SMALL CELL CARCINOMA LUNG

Kanmani Velarasan CMC Vellore

INTRODUCTION

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

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

PROGNOSTIC FACTORS

• Stage • Performance status• Female gender• Normal baseline LDH value

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

• 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

• 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

Pleural effusion

• If effusion is too small or 1. 3 cytopathologic examination are negative2. Fluid is not bloody or not exudate3. Clinical judgement – that effusion not related

to cancer

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

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%)

• 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

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

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

THORACIC RADIATION THERAPY FOR SMALL CELL LUNG CANCER

EVIDENCE

• 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

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 CRTEarly CRT – Improved median survival(21 Vs 16 months)

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

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.

• 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

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.

FIELD

• 1.5 cm of margin between GTV and PTV• Dose to Spinal cord limited to 41 Gy in the

twice daily arm.

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

THORACIC RT FOR METASTATIC DISEASE

• Systemic therapy – Essential element.• Jeremic et al – Patient with partial response1. 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

PROPHYLACTIC CRANIAL RT• Brain metastasis at diagnosis - 10-14 % (Seute

et al)• Meta-analysis – PCI Vs ObservationPCI decreased the incidence of brain metastasis(59 % Vs 33 % at 3 yrs) and improved OS(21 % Vs 15 %).

• 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 %)

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

PARANEOPLASTIC SYNDROMES

• Neurological • ACTH ( Cushing’s syndrome )• Vasopressin ( SIADH )

POORER SURVIVAL (esp Cushing’s syndrome)

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

• SIADH : secondary to vasopressin production• Presents with hyponatremia• Fluid restriction, saline infusion and

demeclocycline • Endocrine syndromes parallel cancer control

• 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)

• Neurologic syndromes – reported to have better survival

• Frequently experience progressive neurologic decline

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

• 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

• 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.

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

FOLLOW UP

A QUICK GLANCE

REFERENCES

• PEREZ• DEVITA• NCCN• MDACC• ESMO GUIDELINES