diagnosis and Staging:
Diagnosis relies on histopathology with immunohistochemistry (cytokeratins, CD5, CD117). Staging follows the TNM (IASLC/ITMIG) system, which guides treatment. Imaging with CT chest, PET-CT, and MRI for local invasion helps surgical planning.

2. Surgical Management:
Complete surgical resection (R0) is the cornerstone and offers the best survival. For early-stage resectable disease (stage I–II), extended thymectomy with en-bloc removal of adjacent structures if invaded is preferred. In locally advanced disease (stage III–IVA), surgery is considered after induction therapy if complete resection is feasible. Incomplete resection (R1/R2) confers poorer outcomes and usually requires adjuvant radiotherapy.

3. Radiotherapy:
Radiotherapy plays a key role as adjuvant, definitive, or palliative treatment. Postoperative radiotherapy is recommended in positive margins, advanced stage, or aggressive histology. For unresectable disease, definitive chemoradiotherapy may provide local control. Modern techniques such as IMRT/VMAT and proton therapy are used to spare adjacent critical structures (heart, lung, esophagus). Typical doses: 50–54 Gy for adjuvant, 60–66 Gy for definitive.

4. Systemic Therapy:
Chemotherapy is used in advanced, unresectable, or metastatic disease. Cisplatin-based combinations (e.g., cisplatin + doxorubicin + cyclophosphamide, or cisplatin + etoposide) are most common. Carboplatin–paclitaxel has also shown activity. Response rates are modest compared to thymoma. Targeted therapy and immunotherapy are emerging: sunitinib and lenvatinib (multikinase inhibitors) show efficacy in refractory disease, while pembrolizumab has demonstrated activity though carries risk of immune-related toxicity (especially myocarditis).

5. Multimodality Approach:
For stage III–IVA disease, induction chemotherapy ± radiotherapy followed by surgery and adjuvant RT improves outcomes. Stage IVB (metastatic) is treated with systemic therapy ± palliative RT. Management should be multidisciplinary, ideally at specialized centers.

6. Prognosis and Follow-up:
Thymic carcinoma has a worse prognosis than thymoma, with 5-year survival ranging from 30–50% depending on stage and resection status. Long-term follow-up with CT chest every 6–12 months is recommended due to risk of recurrence.

7. Guidelines and Trials:
Current management strategies are supported by NCCN, ESMO, and ITMIG guidelines. Prospective trials are limited given rarity, but ongoing studies are exploring targeted and immune-based therapies.

Summary:
Management of thymic carcinoma hinges on complete resection when possible,

1. DR SUMIT KUMAR ECMO I Ex SR AIIMS, New Delhi Assistant professor NEIGRIHMS, Shillong

2. Introduction

3. Epidemiology

4. Thymus gland is located in the anterior mediastinum . Lies behind the sternum and in front of the heart . Midline structure , can extend into both hemithoraces . Bordered by: Superior vena cava (SVC) Aorta and pulmonary trunk Pericardium and lungs Trachea and brachiocephalic veins Phrenic and recurrent laryngeal nerves run adjacent. Tumors often invade pleura, pericardium, and great vessels due to proximity. Anatomical Location: Thymus Gland

5. All subtypes are high-grade, poorly differentiated . Often show necrosis , mitotic activity , and cellular atypia . Lymphovascular and perineural invasion common. Histological Subtypes of Thymic Carcinoma Adenocarcinoma and neuroendocrine variants are very rare.

6. Immunohistochemistry Markers

7. Molecular Features

8. Clinical Presentation

9. Locally invasive tumor — early spread into adjacent mediastinal structures. Pleural and pericardial seeding may occur in advanced stages. High recurrence rates even after surgery and chemoradiation. PET-CT is valuable for staging distant disease. Metastases are often present at diagnosis due to aggressive biology. Patterns of Spread D irect invasion Lymphatic spread Hematogenous metastasis Pericardium , pleura , lungs , great vessels , chest wall Mediastinal, paratracheal, and supraclavicular nodes Lungs, liver, bone, and Brain (rarely )

10. Diagnostic Evaluation Multidisciplinary input essential before biopsy and staging.

11. 🔹 T – Primary Tumor T1a : ≤5 cm, limited to thymus, or invades fat/mediastinal pleura T1b : >5 cm, same extent as T1a T2 : Invades pericardium, lung, or phrenic nerve T3 : Invades brachiocephalic vein, SVC, chest wall, extrapericardial vessels T4 : Invades aorta, arch vessels, myocardium, trachea, or esophagus 🔹 M – Distant Metastasis M0 : No metastasis M1a : Pleural or pericardial nodules M1b : Pulmonary nodules or distant organ mets 🔹 N – Regional Nodes N0 : No nodal involvement N1 : Anterior ( perithymic ) lymph nodes N2 : Deep intrathoracic or cervical nodes (e.g., paratracheal, supraclavicular) AJCC 9th Edition TNM Staging (2024)

12. Chest CT with contrast PET-CT (if clinically indicated) Core needle biopsy (if unresectable/metastatic) Multidisciplinary evaluation essential 🔷 1. Resectable Disease 🔷 2. Locally Advanced Disease 🔷 4. Metastatic Disease 🔷 3. Inoperable or Poor PS Management : Thymic Carcinoma 🟨 Potentially Resectable → Induction Systemic Therapy ± RT → Reassess 🟨 Unresectable → Concurrent Chemoradiotherapy 🟥 Solitary/pleural metastasis If resectable: Surgery ± PORT If not: RT or Systemic Therapy 🟥 Widespread disease → Platinum-based chemo, consider IO/targeted agents ⬛ Local therapy (e.g. RT) or ⬛ Systemic therapy or ⬛ Observation (case-by-case) 🟩 Upfront Surgery (total thymectomy) 🟩 Post-op management: R0 + Stage I → Observation R0 + Stage II–IV → Consider PORT R1 → PORT ± Chemotherapy R2 → Definitive Chemoradiotherapy

13. 🔷 Indications Recommended for all localized, resectable thymic carcinomas. Best outcomes with R0 resection . Resectable = tumor invades pleura , pericardium , or lung , but not major unresectable structures. 🔷 Surgical Approach Complete excision of the lesion with total thymectomy and complete resection of contiguous and noncontiguous disease Include lymph node dissection . Choose approach: Median sternotomy , VATS , or robot-assisted . 🔷 Margin Assessment Surgeon to orient specimen and place radiopaque clips at close/positive margins. Surgical Management Complete resection may require the resection of adjacent structures, including the pericardium, phrenic nerve, pleura, lung, and even major vascular structures Bilateral phrenic nerve resection should be avoided due to severe respiratory morbidity. Margin status (R0/R1/R2) determines adjuvant therapy planning.

14. Surgical Outcomes & Evidence – Thymic Carcinoma 🔷 Prognostic Impact of Resection R0 resection : 5-year overall survival (OS) ~60–70% R1/R2 resections : Associated with high recurrence (~65%) and worse OS Margin status is the strongest predictor of long-term survival 🔷 Special Considerations Adhesion vs invasion : May mimic tumor spread; pathologic clarity essential Phrenic nerve involvement : Pre-op sniff test + PFTs needed Oligometastatic disease : Surgery may still be considered in select cases

15. Radiation - Thymic Carcinoma No elective nodal irradiation

16. 🔷 When to Use PORT Stage II–III (AJCC/ Masaoka ): Strongly recommended after complete (R0) resection Stage I: Only if high-risk features present: Invasion of pleura or mediastinal fat Positive or close surgical margins 🔷 Clinical Rationale High risk of local recurrence in advanced stages or margin-positive resections PORT improves local control and may enhance overall survival (OS) Placement of radiopaque clips intraoperatively aids target localization Surveillance may be appropriate in Stage I R0 cases without risk factors Postoperative Radiotherapy (PORT) – Thymic Carcinoma Decision for PORT is guided by: Stage , margin status , extent of invasion, Institutional preference and patient fitness R1 (microscopic residual): PORT is standard R2 (gross residual): Consider post-op chemoradiotherapy (CRT)

17. Evidence Supporting PORT – Thymic Carcinoma European Society of Thoracic Surgeons (ESTS) database

18. 🔷 Post-CRT Management Resectable → Salvage surgery Unresectable → Surveillance (consolidative systemic therapy unproven) 🔷 Recommended Approach Definitive CRT preferred over RT or chemotherapy alone Extrapolated from Stage III NSCLC protocols Aimed at local control and potential downstaging 🔷 Response to CRT Objective response rate (ORR): 70–100% in retrospective studies Some tumors may convert from unresectable to resectable Post-CRT debulking surgery may improve long-term survival 🔷 Indications Unresectable localized disease , including: Stage IIIB (e.g., invasion of great vessels, trachea, esophagus ) Selected Stage IVA with limited pleural or nodal disease Patients medically ineligible for surgery Concurrent Chemoradiation – Unresectable Thymic Carcinoma 🔷 Regimens & Dose Weekly Carboplatin (AUC 2) + Paclitaxel (45 mg/m²) Alternative: Cisplatin + Etoposide Radiation dose : 60 Gy in 30#

19. 🔷 When to Use Chemotherapy Metastatic disease (Stage IVB) Unresectable or technically inoperable tumors Progression after definitive local therapy (surgery or CRT) Induction therapy in borderline resectable cases (as part of conversion strategy) Palliative intent in poor surgical candidates or with symptomatic disease 🔷 Role of Chemotherapy First-line systemic therapy in most advanced cases May be combined with RT in CRT (definitive or postoperative) Choice guided by performance status , comorbidities , and toxicity profile Chemotherapy – Indications in Thymic Carcinoma

20. 1 st Line Chemotherapy in Metastatic Thymic Carcinoma Regimen Response Rate (RR) PFS OS Notes Carbo + Paclitaxel 21–36% ~7.5 mo 20–71% @ 2 yrs Backbone regimen Carbo + Paclitaxel + Ramucirumab 58–80% — 43.8 mo RELEVENT, S1701 trials CAP (± prednisone) ~30% — — Effective but toxic Cisplatin + Etoposide (PE) ~20–30% — — Often used in CRT ADOC ~30–40% — — High toxicity, less favored 🔷 Preferred Regimens (NCCN) ADOC: Doxorubicin; Cisplatin; Vincristine; Cyclophosphamide

21. Agent(s) Response Rate Notes Lenvatinib 38% REMORA trial, dose-reduction common Pembrolizumab 22.5% Risk of severe irAEs (myocarditis 5–9%) Sunitinib 21–26% STYLE trial, c-KIT independent Gemcitabine ± Capecitabine ~15–20% Modest efficacy, well tolerated 🔷 Preferred Second-Line Options (NCCN) Second-Line Chemotherapy & Targeted Agents

22. 🔷 Other Options :Metastatic Thymic Carcinoma Agent(s) Setting Pemetrexed , Paclitaxel , 5-FU + Leucovorin Single-agent cytotoxics Avelumab + Axitinib 34% RR (CAVEATT trial) Single-agent Etoposide / Ifosfamide Case-by-case

23. Study Patients ORR Duration Notes Phase II (n=40) ≥1 prior line 23% (1 CR, 8 PRs) ~3 years 5-year OS: 18% Phase II (n=33) Refractory cases 19% (TC) PFS ~6 mo Thymoma: ORR 29% 🔷 Efficacy Data (Pembrolizumab) Subgroup ORR VEGF-naïve patients 47% Prior anti-VEGF use 15% Overall (n=32 TC pts) 34% 🔷 IO Combination Option: Avelumab + Axitinib (CAVEATT Trial) 🔷 Indication Second-line for patients with platinum-refractory thymic carcinoma Ideal in those with no autoimmune disease and high PD-L1 expression Role of Immunotherapy – Thymic Carcinoma

24. Agent Trial / Setting ORR Notes Lenvatinib REMORA (Phase II) 38% Risk of AEs; dose reductions common Sunitinib STYLE, Phase II 21–26% Independent of c-KIT mutation Avelumab + Axitinib CAVEATT Trial 34% VEGF-naïve: 47%; prior VEGF: 15% 🔷 Key Agents & Evidence 🔷 When to Use Second-line or beyond in platinum-refractory thymic carcinoma Ideal for patients not eligible for immunotherapy Active regardless of c-KIT or VEGFR mutation status Targeted Therapy – Thymic Carcinoma

25. Phase II , multicenter (TYME network, Italy) 35 treatment-naïve advanced TC patients Ramucirumab + Carboplatin + Paclitaxel ×6 cycles → Ramucirumab maintenance Outcome Result Investigator-assessed ORR 80.0% (95% CI: 63.1–91.6%) Central Review ORR 57.6% (95% CI: 39.2–74.5%) Median PFS 18.1 months Median OS 43.8 months Grade ≥3 AEs 48.6% 🔷 Conclusion Ramucirumab + chemo showed highest activity to date in first-line advanced TC with manageable toxicity — may be considered a new standard option . Ann Oncol 2024 Sep

26. Phase II , single-arm, multicentre (Italy) 32 advanced thymic tumors (27 thymic carcinoma, 3 type B3 thymoma) Eligibility : Post platinum-based chemo, no prior immunotherapy Regimen : Avelumab 10 mg/kg IV q2w+ Axitinib 5 mg PO BID 🔷 Conclusion Avelumab + axitinib showed encouraging activity in pretreated thymic carcinoma , with manageable toxicity . May become a novel second-line option . Outcome Value ORR 34% (all PRs) Stable disease 56% Progressive disease 6% Grade ≥3 AEs 19% (HTN most common) Serious irAEs 12% (e.g., polymyositis, pneumonitis) LancetOncol2022 Oct

27. J Thorac Oncol 2023 Aug Phase II , multicenter , Simon 2-stage, 32 with TC, pretreated Regimen : Sunitinib 50 mg/day , 4 weeks on / 2 weeks off (4/2 schedule) Outcome Result ORR 21.7% (met endpoint) Disease Control Rate 89.3% Median PFS 8.8 months Median OS 27.8 months Grade ≥3 AEs 51.6% Common Toxicities Fatigue, hypertension, hand-foot syndrome 🔷 Key Results (Thymic Carcinoma Cohort) 🔷 Conclusion Sunitinib shows moderate efficacy with high disease control in second-line TC, but requires close toxicity monitoring and dose adjustment in many cases.

28. Phase II , single-arm, multicenter (Japan, 8 sites) Patients : 42 with advanced/metastatic thymic carcinoma Eligibility : Post platinum-based chemo , ECOG 0–1 Regimen : Lenvatinib 24 mg orally, daily in 4-week cycles Outcome Result ORR 38% (16 PRs) Stable disease 57% Clinical benefit rate 95% Median follow-up 15.5 months Grade 3 AEs Hypertension (64%), HFS (7%) Treatment-related deaths 🔷 Conclusion Lenvatinib showed high response rates and manageable toxicity in second-line thymic carcinoma. Supports its role as a preferred NCCN-recommended option .

29. 🔷 Unique Challenges Extremely rare cancer (0.06/100,000 incidence) Limited clinical trials , scarce molecular data , and diagnostic ambiguity Often misclassified on imaging as thymoma or other mediastinal masses 🔷 Potential for AI Early and accurate diagnosis using radiomics + deep learning Prognostic modelling from limited datasets Clinical decision support in rare tumor management where guidelines are weak Why AI in Thymic Carcinoma?

30. Domain AI Use Case Emerging Tools Imaging Radiomics for mass classification (thymoma vs carcinoma) CNN-based models, radiogenomics Pathology Digital slide recognition of rare thymic histologies Vision Transformers (ViT) Radiotherapy Auto-segmentation of mediastinal volumes AI contouring in Eclipse, RayStation Drug Development Pattern-matching for trial matching in rare tumors AI-enabled baskets (NCI-MATCH, DART) Applications of AI in Thymic Carcinoma ✅ AI fills gaps where expertise or evidence is limited

31. 🔷 Current Trials NCI-MATCH : AI matches thymic tumors to targeted drugs based on genomics DART trial : Exploring checkpoint inhibitors in rare tumors using ML-enabled subgroup analysis 🔷 Research Directions Multimodal AI models (integrating CT, histopathology, genomics) Synthetic cohort modeling for virtual thymic carcinoma trials AI registries to learn from scattered case data globally Future AI-Driven Research in Thymic Carcinoma “AI may be the only scalable solution for generating evidence in ultra-rare cancers.”

32. 🔷 Prognostic Factors 🔷 Survival by Stage (Estimated 5-year OS) Stage I: ~80–90% Stage II–III: ~50–65% Stage IVa : ~30–40% Stage IVb : ~15–30% Factor Impact Stage (AJCC/Masaoka) Most powerful predictor of survival Completeness of resection R0 resection → best OS (60–70%) Histology Thymic carcinoma worse than thymoma Margin status R1/R2 → higher recurrence, worse OS Lymph node involvement Associated with poor prognosis PD-L1 expression May predict IO response

33. Thymic Carcinoma – Key Takeaways

34. Summary of Key Second-Line Trials in Thymic Carcinoma Trial Therapy ORR PFS (mo) OS (mo) Key Notes RELEVENT Carbo + Paclitaxel + Ramucirumab 57.6–80% 18.1 43.8 Highest 1st-line activity to date CAVEATT Avelumab + Axitinib 34% — — VEGF-naïve: 47% response REMORA Lenvatinib 38% — — High hypertension rate (64%) STYLE Sunitinib 21.7% 8.8 27.8 Good DCR (89.3%), high grade ≥3 AEs