smallcelllungcancersclc-180916185826.pptx

SMALL CELL LUNG CA

1. SMALL CELL LUNG CARCINOMA DR ANJALIKRISHNA NP PG RESIDENT RADIOTHERAPY AIIMS GORAKHPUR

2. INTRODUCTION Tobacco consumption is the primary cause of small cell lung cancer. Voluntary or involuntary cigarette exposure accounts for 80% to 90% of all cases of SMALL CELL Lung cancer. Indoor Radon exposure is now the 2 nd cause of SMALL CELL Lung cancer in USA Occupationl and environmental carcinogens- Asbestos Arsenic and Polycyclic Hydrocarbons

3. EPIDEMIOLOGY In the world small cell lung cancer accounts for 13% of all lung cancer cases. SCLC is rare below age 40, with rates increasing until age 80, after which the rate tapers off. The natural history of untreated SCLC included rapid tumor progression with a median survival of only 2 to 4 months. Approximately two thirds of patients with SCLC have extensive-stage or stage IV disease at presentation

4. HISTOLOGY Histologically, SCLC is one of the small, round, blue cell tumors (along with neuroblastoma, rhabdomyosarcoma, Merkel cell carcinoma, etc.) with scant cytoplasm and indistinct nucleoli.

5. D/D of Round Blue Cell Tumor CARCINOID TUMOR MESOTHELIOMA MEDULLOBLASTOMA MERKEL CELL CA MESENCHYMAL CHONDROSARCOMA SYNOVIAL SARCOMA SMALL CELL LUNG CANCER SMALL CELL LYMPHOMA EWING SARCOMA / PNET NEUROBLASTOMA DESMOPLASTIC ROUND CELL TUMOR HEPATOBLASTOMA HYBRID ONCOCYTOMA / CHROMOPHOBE RCC RETINOBLASTOMA RHABDOMYOSARCOMA LEIOMYOSARCOMA WILMS TUMOR

6. Marker Expression in SCLC Cytokeratin / EMA Positive in almost all cases Thyroid Transcription Factor-1 (TTF-1) Positive in ~80% Synaptophysin Positive (neuroendocrine marker) Chromogranin A Positive Neuron-Specific Enolase (NSE) Positive CD56 (NCAM) Positive Morphology + IHC = gold standard. TTF-1 positivity supports pulmonary origin .

7. CLINICAL FEATURES Because of the high frequency of extensive mediastinal and hilar nodal involvement in SCLC cases, patients frequently present with symptoms such as Dyspnea , Dysphagia, Hoarseness, And Superior vena cava (SVC) syndrome. Many patients with SCLC present with other thoracic symptoms including Cough, Hemoptysis , Chest Pain, And Weight loss.

8. SUPERIOR VENA CAVA SYNDROME Results from obstruction of blood flow to the heart from the head and neck regions and upper extremities . It occurs as a consequence of compression of the superior vena cava , either from direct invasion by the primary tumor into the mediastinum or from lymphatic spread with enlarged right paratracheal lymph nodes. It is commonly caused by SCLC but can result from any centrally located tumor or mediastinal spread.

9. Features- Feeling of fullness in the head Dyspnea Cough Dilated neck veins Prominent venous pattern on the face and the chest Upper extremitt and facial edema Pappiledema Facial cyanosis Plethora Conjunctival edema (possibly)

10. PARANEOPLASTIC SYNDROMES

11. SIADH – Small cell – It results into Hyponatremia Symptoms include- Headache,Muscle cramps,Anorexia & Decreased urine output Resolves within 1–4weeks of initiating chemotherapy. Demeclocycline is the agent of choice Cushing Syndrome-ACTH-producing tumors – Small cell- Symptoms-Muscle weakness,weight loss,hypertension,hirsutism & osteoporosis. Hypokalemic alkalosis and hyperglycemia are present. It has worse prognosis

12. Lambert-Eaton Myasthenic Syndrome(LEMS) It is characterized by muscle weakness of the limbs. Proximal muscles are affected associated with difficulty in climbing chairs and rising from a sitting position. Chemotherapy is the initial treatment of choice. Neurologic– Encephalomyelitis cerebellar degeneration retinopathy.

13. SMALL CELL LUNG CANCER METASTASIS Site Approx. Frequency Liver 40–50% Bone 30–40% Brain 20–30% at diagnosis → up to 50–60% overall Adrenal glands 20–25% Contralateral lung / Pleura 15–20% Bone marrow 15–30% (often microscopic) Mediastinal / Supraclavicular nodes >70% Other rare sites (skin, pancreas, kidney, GI) <5%

14. DIAGNOSTIC WORK UP Complete history Complete physical examination Chest-may show signs of- Partial or complete obstruction of airways Pneumonia Pleural Effusion Neck Examination-Signs of Supraclavicular lymphadenopathy Abdominal examination-signs of hepatomegaly Neurological examination-signs of Brain metastais

15. Haemogram CBC- anemia due to metastatic disease LFT-May indicate Liver mets Increased ALP-May indicate Liver or Bone mets Increased Calcium ion-May indicate Bone mets or Paraneoplastic syndrome

16. RADIOLOGIC EXAMINATIONS Chest Xray -initial imaging modality. Current Xray should be compared with previous ones to determine if a lesion is- New Enlarging or Stable CT Scan- CECT Chest + Upper Abdomen should be done so that Liver and Adrenals can be visualized In a patient with known lung cancer a lymph node is considered suspicious if it measures >1cm in diameter on its short axis.

17. It can establish T stage by- Determining tumor size Presence of separate tumor nodules Presence of atelectasis Post obstructive pneumonia Invasion of adjacent structures Proximal extent of the tumor PET or PET-CT SCAN It has become standard in the staging work up of lung cancer patients. The biggest advantage is the identification of suspicious lymph nodes or distant metastasis.

18. Kaeff et al prospectively evaluated the utility of PET- They found that PET correctly upstaged 26% patients and downstaged 10-16 patients. Additionally PET can detect malignant disease in lymph nodes of normal size. PET-CT is superior to CT or PET alone and can detect malignancies in tumors as small as 0.5cm. Novel tracers- FDG FMISO(18F-fluoromisonidazole)-For tumor Hypoxia FLT(18F-fluorothymidine)-For tumor proliferation 11C-methionine and 11C-tyrosine-For amino acid metabolism.

19. Sputum Cytology -Sensitivity is 65%. Percutaneous Fine Needle Aspiration(FNA) - CT guided FNA done in lesions which cannot be reached by Bronchoscopy. Overall diagnostic yield is 80%. Bronchoscopy- FOB is done and cytologic brushings,biopsies can be taken.

20. Biopsy - confirm the cancer and determine the type Bronchoscopy CT guided biopsy

21. Endoscopic FNA- Endobronchial USG guided transbronchial needle aspiration(EBUS-TBNA) can be done for ultrasound suspicious lymph nodes- Paratracheal -Level 2 & 4 Subcarinal -Level 7 Hilar lymph node stations-level 10 Thoracocentesis - If on multiple taps of pleural fluid is consistently bloody or exudative ,it should be considered malignant.

22. Thoracoscopy Video assisted thoracoscopy (VAT) is used for- Diagnosis Staging Resection of lung cancer Peripheral nodules can be easily seen and excised. It can also be used to reach mediastinal nodes not accessible by standard mediastinoscopy,EBUS -TBNA or EUS-FNA techniques.

23. PROGNOSTIC FACTORS The most clinically important prognostic factor in SCLC is stage (limited vs. extensive), with a median survival of approximately 23 months for patients with limited disease versus 8 to 9 months for those with extensive disease. Clinical factors consistently reported to correlate with improved survival include good performance status, female gender, and normal lactate dehydrogenase levels at baseline.

24. AJCC STAGING 8 th Edition Tx Primary tumor cannot be assessed, or tumor proven by the presence o f malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

25. T0 No evidence of primary tumor

26. Tis Carcinoma in situ Squamous cell carcinoma in situ (SCIS) Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤ 3 cm in greatest dimension

27. T1 Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence o f invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)

28. T1mi- Minimally invasive adenocarcinoma: adenocarcinoma ( ≤ 3 cm in greatest dimension) with a predominantly lepidic pattern and ≤ 5 mm invasion in greatest dimension. T1a- Tumor ≤ 1 cm in greatest dimension. A superficial, spreading tumor o f any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a , but these tumors are uncommon. T1b- Tumor >1 cm but ≤ 2 cm in greatest dimension T1c- Tumor >2 cm but ≤ 3 cm in greatest dimension

29. T2 Tumor >3 cm but ≤ 5 cm or having any of the following features: Involves the main bronchus regardless of distance to the carina, but without involvement of the carina Invades visceral pleura (PL1 or PL2) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung

30. T2a Tumor >3 cm but ≤ 4 cm in greatest dimension T2b Tumor >4 cm but ≤ 5 cm in greatest dimension

31. T3 Tumor >5 cm but ≤ 7 cm in greatest dimension or directly invading any of the following: Parietal Pleura (PL3), Chest Wall (Including Superior Sulcus Tumors), Phrenic Nerve, Parietal pericardium; or Separate tumor nodule(s) in the same lobe as the primary

32. T4 Tumor >7 cm or tumor of any size invading one or more of the following: Diaphragm, Mediastinum, Heart, Great Vessels, Trachea, Recurrent Laryngeal Nerve, Esophagus , Vertebral Body, Or Carina; Separate tumor nodule(s) in an ipsilateral lobe different from that of the primary

33. M Stage M1a- Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion. Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is non bloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.

34. M1b Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node) M1c Multiple extrathoracic metastases in a single organ or in multiple organs

35. Parameter Limited Stage Extensive Stage Extent of disease Within one hemithorax Beyond one hemithorax RT feasibility Encompassed in one tolerable field Not feasible Metastasis Absent Present (distant or effusions) Patients (%) 30–40% 60–70% Median survival 15–20 months 8–10 months 5-year survival 20–25% <5% Traditional SCLC staging follows the Veterans Administration Lung Study Group (VALSG) system: ➤ Limited Stage (LS) ➤ Extensive Stage (ES) TNM staging may further refine prognosis and guide clinical trials but VALSG system remains clinically relevant for treatment intent .

36. Management

37. Combining Radiation and Chemotherapy for Limited-Stage Disease A randomized trial by the JCOG evaluated concurrent versus sequential chemotherapy and thoracic radiation in patients with limited-stage SCLC. All patients received 45 Gy in 1.5-Gy fractions twice daily were randomized to receive four cycles of cisplatin (80 mg/m 2 on day 1) and etoposide (100 mg/m 2 day 1-3) every 4 weeks concurrent with radiotherapy (beginning day 2) or every 3 weeks sequentially before radiotherapy. Patients treated concurrently had longer median survival compared to patients treated sequentially: 27 months versus 20 months.

38. A second randomized trial by the National Cancer Institute of Canada compared early with late concurrent chemoradiotherapy. In this trial, 308 patients received cyclophosphamide, doxorubicin, and vincristine alternating with EP and were randomized to 40 Gy in 15 daily fractions given with either the first cycle of EP (week 3) or the last (week 15). The median survival improved to 21 months with early radiotherapy versus 16 months with late treatment ( p = .008).

39. Fried et al did a meta-analysis that included >1,500 patients from seven randomized trials evaluating the timing of radiotherapy when given concurrently with multiagent chemotherapy. The use of early thoracic radiotherapy, with cycle 1 or 2 of chemotherapy, was associated with improved 2-year OS compared to delayed or sequential chemotherapy and radiation.

40. The EP ( Cis+Etopo ) combination is the most commonly used first-line chemotherapy regimen in patients with SCLC, either alone (in patients with extensive disease) or in combination with thoracic radiation (in patients with limited-stage disease). In patients with extensive disease , alternative combinations including cisplatin and irinotecan (IP), the addition of an anthracycline or taxane to EP, and higher-dose therapy have been investigated; however, to date, they have not proven superior to EP.

41. Dose and Fractionation SCLC is highly radiosensitive, suggesting that hyperfractionation could be employed to reduce late normal tissue toxicity. It also has a high proliferative rate, arguing for accelerated treatment to counteract repopulation.

42. 417 patients were enrolled in a randomized, intergroup trial of concurrent accelerated hyperfractionated radiotherapy versus standard daily radiotherapy in patients with limited-stage SCLC. All patients received four cycles of cisplatin (60 mg/m 2 on day 1) and etoposide (120 mg/m 2 on days 1, 2, and 3), and radiotherapy began with cycle 1. In the once-daily arm, patients received 45 Gy in 1.8-Gy fractions over 5 weeks. In the twice-daily arm, patients received 45 Gy in 1.5-Gy fractions over 3 weeks. Patients who achieved a complete response were offered PCI.

43. OS was significantly higher in the twice-daily arm, 26% versus 16% at 5 years, and local recurrence was significantly lower, 36% versus 52%. There was a significant increase in grade 3 acute esophagitis, 26% versus 11%, in the twice-daily arm, with no difference in late toxicity. The 5-year survival rate observed in this study is among the best reported for limited-stage disease; consequently, this treatment approach is considered by many the current standard of care for the management of limited-stage disease.

44. The Concurrent Once-daily Versus Twice-daily Radiotherapy (CONVERT) trial is a 2-arm randomized phase III study: patients receive either 45 Gy in 30 fractions twice daily or 66 Gy in 33 fractions once daily. All patients receive EP; radiotherapy begins with cycle 2.

45. Result Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.

46. Thoracic Radiotherapy for Extensive-Stage Disease Systemic therapy is the essential element in the treatment of patients with extensive-stage SCLC with good performance status. In a study by Jeremic et al, 209 patients with extensive disease were enrolled and treated with three cycles of EP ( Cis+Etopo ). Total of 109 patients with response were randomized to: (1) ACC hypofraction thoracic RT (54 Gy/1.5 Gy twice daily) plus CE ( Carbo+Etopo ) and PE × 2, or (2) PE × 4 alone without radiation. Overall median survival and 5-year OS were 9 months and 3.4%, respectively Median survival = 17 months (group 1) versus 11 months (group 2); 5-year OS = 9.1% (group 1) versus 3.7% (group 2) ( p =0.041)

47. Prophylactic Cranial Irradiation Brain metastases are present at diagnosis in approximately 20% of patients with SCLC. The brain is also a frequent site of failure after chemotherapy for extensive disease or chemoradiotherapy for limited-stage disease. Several randomized trials have addressed the value of PCI following a response to initial therapy and have consistently demonstrated a decrease in the incidence of brain metastases.

48. A meta-analysis reported the results of 987 patients treated in seven randomized trials enrolling between 1977 and 1995. Here, 85% of these patients had limited stage and 15% extensive. All were randomized to either PCI or to observation following a complete response to initial therapy. PCI regimens varied from 8 Gy in a single fraction to 40 Gy in 20 fractions. At 3 years, PCI was found to significantly decrease the incidence of brain metastases (59% vs. 33%) and significantly improve OS (21% vs. 15%). There was trend toward improved brain control when PCI was administered earlier and at higher dose. The publication of this study demonstrated the value of PCI in limited-stage SCLC. PCI in extensive-stage SCLC was specifically addressed in a more recent randomized trial conducted by the EORTC.

49. In this EORTC trial , 286 patients with extensive-stage SCLC were randomized to either PCI or observation after any response to four to six cycles of chemotherapy. Those assigned to the PCI arm were treated within 4 to 6 weeks of completing systemic therapy. The 1-year cumulative incidence of brain metastases was significantly decreased in the PCI arm at 15% versus 40%, and 1-year OS was significantly increased in the PCI arm at 27% versus 13%. Six different PCI regimens were permitted, with biologically effective dose ranging from 25 to 39 Gy.

50. Despite the survival benefit reported in the Auperin meta-analysis and the EORTC trial in extensive-stage disease, a variety of dose and fractionation schemes were employed to treat the patients enrolled in the trials. To help define the optimal dose and fractionation for PCI, a multi-institutional intergroup trial was launched to examine standard-dose PCI versus high-dose PCI.

51. Patients with limited-stage SCLC who had achieved a complete response to chemoradiotherapy were randomized to receive PCI in standard dose, 25 Gy in 10 daily fractions, or high-dose, 36 Gy in either 18 daily fractions or 24 twice-daily fractions. At 2 years, the cumulative incidence of brain metastases was not significantly different between the two arms: 29% in the standard dose arm versus 23% for high dose.

52. Surprisingly, there was poorer OS in the high-dose arm: 2-year survival was 42% in the standard dose arm versus 36% for high dose. This was attributed to a higher cancer-related mortality in the high-dose arm. Wolfson et al recently reported the results of these assessments and observed an increased incidence of chronic neurotoxicity at 12 months after PCI in the 36-Gy cohort ( p = .02). Taken together, these results establish 25 Gy in 10 fractions as the current preferred regimen to deliver PCI.

53. Chemotherapy The selection of chemotherapeutic agents to combine with Thoracic RT (TRT) for patients with Limited stage SCLC is largely based on trials of multiagent regimens used for E-SCLC. The currently accepted standard chemotherapy regimen for both E-SCLC and L-SCLC is the two-drug regimen of EP (Cis + Etopo ). SWOG was the first group to report a completed trial of concurrent TRT with EP for L-SCLC. They reported a median survival time of 17.5 months and 4-year survival rate of 30%, which appeared superior to the previously reported results with TRT combined with other non–platinum-containing regimens.

54. A recent Japanese Trial compared irinotecan and cisplatin compared with EP for E-SCLC. The median survival was 12.8 months with irinotecan and cisplatin compared to 9.4 months with EP ( p = 0.002). A similarly designed SWOG Trial S0124 was unable to confirm a survival advantage obtained by irinotecan and cisplatin. Hanna et al reported similarly negative findings from a third similar Phase III trial. Paclitaxel has also been studied extensively in SCLC. A Phase III study in extensive stage disease showed increased fatal toxicity without an improvement in survival with the addition of paclitaxel to EP.

55. Role of Surgery A randomized trial was conducted by the Lung Cancer Study Group in which patients with L-SCLC achieving a partial response (PR) or complete response (CR) to chemotherapy received either resection or none. There was no survival difference between the arms, with a 2-year survival rate of 20% in both arms ( p = 0.55). Based on this trial and on the proven survival benefit of concurrent chemotherapy and TRT, adjuvant surgery following chemotherapy is not recommended .

56. There may be a role for resection in patients with stages I or II SCLC, it is unclear that surgical intervention would provide a benefit when compared to TRT for similar volumes or stages of disease. While it appears that some patients may be salvaged after a PR or local failure, resection has not been widely employed.

57. Management of Recurrent SCLC The prognosis of any patient with recurrent SCLC is grave, regardless of the site of relapse. Although there are responses noted to second-line chemotherapy, these responses are usually short-lived and often precede rapid tumor progression. Palliative or salvage RT or re-RT (including re-irradiating brain metastases) can be of substantial benefit to such patients .

58. summary Accounts for 13% of all lung cancers. Tobacco consumption is the most common cause. It is a type of round blue cell tumor. SIADH is the most common Paraneoplastic Syndrome. Patients treated concurrently has longer median survival as compared to patients treated sequentially. 45 Gy in 30 fractions twice daily is better than 66 Gy in 33 fractions once daily. Intracranial metastasis occur in more than 50% of patients.

59. PCI is a Category I recommendation for patients with limited stage disease who attain a complete or partial response. PCI should not be given concurrently with systemic therapy or high dose radiation therapy. Optimal dose of PCI is 25Gy in 10#. Cisplatin + Etoposide is the most commonly used chemotherapy regimen.

60. THANK YOU