Author: Douglas A. Arenberg, M.D., 2008-2010License: Unless otherwise noted, this material is made available under the ter...
Citation Key                           for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Ad...
!"#$%&#()*                            %              +,%-%.)/01*23*4%5)6")#()%               73"$8/%9*)#:)*$;%+<7<%Fall, 2...
Cancer Mortality Rates - Male  CDC
Cancer Mortality Rates - Female    CDC
One of these things is not         like the others                                                                        ...
Approximate Cancer Stage at                           Diagnosis                                  I        II     III-IV   ...
With respect to lung cancer, which of         the following is true?•  Surgery offers the only chance for a cure in lung  ...
•  How do lung cancer patients differ   from other cancer patients? – Many co-morbid diseases – Surgery implies part remov...
Patients with lung nodules should be assumed to havecancer until proven otherwise   Dr. Arenberg, have you taken       lea...
Principles guiding the evaluation of       patients with lung nodules•  #1 Do you or do you not have lung cancer  – Lung n...
Cancer until proven otherwise?•  Clinical history                                                   Increasing risk & cost...
FDG-PETDiagnostic Performance of PET in Assessment ofMediastinal Lymph Nodes of Lung Cancer. 2007 J Nuc Med 48(11)    Inde...
Principles guiding the evaluation of        patients with lung nodules•  #2 If you have lung cancer, is it resectable  –  ...
Factors which predict a higher          likelihood of cancer•  Size of the nodule•  Border (spiculated versus smooth)•  Ag...
Causes of lung cancer•  Tobacco smoking•  Tobacco smoking•  Tobacco smoking    – Some types of lung cancer more closely   ...
Causes of lung cancer•  Tobacco  – Fewer than 10% of smokers get lung cancer•  Tobacco  – Smokers with COPD are at much gr...
Lung cancer signs and symptoms        at presentation*  •  Finding                   % of Pts (n=214)  •    Cough         ...
Squamous Cell Carcinoma•  Used to be the most common type•  More common in the proximal of the   tracheobronchial (60 to 8...
AdenocarcinomaThe most common type of lung cancer !!Most frequent histologic type in women and nonsmokersof either sex. !M...
Small Cell Carcinoma•  15 to 20%. Smokers (nearly only)•  Are neuroendocrine lung tumors•  Rapid doubling time, early deve...
Goals in work-up of patients with        suspected lung cancer•  Find every patient who can tolerate surgery•  Find every ...
NSCLC stages             Lymph nodes          Invasion of          chest wall                                             ...
Staging in practice              Physiologic         Anatomic                 Poor lung       N3                 function,...
Therapy of non-small cell lung               cancer•  Stage I-II (disease confined to lungs and/or   peribronchial lymph n...
Chemotherapy for Non-small cell      lung cancer (NSCLC)•  Cell type (squamous vs adeno vs large cell) does not   matter• ...
Advanced NSCLC:                            chemotherapy agents!  Platinum-based combination therapy gives   better respons...
Clinical CharacteristicsPredictive of Response to EGFR            inhibitors  •  Female  •  Adenocarcinoma, especially    ...
anti-VEGF (Bevacizumab) in          Advanced Stage Lung Cancer                                                            ...
Novel biological approaches•  Anti-angiogenic agents    –  monoclonal antibodies, eg       bevacizumab       (rhuMab-VEGF)...
Radiation therapy in non-small cell              lung cancer•  Curative intent for early stage medically unresectable   lu...
Treatment of lung cancer requires   multi-modality cooperation•  Primary Provider•  Pulmonologist•  Diagnostic radiologist...
Why?                                                                                 Incidence                            ...
…why?                                 I        II     III-IV              100%% of All Stages                  80%        ...
Summary of screening vs         “controls”• Mayo, Johns Hopkins, Memorial  Sloan-Kettering, and Czeck Lung  projects (Over...
ELCAP & Mayo data•  ELCAP: 1000 smokers over age 60    – 233 patients had non-calcified nodules by CT    – 28 cancers, 27 ...
95% of new nodules                                                                        were benign                     ...
Kaplan-Meier Survival Curves for 484 Participants with Lung Cancer and 302 Participants         with Clinical Stage I Canc...
NLST•  50,000 current or former smokers•  30 study sites•  Closed to enrollment in February 2004•  Slated to collect data ...
“Critical Point”The point in the natural history of diseaseafter which therapy will not alter the outcome
Screening is ineffective                            Screening is effective                                                ...
Prevention!  Education and primary prevention   –  avoidance of environmental carcinogens,      eg tobacco smoke!  Chemopr...
Phase III chemoprevention:               trials in progress, July 2003•  Gefitinib vs placebo (SPORE trial)    –  former/c...
Lung cancer:                Summary•  Deadliest of all common solid tumors•  Screening not yet proven effective•  Treatmen...
Lung cancer:                  SummaryTreatment   – Concurrent chemoradiation therapy for stage III     disease (~15% five ...
Additional Source Information                                for more information see: http://open.umich.edu/wiki/Citation...
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10.18.10: Lung Cancer

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10.18.10: Lung Cancer

  1. 1. Author: Douglas A. Arenberg, M.D., 2008-2010License: Unless otherwise noted, this material is made available under the terms ofthe Creative Commons Attribution–Noncommercial–Share Alike 3.0 License:http://creativecommons.org/licenses/by-nc-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physicianif you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. !"#$%&#()* % +,%-%.)/01*23*4%5)6")#()% 73"$8/%9*)#:)*$;%+<7<%Fall, 2009!
  4. 4. Cancer Mortality Rates - Male CDC
  5. 5. Cancer Mortality Rates - Female CDC
  6. 6. One of these things is not like the others Incidence Mortality 200,000 176,300 179,300 171,600 158,900 150,000 94,700 100,000 43,700 47,900 50,000 37,000 0 Breast Colon Lung ProstateD. Arenberg, American Cancer Society. Cancer Facts & Figures–1999.
  7. 7. Approximate Cancer Stage at Diagnosis I II III-IV 100%% of All Stages 80% 60% 40% 20% 0% Breast Prostate Colorectal Lung D. Arenberg
  8. 8. With respect to lung cancer, which of the following is true?•  Surgery offers the only chance for a cure in lung cancer•  Below a certain absolute level of lung function, surgery is absolutely contraindicated•  Thoracoscopic lobectomy is less painful but results in inadequate staging of mediastinal lymph nodes•  Post-operative chemotherapy prolongs survival and offers a greater chance of long term cure
  9. 9. •  How do lung cancer patients differ from other cancer patients? – Many co-morbid diseases – Surgery implies part removal of a vital organ – Surgery for locally advanced disease is not usually standard of care – Role(s) of adjuvant and neoadjuvant therapy is less well defined (until recently)
  10. 10. Patients with lung nodules should be assumed to havecancer until proven otherwise Dr. Arenberg, have you taken leave of your senses?
  11. 11. Principles guiding the evaluation of patients with lung nodules•  #1 Do you or do you not have lung cancer – Lung nodules are cancer until proven otherwise – Certainty/urgency of proof differs for each patient•  Over 98% of lung nodules detected by CT scan are benign
  12. 12. Cancer until proven otherwise?•  Clinical history Increasing risk & cost – Recent febrile illness•  Radiologic Increasing uncertainty –  Size stability? –  CT evidence of benign calcification pattern•  PET scanning•  Biopsy –  Bronchoscopic or FNA –  Surgical
  13. 13. FDG-PETDiagnostic Performance of PET in Assessment ofMediastinal Lymph Nodes of Lung Cancer. 2007 J Nuc Med 48(11) Index Visual interpretation SUV Cutoff of 2.5 (%) (%) Sensitivity 91 (85–98) 89 (81–96) Specificity 85 (81–90) 84 (79–88) Accuracy 87 (82–91) 85 (81–89)Positive predictive 64 (55–73) 61 (52–71) value
  14. 14. Principles guiding the evaluation of patients with lung nodules•  #2 If you have lung cancer, is it resectable –  For now, surgery offers the greatest possibility of cure (assume a cancer is resectable until proven otherwise) – Risk of morbidity & mortality – No benefit in locally advanced disease (IIIa or worse) – Accurate staging is a must•  A surgeon must be involved in the determination of whether a patient has “resectable” cancer
  15. 15. Factors which predict a higher likelihood of cancer•  Size of the nodule•  Border (spiculated versus smooth)•  Age of the patient•  History of tobacco use•  Location of the nodule (upper lobe higher risk than lower lobe)•  Prior history of cancer – http://www.chestx-ray.com/SPN/SPNProb.html
  16. 16. Causes of lung cancer•  Tobacco smoking•  Tobacco smoking•  Tobacco smoking – Some types of lung cancer more closely associated with tobacco than others – Small cell > squamous > adeno – All are more common in smokers•  Asbestos•  Radon•  Genetic susceptibility? – Common risk factors for both lung cancer and tobacco addiction/dependence
  17. 17. Causes of lung cancer•  Tobacco – Fewer than 10% of smokers get lung cancer•  Tobacco – Smokers with COPD are at much greater risk than smokers without COPD•  Over 50% of newly diagnosed lung cancer patients are former or never smokers
  18. 18. Lung cancer signs and symptoms at presentation* •  Finding % of Pts (n=214) •  Cough 54 •  Dyspnea 36 •  Weight loss 33 •  Chest pain 32 •  Fatigue 20 •  Anorexia 16 •  Hemoptysis 15 •  Hoarseness 9• Most people with these symptoms DO NOT have lung cancer• Early stage lung cancer causes NO symptoms!!
  19. 19. Squamous Cell Carcinoma•  Used to be the most common type•  More common in the proximal of the tracheobronchial (60 to 80%)•  Squamous cancers are more likely to be cavitated than other types•  A subset occur as endobronchial lesions in patients with a normal CXR. –  Patients present with persistent cough, recurrent hemoptysis, or relapsing pulmonary infections due to airway obstruction.•  5 year survival 65% (combined stages)
  20. 20. AdenocarcinomaThe most common type of lung cancer !!Most frequent histologic type in women and nonsmokersof either sex. !Most adenocarcinomas are located peripherally (75%).!Bronchoalveolar carcinoma —subtype ofadenocarcinoma, probably more indolent!• An origin distal to grossly recognizable bronchi!• Well-differentiated cytology!• A propensity for aerogenous and lymphatic spread !• Growth along intact alveolar septa! ! ("lepidic" growth pattern; Air-bronchograms)!!
  21. 21. Small Cell Carcinoma•  15 to 20%. Smokers (nearly only)•  Are neuroendocrine lung tumors•  Rapid doubling time, early development of widespread metastases.•  Highly sensitive to chemo- and radiotherapy –  Almost always relapses in < 2 years. Only 3-8% survive beyond 5 years. Not a surgical disease.•  Typically a large hilar mass with massive mediastinal adenopathy –  Cough, dyspnea, weight loss, debility, post- obstructive pneumonia.•  70% present with metastatic disease!
  22. 22. Goals in work-up of patients with suspected lung cancer•  Find every patient who can tolerate surgery•  Find every patient whose disease is anatomically amenable to surgery•  For patients who meet both criteria, introduce them to a surgeon, quickly –  Do not pass go, do not collect $200 and DO NOT biopsy!!•  Minimal work-up –  Spirometry, liver/renal/coagulation –  Assessment of exercise tolerance (usually clinical) –  CT scan with IV contrast –  Consider PET scanning if available
  23. 23. NSCLC stages Lymph nodes Invasion of chest wall Metastasis to distant organs Main bronchus Stage 0 Stage IA Stage IIB Stage IIIB Contralateral Stage IV lymph nodeD. Arenberg, Adapted from Lungs Diagram Simple, Patrick J. Lynch, Wikipedia
  24. 24. Staging in practice Physiologic Anatomic Poor lung N3 function, T4 co- morbidity etc., T3 N2 Healthy Normal N1 T2 PFT N0 T1 Barriers to surgical resectionD. Arenberg
  25. 25. Therapy of non-small cell lung cancer•  Stage I-II (disease confined to lungs and/or peribronchial lymph nodes) –  Surgery for patients with adequate pulmonary reserve –  Limited resection (less than lobectomy) for patients with borderline lung function•  Stage III (disease which has spread to mediastinal lymph nodes) –  Chemoradiation therapy (concurrent is better than sequential, but at a greater cost in toxicity) –  Partial resection (leaving tumor behind) is of no value
  26. 26. Chemotherapy for Non-small cell lung cancer (NSCLC)•  Cell type (squamous vs adeno vs large cell) does not matter•  Response rates generally better in phase I-II trials than in phase III RCTs•  Until recently survival difference measured in weeks
  27. 27. Advanced NSCLC: chemotherapy agents!  Platinum-based combination therapy gives better response rates than monotherapy and remains the ‘gold standard’ for first-line therapy for advanced disease!  Paclitaxel, vinorelbine, docetaxel, gemcitabine!  In the past 3 decades, median survival in NSCLC patients has only improved by approximately 2 months Source: Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002
  28. 28. Clinical CharacteristicsPredictive of Response to EGFR inhibitors •  Female •  Adenocarcinoma, especially Bronchioloalveolar (BAC) •  Non-Smoker •  Asian (Japan, Taiwan, Singapore) •  Development of Rash
  29. 29. anti-VEGF (Bevacizumab) in Advanced Stage Lung Cancer Survival by TreatmentResponse PC PCBCategory 1.0 PC(Patients) (383) (391) PCB Probability 0.8CR 0.3% 1.4% P = 0.007 0.6 Medians: 10.2, 12.5PR 10% 26% 0.4CR/PR 10% 27%* 0.2 0.0 0 6 12 18 24 30 36 *p<0.0001 Months D. Arenberg, Sandler; ASCO 2005
  30. 30. Novel biological approaches•  Anti-angiogenic agents –  monoclonal antibodies, eg bevacizumab (rhuMab-VEGF) –  VEGF receptor TKIs, eg ZD6474, PTK787 –  matrix metalloproteinase inhibitors –  thalidomide•  Vascular targeting agents, eg combretastatin A4 phosphate, ZD6126
  31. 31. Radiation therapy in non-small cell lung cancer•  Curative intent for early stage medically unresectable lung cancer –  Cure rates approaching surgery when high doses can be delivered•  Excellent Palliation of bony pain, endobronchial obstruction, bleeding•  Post-operative radiotherapy yields no survival advantage for completely resected lung cancer –  Eliminates local recurrences, but patients die of metastases•  Symptomatic radiation-pneumonitis in 4-15%
  32. 32. Treatment of lung cancer requires multi-modality cooperation•  Primary Provider•  Pulmonologist•  Diagnostic radiologist, Interventional radiologist, Nuclear Medicine•  Pathologist•  Thoracic Surgeon•  Medical and radiation oncologists
  33. 33. Why? Incidence Mortality 200,000 176,300 179,300 171,600 158,900 150,000 94,700 100,000 43,700 47,900 50,000 37,000 0 Breast Colon Lung ProstateD. Arenberg, American Cancer Society. Cancer Facts & Figures–1999.
  34. 34. …why? I II III-IV 100%% of All Stages 80% 60% 40% 20% 0% Breast Prostate Colorectal Lung D. Arenberg
  35. 35. Summary of screening vs “controls”• Mayo, Johns Hopkins, Memorial Sloan-Kettering, and Czeck Lung projects (Over 35,000 patients) – More cases detected – More early stage disease – Improved survival in the screened group – No difference in one’s likelihood of dying from lung cancer
  36. 36. ELCAP & Mayo data•  ELCAP: 1000 smokers over age 60 – 233 patients had non-calcified nodules by CT – 28 cancers, 27 stage I – One patient with a benign nodule had surgery•  Mayo: 1520 smokers over 50 (prevalence and two annual follow up scans) – 1,049 (69%) patients had >2,000 nodules – 40 cancers detected after 3 years (26 prevalence) – IA (22), IB (3), IIA (4), IIB (1), IIIA (5), IV (1), and limited small cell (4) – 7 patients had benign nodules resected Source: Swensen. Radiology 2003 Henscke. LANCET 1999
  37. 37. 95% of new nodules were benign Diagnoses of Lung Cancer Resulting from Baseline Screening and Annual Screening with CTThe International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771
  38. 38. Kaplan-Meier Survival Curves for 484 Participants with Lung Cancer and 302 Participants with Clinical Stage I Cancer Resected within 1 Month after Diagnosis The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771
  39. 39. NLST•  50,000 current or former smokers•  30 study sites•  Closed to enrollment in February 2004•  Slated to collect data for 8 yr•  Powered to detect a 20 percent or greater drop in lung cancer mortality from using spiral CT compared to chest X-ray
  40. 40. “Critical Point”The point in the natural history of diseaseafter which therapy will not alter the outcome
  41. 41. Screening is ineffective Screening is effective Screening is unnecessaryOnset of Detectable Signs or Death fromDisease by screening Symptoms Disease or Other causes Critical Point Critical Point Critical PointD. Arenberg
  42. 42. Prevention!  Education and primary prevention –  avoidance of environmental carcinogens, eg tobacco smoke!  Chemoprevention –  retinoids –  EGFR inhibitors –  selenium –  COX-2 inhibitors –  green tea
  43. 43. Phase III chemoprevention: trials in progress, July 2003•  Gefitinib vs placebo (SPORE trial) –  former/current smokers with previous history of smoking-related cancer –  6 months of treatment –  efficacy endpoints: histological response, biomarkers including the Ki-67 labelling index –  expected accrual: 2 years to recruit 150 patients•  Selenium study E5597 –  patients following surgery for stage I NSCLC –  4 years of treatment –  evaluation of effectiveness of selenium in reducing incidence of new lung tumours, and of toxicity and effects on survival compared with placebo –  expected accrual: 1960 (980 per arm) participants within 4 years
  44. 44. Lung cancer: Summary•  Deadliest of all common solid tumors•  Screening not yet proven effective•  Treatment – Surgery for early stage patients with adequate pulmonary reserve – Radiation therapy for medically unresectable, early stage disease – Adjuvant chemotherapy for stage II or more
  45. 45. Lung cancer: SummaryTreatment – Concurrent chemoradiation therapy for stage III disease (~15% five year survival) – Unresectable does not mean incurable – Stage IV, only chemotherapy, long term cures rare•  Future predictions – Enhanced screening based upon better risk prediction – Chemoprevention strategies – Improved treatment and prevention of tobacco dependence – Individualized therapy
  46. 46. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 4: Source UndeterminedSlide 5: Source UndeterminedSlide 6: D. Arenberg, American Cancer Society. Cancer Facts & Figures–1999.Slide 7: D. ArenbergSlide 23:D. Arenberg, Adapted from Lungs Diagram Simple, Patrick J. Lynch, Wikipedia, http://commons.wikimedia.org/wiki/File:Lungs_diagram_simple.svg, CC BY: http://creativecommons.org/licenses/by/2.5/Slide 34: D. ArenbergSlide 27: Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002Slide 29: D. Arenberg, Sandler; ASCO 2005Slide 33: D. Arenberg, American Cancer Society. Cancer Facts & Figures–1999.Slide 34: D. ArenbergSlide 36: Swensen. Radiology 2003 Henscke. LANCET 1999Slide 37: The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771Slide 38: The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771Slide 41: D. Arenberg

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