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Small cell carcinoma

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Small cell carcinoma lung

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Small cell carcinoma

  1. 1. SMALL CELL CARCINOMA LUNG Kanmani Velarasan CMC Vellore
  2. 2. INTRODUCTION  Highly aggressive malignant epithelial tumor • Tobacco exposure - >95% cases • Screening – not recommended
  3. 3. PATHOLOGY(WHO 1999) • Small round blue cell tumor with scant cytoplasm, fine granular nuclear chromatin and indistinct nucleoli. • Immnoreactive to Keratin, EMA and TTF1(80%). • Majority stain for Synaptophysin, chromogrannin A, NSE and CD56
  4. 4. PROGNOSTIC FACTORS • Stage • Performance status • Female gender • Normal baseline LDH value
  5. 5. STAGING WORKUP • History, physical examination, lab and radiological evaluation. • Clinical examination – Special attention to paraneoplastic syndromes. • All patients regardless of stage – Image brain. • CT of chest & abdomen and bone scan • Staging should not delay onset of treatment more than 1 week
  6. 6. • PET-CT - 9% patients are up- and 4% downstaged. • PET-CT findings which could impact treatment decisions should be pathologically confirmed. • In case of abnormal blood count or signs of blood–bone marrow barrier rupture (e.g. peripheral blood erythroblasts), a BM aspiration and biopsy indicated
  7. 7. • Solitary metastasis – Pathological confirmation should not delay treatment start. • Solitary metastatic lesion’s size should be re- evaluated after two cycles. • Alternatively, an initial second radiological method is recommended. • If a pleural or pericardial effusion is the only site of M1, no malignant cells are identified in the pleural fluid, treatment should be according to an M0 status
  8. 8. Pleural effusion • If effusion is too small or 1. 3 cytopathologic examination are negative 2. Fluid is not bloody or not exudate 3. Clinical judgement – that effusion not related to cancer
  9. 9. STAGE (VALSG system) LIMITED STAGE DISEASE • Disease confined to ipsilateral hemithorax, which can be safely encompassed within a tolerable radiation field. EXTENSIVE STAGE DISEASE • Disease beyond ipsilateral hemithorax which may include malignant pleural or pericardial effusion or hematogenous metastasis
  10. 10. Management of localised disease (T1-4, N0-3 M0) • Median survival - 15–20 months • 2-year survival rates - 20%–40% • 5 year survival - 20%–25% • 5% of patients with SCLC present as T1, 2 N0,1 M0 tumours (5-year survival rates in the order of 50%)
  11. 11. • Surgical approach in this group of patients is justified after ruling out mediastinal lymph node involvement (CT scan, PET-CT scan or EBUS and/or mediastinoscopy if enlarged) . • Postoperatively, four cycles of adjuvant chemotherapy should be administered. • In case of unforeseen N2 or N1 or who have not undergone systematic nodal dissection, postoperative radiotherapy should be considered. • There is no role for surgery after induction chemotherapy in N2 disease
  12. 12. • General condition of the patient - concurrent treatment or lung constraints -- chest irradiation may be postponed until the start of the third cycle of chemotherapy
  13. 13. Management of metastatic disease • Outcomes remain poor with a median progression-free survival (PFS) of only 5.5 months and a median OS of <10 months • 4–6 cycles of etoposide plus cisplatin or carboplatin are recommended • Patients in a reasonably good PS with any response to first-line treatment should be evaluated for PCI
  14. 14. THORACIC RADIATION THERAPY FOR SMALL CELL LUNG CANCER EVIDENCE
  15. 15. • Pignon et al – Chemoradiotherapy arm vs chemotherapy alone arm – 5.4% difference in 3 year survival. Local failure – 52% vs 77% • 25-30% reduction in local failures and 5-7% improvement in 2 year survival
  16. 16. ROLE OF CHEMORT IN LOCALISED DISEASE • JCOG Trial – Concurrent Vs Sequential chemotherapy and radiation Concurrent CRT – Longer median survival(27 months Vs 20 months) • NCIC – Early Vs Late concurrent CRT Early CRT – Improved median survival(21 Vs 16 months)
  17. 17. TIMING • Fried et al – Early thoracic RT with cycle 1 or 2- Improved 2yr OS – benefit more pronounced with platinum based chemotherapy. • Pijls et al – higher survival rates when thoracic RT started within 30 days of initiation of chemotherapy
  18. 18. DOSE & FRACTIONATION • Highly radiosensitive – Hence role of hyper fractionation. • Inter group trial 0096 (Turrisi et al) – Once daily RT Vs Twice daily RT 1. In twice daily arm - OS significantly higher(26 % Vs 16 % at 5 yr), Lower local recurrence rate(36% Vs 52%) 2. Increased grade3 Esophagitis(26 % Vs 11%) 3. No difference in late toxicity.
  19. 19. • Optimal dose and fractionation remains to be defined. • Dose escalation trial – RTOG 0239(50.4 Gy to 64.8 Gy). • CALGB 39808 – Tested 70 Gy in 35 fractions. • CONVERT TRIAL – 45 Gy in 30 fractions BD Vs 66 Gy in 33 fractions in OD
  20. 20. RADIOTHERAPY VOLUME • SWOG TRIAL – Pre induction Vs Post induction volume. No difference in local recurrence rate (32% Vs 28%) No elective nodal irradiation as most intrathoracic failures occur in post chemoRT field.
  21. 21. FIELD • 1.5 cm of margin between GTV and PTV • Dose to Spinal cord limited to 41 Gy in the twice daily arm.
  22. 22. DOSE CONSTRAINTS (RTOG 0538 PROTOCOL) • Spinal cord – <41 Gy(BD arm) and <50.5Gy (OD arm) • Lungs – V20 <40%, MLD - <20 Gy • Esophagus - < 34 Gy • Heart – 60 Gy < 1/3, 45 Gy <2/3 and 40 Gy < 100% of heart
  23. 23. THORACIC RT FOR METASTATIC DISEASE • Systemic therapy – Essential element. • Jeremic et al – Patient with partial response 1. ChemoRT Vs Further chemotherapy. 2. Higher OS in the ChemoRT arm (9% Vs 5% at 5 yrs) • RTOG 0937 and CREST trial – Role of thoracic RT studied
  24. 24. PROPHYLACTIC CRANIAL RT • Brain metastasis at diagnosis - 10-14 % (Seute et al) • Meta-analysis – PCI Vs Observation PCI decreased the incidence of brain metastasis(59 % Vs 33 % at 3 yrs) and improved OS(21 % Vs 15 %).
  25. 25. • Preferred regimen : 25 Gy in 10 fractions (less neurologic toxicity) • EORTC trial – PCI found to be beneficial in extensive stage (Incidence decreased 15% Vs 40% and 1 yr OS 27% Vs 13 %)
  26. 26. CHEMOTHERAPY • EP regimen – standard of care • Carboplatin can be substitute for cisplatin (Skarlos et al , Ann oncol 1994) • Role of maintenance chemotherapy – Not beneficial • Chemotherapy intensification – not beneficial in extensive stage and also have greater toxicity
  27. 27. PARANEOPLASTIC SYNDROMES • Neurological • ACTH ( Cushing’s syndrome ) • Vasopressin ( SIADH ) POORER SURVIVAL (esp Cushing’s syndrome)
  28. 28. PARANEOPLASTIC SYNDROMES • Cushing’s syndrome – 3-7% patients , secondary to ACTH production • Present with hypertension, edema , hyperkalemia and weakness. • At high risk of opportunistic infections • Advisable to treat with Metyrapone or ketaconazole prior to chemotherapy
  29. 29. • SIADH : secondary to vasopressin production • Presents with hyponatremia • Fluid restriction, saline infusion and demeclocycline • Endocrine syndromes parallel cancer control
  30. 30. • Neurologic syndromes – Autoimmune in origin • Lambort eaten myasthenic syndrome – Autoantibodies against presynaptic motor terminal(Calcium channels) • Presents with proximal leg weakness • Encephalomyelitis, cerebellar degeneration (anti Hu antibodies ANNA -1) and stiff man syndrome (anti amphiphysin antibodies)
  31. 31. • Neurologic syndromes – reported to have better survival • Frequently experience progressive neurologic decline
  32. 32. ROLE OF TARGETED AGENTS • Angiogenesis : Elevated VEGF – poorer outcomes. Bevacizumab was tried . High rates of tracheo oesophageal fistula. • Thalidomide – No significant difference . More thrombotic events • Vandetanib – oral small molecule TKI. No difference in PFS or OS • Sorafenib – Low response rates
  33. 33. • c – Kit : Transmembrane receptor. Imatinib showed no activity • Apoptosis : cell line studies showed inhibition of bcl2 may increase efficacy • Oblimersen , a bcl 2 antisense oligoucleotide, addition found to have no benefit
  34. 34. • MMP’s inhibitor: MMP overexpression facilitates metastasis . Marimastat – no improvement in survival. • EGFR mutation – rare • Insulin growth factor receptor 1 – Important role in growth, division and apoptosis. Promising area of research.
  35. 35. SALVAGE THERAPY • Relapse or progress less than three months – response to next line < 10% • > 3 months – Expected response upto 25%. • Agents in phase 2 trial – Docetaxel, Etoposide(oral), gemcitabine, paclitaxel, toptecan and vinorelbine • Single agent Topotecan – US FDA approved (O Brien et al JCO 2006) – 2.3 mg /m2 D1-D5 Q21 days
  36. 36. FOLLOW UP
  37. 37. A QUICK GLANCE
  38. 38. REFERENCES • PEREZ • DEVITA • NCCN • MDACC • ESMO GUIDELINES

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