Small cell carcinoma lung

1. SMALL CELL CARCINOMA LUNG
Kanmani Velarasan
CMC Vellore

2. INTRODUCTION
 Highly aggressive malignant epithelial tumor
• Tobacco exposure - >95% cases
• Screening – not recommended

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. PROGNOSTIC FACTORS
• Stage
• Performance status
• Female gender
• Normal baseline LDH value

6. 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

7. • 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

8. • 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

9. 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

11. 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

15. 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%)

16. • 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

17. • General condition of the patient - concurrent
treatment or lung constraints -- chest
irradiation may be postponed until the start of
the third cycle of chemotherapy

18. 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

20. THORACIC RADIATION THERAPY
FOR SMALL CELL LUNG CANCER
EVIDENCE

21. • 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

22. 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)

23. 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

24. 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.

25. • 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

26. 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.

27. FIELD
• 1.5 cm of margin between GTV and PTV
• Dose to Spinal cord limited to 41 Gy in the
twice daily arm.

28. 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

29. 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

30. 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 %).

31. • 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 %)

32. 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

33. PARANEOPLASTIC SYNDROMES
• Neurological
• ACTH ( Cushing’s syndrome )
• Vasopressin ( SIADH )
POORER SURVIVAL (esp Cushing’s syndrome)

34. 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

35. • SIADH : secondary to vasopressin production
• Presents with hyponatremia
• Fluid restriction, saline infusion and
demeclocycline
• Endocrine syndromes parallel cancer control

36. • 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)

37. • Neurologic syndromes – reported to have
better survival
• Frequently experience progressive neurologic
decline

38. 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

39. • 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

40. • 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.

41. 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

42. FOLLOW UP

43. A QUICK GLANCE

49. REFERENCES
• PEREZ
• DEVITA
• NCCN
• MDACC
• ESMO GUIDELINES