SMALL CELL LUNG CANCER Updated June 2018 by Dr. Kirstin Perdrizet (PGY-5 Medical Oncology Resident, University of Toronto)

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1 SMALL CELL LUNG CANCER Updated June 2018 by Dr. Kirstin Perdrizet (PGY-5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Adrian Sacher (Staff Medical Oncologist, Princess Margaret Cancer Centre, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5s medical oncology resident and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH AND EPIDEMIOLOGY Incidence: 69.9 per 100, Among both sexes it is the cancer with the highest incidence in Canada (this is all lung cancers, NSCLC and SCLC) (2017 Canadian Cancer Statistics) Mortality: Most common cause of cancer death in Canada (51.4 deaths per 100,000) (this is all lung cancers, NSCLC and SCLC) (2017 Canadian Cancer Statistics) Risk Factors: Environmental/Chemical/Infections: smoking, radiation therapy, air pollution, radon, metals (arsenic, chromium and nickel), ionizing radiation, asbestos, polycyclic aromatic hydrocarbons, pulmonary fibrosis, HIV infection Genetic: inherited susceptibility variants for lung cancer have been found on several chromosomal loci such as15q25 (nicotinic acetylcholine receptor subunit CHRNA5) and 6q23-25 Prevention/Screening: Prevention: Smoking cessation Screening: Evidence from the National Lung Screening Trial (NLST) found that screening high- risk patients (defined as >/= 30 pack year smoking history or quit smoking <15 years ago and aged between 55 and 74 years old) with an annual low dose CT scan reduced lung cancer mortality by 20% and all-cause mortality by 6.7%. N=53,454 randomized to 3 annual low dose CT vs PA CXR 24% CT vs 7% XRay detection ~ 95% screenings were false positives in both groups The Prostate, Lung, Colorectal, Ovarian (PLCO) trial found that Chest X-ray is not effective for lung cancer screening, when compared to no screening. Canadian Task Force 2016 guidelines recommend Low dose computed tomography (LDCT)

2 For adults aged years with at least a 30 pack-year* smoking history who currently smoke or quit less than 15 years ago, we recommend annual screening with LDCT up to three consecutive times. Screening should ONLY be carried out in health care settings with expertise in early diagnosis and treatment of lung cancer. CCO guidelines on lung cancer screening are still pending as of July ; pilot projects are ongoing at multiple sites across Ontario. B) PRESENTATION & DIAGNOSIS Common Symptoms: Symptoms from local tumour effect: cough, hemoptysis, dyspnea, chest pain, hoarseness Symptoms from extrathoracic metastases to supraclavicular lymph nodes, liver, adrenals, bone, brain Symptoms from paraneoplastic syndromes: hypercalcemia symptoms, hyponatremia symptoms, cushing s syndrome symptoms, hypertrophic osteoarthropathy symptoms, dermatomyositis/polymyositis symptoms, neurologic symptoms, hypercoagulable disorders Common Signs: Signs from local tumour effect: airway compromise, hoarseness, superior vena cava syndrome, pancoast syndrome Signs from extrathoracic metastases to supraclavicular lymph nodes, liver, adrenals, bone, brain Signs from paraneoplastic syndromes Non-small cell hypertrophic pulmonary osteoarthropathy, hypercalcemia Small cell SIADH (10%), ectopic ACTH, eaton-lambert syndrome Common Presentations: pancoast syndrome, paraneoplastic syndrome, majority of patients have advanced disease at presentation Prognostic factors: weight loss, stage, performance status, sex (M worse than F), LDH age is not a prognostic factor INVESTIGATIONS Laboratory: anemia, leukocytosis, thrombocytosis, eosinophilia has been reported in

3 patients with large cell carcinoma, features of microangiopathic hemolytic anemia can be seen (ex. DIC/TTP), electrolytes (can show features of SIADH/ectopic ACTH secretion in small cell lung cancer patients), calcium, albumin, LDH, AST, CEA if elevated can help with assessment of treatment in patients with difficult-to-evaluate index lesions (ex. Bone lesions) Diagnostic Imaging: CT Chest Enhanced that encompasses the liver and adrenal glands, CT head if neuro symptoms, MR brain if persistent neuro symptoms despite normal CT head, Bone scan if bony symptoms, PET for SCLC if potentially early stage disease. Diagnostic Procedures: Tissue diagnosis tissue biopsy preferred with bronchoscopy, percutaneous fine needle biopsy, excisional or needle biopsy as appropriate for the patient. Bone marrow aspirate is not recommended unless an otherwise unexplained hematologic abnormality is present. Pretreatment Evaluation: Pulmonary function testing if patient is potentially operable. PET scan if patient thought to be limited stage in order to confirm PATHOLOGY & MOLECULAR BIOLOGY - Common Histology (Lung CA in general): Small cell lung cancer (SCLC): 13% Non-small cell lung cancer (NSCLC): o Adenocarcinoma: 38% o Squamous cell carcinoma: 20% o Large cell carcinoma: 5% o Other NSCLC s (ex. NSCLC NOS): 24% Common Metastatic Sites: liver, bone, brain, bone marrow Relevant Molecular Biology: o None for small cell lung cancer. - STAGING SCLC Staging Limited Stage tumour that is encompassable by a reasonable radiotherapy treatment volume. Usually limited to one hemithorax and may include mediastinal and ipsilateral supraclavicular nodes.

4 Extensive Stage disease beyond limited stage criteria. Patients with regional extensive stage disease (such as pleural effusion, cervical lymph nodes or contralateral supraclavicular lymph nodes) may benefit from limited stage type treatment. TNM staging same as NSCLC i) LIMITED STAGE Bottom Line General Approach: First-line therapy: Curative intent combined thoracic irradiation with 4 6 cycles of chemotherapy (cisplatin and etoposide). The combination of thoracic irradiation with chemotherapy improves long-term survival for patients with limited stage disease controversial. Prophylactic cranial irradiation should follow treatment for patients with response to treatment. The integration of thoracic irradiation with chemotherapy early in the treatment program (ie. concurrently with cisplatin and etoposide at week 3) is superior to late addition of radiation. Recurrent disease: See SMALL CELL LUNG CANCER, EXTENSIVE STAGE (below). Prognosis: median survival with treatment is 14 months for limited stage with treatment. Important Phase III Clinical Trials: Prophylactic Cranial Irradiation (PCI) for Patients with Small-Cell Lung Cancer in Complete Remission Auperin A. et al. N Engl J Med 1999; 341: Regimen PCI or no PCI Mechanism of Action of Experimental Drug prophylactic cranial irradiation Primary Endpoint OS

5 Patients with SCLC in complete remission Inclusion/Exclusio n Criteria No evidence of brain mets before randomization No previous cranial irradiation Size (N) 987 patients Results Survival: rate of survival at 3 years 20.7% in treatment group vs 15.3% in control group (RR = 0.84). DFS: relative risk of recurrence or death was 0.75 Toxicity (e.g. common toxicities overall, common grade 3/4 toxicities) Conclusion Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission. Other Comments Other Important Published Data: (e.g. meta-analysis, restrospective analyses, phase II) 1. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited stage small-cell lung carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10: Sundstrom S, Bremnes R, Kaasa S, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years follow-up. J Clin Oncol 20: , Murray N, Coy P, Pater J, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 1993;11: ii) EXTENSIVE STAGE

6 Bottom Line General Approach: First-line therapy: Combination palliative intent chemotherapy with a platinum agent for 4 to 6 cycles. Thoracic irradiation is ONLY recommended for palliation of symptoms that are not controlled by chemotherapy. Prophylactic cranial irradiation for extensive stage small cell lung cancer with response to chemotherapy decreases the risk of brain metastases and prolongs survival, however there is conflicting data on this. Consider consolidative thoracic radiation in patients who have achieved a favorable response to initial chemotherapy and who have residual disease limited to the chest. Consolidative thoracic RT has been associated with improved overall survival. Recurrent disease/second-line therapy: Time of recurrence since completion of chemotherapy is an indicator of prognosis, with patients who relapse within 3 months of completing first-line treatment carrying the worst prognosis. Patients with longer remissions (greater than 3-6 months) may be considered for retreatment with platinum and etoposide. Consider second-line chemotherapy in patients with an acceptable performance status. Topotecan may be considered for recurrent disease. There is also evidence for CAV chemotherapy (currently funded in Ontario, 2018). Irinotecan and temozolomide also demonstrate activity in second- and third-line settings. Single agent oral etoposide may also be considered for patients who are reluctant to receive IV chemotherapy. Prognosis: Median survival with standard treatment is 12 months Important Phase III Clinical Trials: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. Lara PN Jr1, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR. J Clin Oncol May 20;27(15): doi: /JCO Epub 2009 Apr 6 Regimen Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks)

7 Mechanism of Action of Experimental Drug Cisplatin: DNA crosslinks induce double strand breaks Etoposide: Topoisomerase II inhibitor Irinotecan: Topoisomerase I inhibitor Primary Endpoint OS Secondary: PFS, RR Histological confirmation of extensive stage SCLC Inclusion/Exclusio n Criteria no prior radiotherapy, chemotherapy, or surgery; a Zubrod performance status of 0 or 1, a life expectancy of at least 3 months Size (N) 651 patients Overall Survival: Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P =.71) Results PFS: Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P =.07) RR: In the IP arm, the response rate was 60% (95% CI, 54% to 65%), whereas in the EP arm, it was 57% (95% CI, 53% to 63%) Toxicity More grade 3 toxicity in IP arm (predominantly diarrhea). Grade 5 toxicity in 11 in the IP arm, 8 in EP arm Conclusion This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP Other Comments

8 Prophylactic Cranial Irradiation (PCI) in Extensive Small-Cell Lung Cancer Slotman B et al. N Engl J Med 2007; 357: Regimen PCI or no further therapy Mechanism of Action of Experimental Drug Prophylactic cranial irradiation Primary Endpoint Time to symptomatic brain mets Inclusion/Exclusio n Criteria Patients between age 18 and 75 years of age with extensive stage SCLC who achieved response after 4 to 6 cycles of initial chemotherapy. ECOG0to2 No previous brain/leptomeningeal mets No previous radiotherapy to the head and neck area Size (N) 286 patients Results Survival: Median survival, 6.7 mos in treatment group vs. 5.4 mos in control group Symptomatic brain mets was observed in 16.8% in the treatment group vs 41.3% in the control group.

9 Cumulative risk of brain mets within 1 year was 14.6% in the treatment group vs 40.4% in the control group. DFS: 14.7 weeks in treatment group vs. 12 weeks in control group Quality of Life: irradiation did not have a clinically significant effect on global health status. Toxicity Headache, nausea/vomiting, fatigue/lethargy Conclusion PCI prolongs disease-free and overall survival and decreases the incidence of symptomatic brain metastases. Other Comments Prophylactic cranial irradiation versus observation in patients with extensivedisease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Takahashi et. al. Lancet Oncology Volume 18, No. 5, p , May Regimen PCI or MRI surveillance Mechanism of Action of Experimental Drug Prophylactic cranial irradiation Primary Endpoint Overall survival Inclusion/Exclusio n Criteria Extensive stage SCLC who achieved response after 4 to 6 cycles of initial chemotherapy

10 ECOG 0to2 No previous brain/leptomeningeal mets 224 patients Size (N) Patients were assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2 5 Gy) or observation. All patients were required to have brain MRI at 3- month intervals up to 12 months and at 18 and 24 months after enrolment. Results Survival: Median survival, 11.6 mos in treatment group vs mos in MRI observation group Toxicity anorexia, fatigue/lethargy, lower limb weakness in PCI group Conclusion PCI did not significantly improve OS when patients were having regularly scheduled MRIs Other Comments Slotman BJ et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet Jan;385(9962): Epub 2014 Sep 14. N=498 ext stage SCLC with response to chemotherapy Thoracic RT 30 Gy in 10 Fr vs no RT No diff in 1-yr OS 33% vs 28% (ns) 2-yr OS was better in the RT group (13% vs 3%, s). 46% isolated intrathoracic progression in the control (no RT) group, vs 20% in the experimental (RT) group. Other Important Published Data: (e.g. meta-analysis, restrospective analyses, phase II) 1. Consolidative thoracic radiation: Jeremic B et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J

11 Clin Oncol Jul;17(7): Slotman BJ et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet Jan;385(9962): Epub 2014 Sep Rossi A, Di Maio M, Chiodini P, et al. Carboplatin or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol 30: , Relapsed SCLC - Van Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17: , O Brien M, Ciuleanu T, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 24: , Chemotherapy combined with atezolizumab improves OS (phase 1b trial) DOI: /JCO _suppl.9092 Journal of Clinical Oncology 35, no. 15_suppl (May ) C) OTHER REFERENCES (not previously cited above) 1) Canadian Cancer Statistics ) UpToDate 3) Alberta Cancer Guidelines 4) BC Cancer Agency Clinical Practice Guidelines