Management of Small cell Lung Carcinoma.pptx

Management of Small cell lung cancer, limited and extended stage, surgery, chemotherapy, radiation therapy, Treatment regimen

1. Management of Small Cell Lung Carcinoma Dr Vikas Mohan Sharma

2. Introduction SCLC represents ~15% of all lung cancer diagnoses with decreasing incidence. More common in men although gender difference is narrowing. Occurs almost exclusively in smokers (>98%)—typically heavy smokers. Uranium mining is another risk factor. SCLC is of neuroendocrine origin and and lies along spectrum of other lung neuroendocrine tumors including low-grade neuroendocrine carcinoma (typical carcinoid), intermediate grade (atypical carcinoid), and high grade (LCNEC and SCLC).

3. Histopathology Light microscopy classically reveals clusters or sheets of small round blue cells, twice the size of normal lymphocytes. “Crush artifact” clas - sic descriptor on cytology and is considered diagnostic. Cytoplasm is sparse and nucleus manifests finely dispersed chromatin without distinct nucleoli. Mitotic rates are high and necrosis is common.

4. Three groups of antigen clusters have been identified: neural, epithelial, and neuroendocrine. Epithelial markers include keratin, epithelial membrane antigen, and TTF1. Neuroendocrine and neural markers include DOPA decarboxylase, calcitonin, NSE, synaptophysin, chromogranin A, CD56 (NCAM), gastrin releasing peptide, and IGF-1.

5. Clinical Presentation SCLC arises submucosally in central airways, often obstructing bronchial lumen. Common symptoms include new or worsening cough, dyspnea, chest pain, hoarseness, hemoptysis, malaise, anorexia, and weight loss. If other thoracic structures are compromised by enlarging mass, dysphagia or SVC syndrome (facial edema/plethora, distension of superficial veins, laryngeal edema, altered mental status) may be present. Most common sites of distant spread are liver, adrenals, bone, and brain. Brain mets incidence: 10% to 20% at diagnosis, 50% to 80% at 2 years. Patients may also present with Paraneoplastic syndromes.

6. Paraneoplastic Syndromes Commonly Diagnosed in SCLC SIADH Overproduction of ADH with euvolemic hyponatremia. May present with altered mental status, seizures. Treat with water restriction, hypertonic saline, demeclocycline, vasopressin inhibitors, and/or lithium Cushing's syndrome Ectopic production of ACTH. Treat with ketoconazole Lambert–Eaton Auto-antibodies to presynaptic calcium channels. Proximal muscle weakness that improves later in day. Treat with pyridostigmine, prednisone, IVIG and by treating cancer Others (rare) Subacute cerebellar degeneration, subacute sensory neuropathy, limbic encephalopathy, encephalomyelitis (anti-Hu antibodies)

7. Work up History and Examination CBC, BMP, LFTs, LDH, alkaline phosphatase, PFTs. Imaging: CT chest with contrast (including liver and adrenals) and PET/CT (nearly 100% sensitive for SCLC; note that PET upstages 19% of patients initially diagnosed with LS disease).13 Forego bone scan if PET obtained. Contrast-enhanced brain MRI (preferred) or CT brain (CT brain positive in 10%; MRI brain positive in 20%). Biopsy: For tissue diagnosis: sputum, bronchoscopy with biopsy/FNA (though note that FNA may not always adequately differentiate SCLC from carcinoid tumors), CT-guided biopsy or thoracentesis for pleural effusion. Consider bone marrow biopsy if neutropenia/thrombocytopenia/nucleated RBCs on peripheral smear.

8. Prognostic Factors Favorable: limited stage, female gender, performance status (0–1), absence of weight loss, absence of paraneoplastic syndromes, normal lab reports (LDH, sodium, albumin), smoking cessation. Hyponatremia (MS 9 months if Na <135, 13 months if Na ≥135, p < .001). LDH has been shown to correspond with disease burden, can raise concern for bone marrow involvement, and may be risk factor for early death. More than 5% weight loss is a poor prognostic factor.

9. Staging VA Lung Cancer Study Group Limited stage Tumor confined to one hemithorax (including both ipsilateral and contralateral mediastinum) and ipsilateral SCV nodes MS: 20–30 mos 2-yr OS: 40% 5-yr OS: 20% to 30% Extensive stage Tumor beyond boundaries of limited disease, including distant metastases, malignant pericardial/pleural effusions, and contralateral SCV/ hilar LN involvement MS: 12 mos 2-yr OS: 5% 5-yr OS: <5%

10. Treatment options Surgery Surgery is not standard for most LS-SCLC based on historic MRC trial published in 1973 randomizing patients to either surgery or RT, with improved survival observed in those who received RT (mean OS improved from ~7 to 10 months, p = .04). However, ~4% to 5% of SCLC diagnosis present as Single Pulmonary Nodule (SPN). For T1–2 SPN SCLC tumors, lobectomy with mediastinal LN dissection is recommended, followed by CHT and/or mediastinal radiation depending on pathologic nodal status.

11. Chemotherapy Compared with no therapy, CHT improves MS fivefold. Cisplatin and EP are standard and found to be equally effective and less toxic than older regimens. Current standard is 4 cycles of EP with concurrent RT. Dose of cisplatin is 60 to 100 mg/m2 on day 1, and EP 120 mg/m2 on days 1 to 3, every 3 weeks.

12. Radiotherapy Radiation, when added to CHT, was found to reduce intrathoracic failures by 50%. LS-SCLC patients who have complete response or good partial response to primary therapy should be treated with PCI to 25 Gy /10 fx , as this reduces incidence of brain metastases and improves OS (see Auperin meta-analysis). SBRT may have a role similar to surgery in inoperable early-stage patients. Dose: Standard accelerated dose is 45 Gy /30 fx at 1.5 Gy / fx BID in 3 weeks with concurrent EP CHT based on results from the landmark Turrisi trial.

13. Proposed radiobiologic advantages of BID fx in SCLC include high growth fraction, short cell cycle time, and small/absent shoulder on cell survival curve. NCCN states that if daily fractionation is used, 60 to 70 Gy should be given and hypofractionated regimens such as 40 Gy /15 fx at 2.67 Gy / fx as employed by Murray et al. are not included in most recent guidelines. Toxicity - Acute: Fatigue, esophagitis, pneumonitis, nausea. Chronic: Pneumonitis, cardiac injury, dysphagia.

14. Treatment Approach to LS-SCLC For patients with LS-SCLC who have no distant metastases, no evidence of disease in the mediastinum, and no other contraindications to surgery, resection is indicated. Followed by adjuvant chemotherapy with four cycles of cisplatin-based therapy.

15. For patients in whom surgery identifies lymph node involvement in the pathologic specimen, chemoradiotherapy is generally indicated. For most patients with LS-SCLC who have clinical or pathologic evidence of mediastinal disease, chemoradiotherapy is indicated as the initial treatment. In addition to chemotherapy, there is a significant role for radiation therapy (RT) in the treatment of LS-SCLC. Multiple RCTs compared CHT alone to chemoRT , which formed the basis of the seminal Warde and Pignon meta-analyses, both of which showed 5% benefit in OS with addition of thoracic RT to CHT.

16. Warde , Ontario Meta-Analysis : Meta-analysis of 11 randomized trials of LS-SCLC patients treated with CHT alone vs. chemoRT . Demonstrated significant 25.3% improve- ment in LC (47% vs. 24%) and 5.4% improvement in 2-year OS (20% vs. 15%) with addition of RT, with patients under age 60 deriving greatest benefit. Pignon , French Meta-Analysis : Meta-analysis of 13 randomized tri- als of 2,140 patients with LS-SCLC treated with CHT alone vs. chemoRT . Addition of thoracic RT improved 3-year OS by 5.4% (14.3% vs. 8.9%) over CHT alone, with 14% relative reduction in mortal- ity rate.

17. Early Vs Late RT De Ruysscher , Netherlands Meta-Analysis (Ann Oncol 2006, PMID 16344277): Meta-analysis of seven trials to determine whether timing of chest RT may influence survival of patients with LS-SCLC. When including all seven trials, 2- and 5-year OS was not improved between early and late RT. Looking at only trials using concurrent platinum CHT w/ RT, 5-year OS was significantly improved with early RT, OR 0.64 (p = .02).

18. Prophylactic cranial irradiation Indicated for patients with a complete or partial response to their initial chemotherapy treatment.

19. SCLC - Meta-analysis of PCI From 7 randomised trials of PCI vs no-PCI Patients 987 (140 patients had ED-SCLC) Chemo- & RT schemes various Overall survival benefit +5% (95% CI: 1 -10%) 3 year survival 20 vs 15% Incidence of brain mets 33 vs 59% Auperin et al. NEJM 1999

20. Role of Immunotherapy There is no data currently supporting use of IO in LS-SCLC. This is being explored by NRG-LU005, which is an ongoing RCT randomizing patients with LS-SCLC to chemoRT with or without concurrent atezolizumab beginning cycle 2 followed by 1 year of maintenance atezolizumab.

21. Approach to ES-SCLC Primary therapeutic modality is systemic chemotherapy. Good response to chemotherapy-: RT additional benefit. Prophylactic cranial irradiation-: decreases the incidence of symptomatic brain metastases in patients who have responded to systemic chemotherapy.

22. Cisplatin + Etoposide-: Most frequently used. Carboplatin + Etoposide Cisplatin + Irinotecan-: Favourable results Japanese Cooperative Oncology Group trial (JCOG 9511) Topotecan plus cisplatin Epirubicin plus cisplatin

23. Should consolidative chest RT be delivered to ES-SCLC patients with response to CHT? With the addition of IO to standard of care CHT for ES-SCLC, the role, if any, and timing of chest RT is now highly controversial. Jeremic, Yugoslavia (JCO 1999, PMID 10561263): Addition of hyperfractionated RT for most favorable subset of patients leads to improved OS over CHT alone. Slotman , Netherlands (Lancet 2015, PMID 25230595): Thoracic RT + PCI should be considered for patients with ES-SCLC who respond to CHT. Gore, RTOG 0937 (J Thorac Oncol 2017, PMID 28648948): OS analysis was underpowered due to high rate of survival. Consolidation may reduce progression but did not alter OS.

24. Role of Immunotherapy Horn, IMpower133 (NEJM 2018, PMID 30280641): Phase III, double-blind, placebo-controlled RCT of patients with ES-SCLC treated first line with carboplatin and EP with or without atezolizumab during both induction and maintenance phases. Coprimary end point OS and PFS; 403 patients at median f/u 14 months, median OS improved with atezolizumab vs. placebo, 12.3 vs. 10.3 months (HR: 0.70, p = .007), and median PFS 5.2 vs. 4.3 months (HR: 0.77, p = .02). Immune-related AEs 40% with atezolizumab vs. 25% with placebo (rash and hypothyroidism most common). Conclusion: For first-line treatment of ES-SCLC, the addition of atezolizumab to carboplatin/EP improves OS and PFS.

25. Paz-Ares, CASPIAN (Lancet 2019, PMID 31590988): Phase III PRT of patients with ES-SCLC rand- omized 1:1:1 to durvalumab + EP, durvalumab + tremelimumab + EP, or EP alone. PCI was given at investigator’s discretion in the EP group. Primary end point OS. Planned interim analysis of durvalumab + EP vs. EP alone is reported. OS improved with addition of durvalumab, 13.0 vs. 10.3 months with 34% vs. 25% of patients alive at 18 months. Grade 3/4 AEs were similar in the two groups (62%), AEs leading to death were 5% vs. 6%. Conclusion: First-line durvalumab + platinum/ EP significantly improves OS compared with platinum/EP alone, with similar safety profile.

26. Points to Remember Small cell Lung Carcinoma o ccurs almost exclusively in smokers (>98%)—typically heavy smokers. Most common sites of distant spread are liver, adrenals, bone, and brain. Brain mets incidence: 10% to 20% at diagnosis, 50% to 80% at 2 years. VA Lung Study Group classified SCLC into LS-SCLC and ES-SCLC. Surgery is only indicated in early stage (T1-2, N0) disease Thoracic RT is indicated in LS-SCLC with concurrent chemo. PCI is indicated in patients with complete to partial response. In ES-SCLC, systemic chemotherapy is the preferred modality along with immunotherapy.

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