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last update of bronchogenic carcinoma
prepared by Dr hemin khalid department of pulmonary medicine hawler medical university

last update of bronchogenic carcinoma
prepared by Dr hemin khalid department of pulmonary medicine hawler medical university

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Bronchogenenic ca seminar

  1. 1. lung tumors Prepared by Dr Hemin Khalid Saber
  2. 2.  Lung neoplasms can be classified as benign or malignant.  Most benign lung tumors present as asymptomatic solitary pulmonary nodules,  incidentally discovered radiographically. About 50% of benign lung neoplasms are hamartomas.
  3. 3.  Benign lung tumors are broadly divided into epithelial and nonepithelial tumors. EPITHELIAL NEOPLASMS Types include: Papilloma Micronodular pneumocyte hyperplasia NONEPITHELIAL NEOPLASMS Types include: Hamartomas Solitary fibrous tumors
  4. 4. Papillomas  SQUAMOUS PAPILLOMA—Most often associated with cigarette smoking and human papilloma virus. Most occur in central large airways.
  5. 5. RECURRENT RESPIRATORY PAPILLOMATOSIS.  Associated with human papilloma virus types 11 and 6.  Surgical excision and laser ablation are the mainstays of treatment.  Squamous cell carcinoma is the most feared complication and may appear as cavitating nodules or masses
  6. 6. Micronodular Pneumocyte Hyperplasia  Characterized by numerous small, well- demarcated parenchymal nodules.  Classically associated with tuberous sclerosis and/or lymphangioleiomyomatosis.  Histopathology shows hyperplastic type II pneumocytes.  Findings are not progressive, so no treatment is indicated.
  7. 7. Hamartoma
  8. 8. Bronchogenic carcinoma
  9. 9. Epidemiology of Lung Cancer  Lung cancer is the leading cause of cancer death worldwide  Cancer of the lung and bronchus ranked second in cancer incidence in both sexes, with an estimated cases in males (14% of all new cancers) and in females (13-14% of all new cancers)
  10. 10. Estimated new cancer cases
  11. 11. Epidemiology of Lung Cancer  Lung cancer ranked as number one in causing deaths in both sexes yearly 27-28% and 26%of all cancer deaths for males and females)
  12. 12. Estimated death rate
  13. 13. Epidemiology of Lung Cancer
  14. 14. Classification of ca bron.
  15. 15. Central Squ.ca Sm.ca Peripheral Aden,larg.
  16. 16. Histological class.
  17. 17.  In the recent past, a relative increase in the incidence of ADC has been witnessed  In most of the developed countries, it has become the dominant histological type of lung cancer  overtaken SqCC . among males in some countries while it has continued to be the commonest type among females
  18. 18.  Link between Histology and Smoking  Use – filters--- lower content of tar and nicotine resulted in a tendency for their smoke to be inhaled more deeply  hig.concen. of carcinogens in the perip.
  19. 19. Adenocarcinoma  Adenocarcinoma is the most frequently diagnosed histologic type of lung cancer.  It is the most common subtype in women and nonsmokers.  Most tumors occur in the periphery.  Positive immunohistochemical stains include thyroid transcription factor-1, napsin A, and cytokeratin 7.
  20. 20. Squamous Cell Carcinoma (SCC)  Central mass, but approximately 25% are located peripherally and 5% show central cavitation.  Histologically, two features are important for diagnosis;  keratinization and intercellular bridges.
  21. 21. Histopathologic specimen of squamous cell carcinoma of the lung with intercellular bridges (arrow).
  22. 22. Squamous Cell Carcinoma (SCC)  The WHO classification recognizes four variants namely; papillary, clear cell, small cell and basaloid.  The small cell variant of Scc poorly differentiated variant which contains small tumor cells but retains cellular characteristics of a non-SCC such as coarse chromatin, nucleoli and distinct cell borders
  23. 23.  Compared with hist. subtypes, commonly assoc, cavitation, Pancoast syndrome, and hypercalcemia.  Immunohistochemistry: Usually stains positive for p63, cytokeratin 5/6. <
  24. 24. Large Cell Carcinoma  Undifferentiated malignant epithelial tumors that lack features of small cell carcinoma and glandular or squamous differentiation.  They are characterized by large nuclei, prominent nucleoli, and a moderate amount of cytoplasm.
  25. 25.  These tumors are usually peripherally located with pleural and chest wall invasion.  The tumor cells do not show intercellular bridges or keratinizations which are characteristic of squamous cell carcinoma and devoid of any gland formation as seen in adenocarcinoma
  26. 26. SMALL CELL LUNG CANCER  SCLC is characterized by proliferation of small cells with scant cytoplasm, illdefined borders, salt and pepper chromatin, frequent nuclear molding, and a high mitotic count.  Staining is usually positive for thyroid transcription factor-1,CD 56, synaptophysin, and chromogranin.  Up 98% patients SCLC Hx smoking.
  27. 27.  The natu. hx of SCLC early meta. and death. Unlike NSCLC, SCLC is always  SCLC shows an excellent response to chemotherapy, but almost always recurs.
  28. 28. Etiology of bronchogenic carcinoma  Tobacco smoking More than 85-90% of lung cancers develop in smokers,  one in nine smokers develops lung cancer  The cumulative lung cancer risk among lifelong heavy smokers can be as high as 30% compared with a lifetime risk of less than 1% in nonsmokers
  29. 29.  In one study, household exposure of 25 or more smoker-years before adulthood doubled the risk for lung cancer.  exposure of less than 25 smoker-years did not increase risk.  At least 17% of lung cancers in nonsmokers are thought to be attributable to exposure to high levels of ETS during childhood and adolescence
  30. 30. Etiology of bronchogenic carcinoma  Other Types of Smoking  1- Cigar smoking  associated with increased risk for lun.Ca, although seemingly not as great a risk as with cigarette smoking.  The tobacco content of cigars can vary from 1 g to 20 g. Smoking five cigars a day on average is equivalent to smoking one pack of cigarettes a day.
  31. 31. Etiology of bronchogenic carcinoma  Other Types of Smoking  2-PIP smoking  The risk for lung cancer in pipe smokers is similar to that in cigar smokers  Cig.& pip smok. have a relative risk of lung cancer of 2.1 to 5.1 compared to nonsmokers
  32. 32. Etiology of bronchogenic carcinoma  Other Types of Smoking  3-smoking marijuana and cocaine  The effects of them have not been extensively studied, and an association has not been fully established between such inhalant drug use and lung cancer
  33. 33. Etiology of bronchogenic carcinoma  Never Smokers < 100 cigarate  An estimated 15% of lung cancers in men and up to 53% in women worldwide occur in never smokers
  34. 34. Etiliogy . clinical and Molecular Characteristics of Lung Cancer in Smokers and Never Smokers N.SmokerSmoker Younger than 60Older than 60Age Usually femaleUsually maleGender East asiancaucasianEthnicity Aden.caALLHistolo.Sub. Tp EGFR,EML4-ALKKRAS,PIK3CA,RP,P53Asso.mutation/alteration
  35. 35. Etiology of bronchogenic carcinoma synergestic effect smok. smoking
  36. 36. Etiology of bronchogenic carcinoma  lung Scars Any granulomatouse disease in lung Fibrosis scleroderma Asbestosis
  37. 37. Etiliogy …..  Genetic Factors  Familial aggregation of cases has also been documented.  In a case control study conducted at the author’s institute, patients with lung cancer were more likely than controls to have relatives with cancers
  38. 38. Etiliogy …..  Genetic Factors  Cassidy et al.  also highlighted a significantly increased risk for lung cancer specifically for persons with a family history of early-onset lung cancer(<60 years of age)
  39. 39. Etiliogy …..  Gender  In the late 1980s, lung cancer surpassed breast cancer as the leading cause of cancer death in women  Since 1950 there has been a more than 600% increase in the lung cancer mortality rate in women.  lung cancer in never smoking women is more common than in never smoking men
  40. 40. Etiliogy …..  Gender  The gender differences in susceptibility may be related to differences in nicotine metabolism and in metabolic activation or detoxification of lung carcinogens;  women have higher levels of DNA adducts than men, which may result in greater susceptibility to carcinogens.
  41. 41. Etiliogy …..  Gender  Hormonal factors may also play a role in susceptibility.  A case-control study showed that estrogen replacement therapy was significantly associated with an increased risk for adenocarcinoma(odds ratio 1.7), and the combination of cigarette smoking and estrogen replacement increased that risk substantially (odds ratio 32.4)  Conversely, early menopause (age 40 years or younger) was associated with a decreased risk for adenocarcinoma
  42. 42. Etiliogy …..  Race and ethnicity  the incidence of lung cancer is substantially higher among blacks  and lower among Japanese Americans and Hispanics than among whites in the United States  These differences initially have been attributed to the variations in cigarette smoking pattern  The explanation for these racial or ethnic variations in risk for lung cancer is not known.  Black Americans also have higher mortality rates from lung cancer than white Americans
  43. 43. Etiliogy …..  Age  Although smoking prevalence is lowest among persons aged 65 years and older (9.3%)  More than 65% of patients with lung cancer are older than 65 years  The mean age at the time of diagnosis is 71 years old
  44. 44. Etiliogy …..
  45. 45. Etiliogy …..  Diet and obesity  It has been suggested that diet is responsible for approximately 30%of all cancers.  For example, low serum concentrations of antioxidants,such as vitamins A, C, and E, have been associated with the development of lung cancer.  several large intervention trials have been conducted to examine the relationship. found that vitamin supplementation did not reduce lung cancer risk, and in some circumstances, actually increased the incidence of lung cancer. Therefore, the use of supplemental β-carotene and vitamin A is discouraged
  46. 46. Etiliogy …..  Other lung disease  COPD  Study (evaluated 602 patients with L.CA)  50% of them had prebronchodilator pulmonary function test results consistent with a diagnosis of COPD GOLD stage 2 and higher, independent of age, sex, and smoking history, with an odds ratio of 11.6  The prevalence of COPD in patients with newly diagnosed lung cancer was six fold greater than matched smokers  COPD,CRP & HIGH DOSE INHALED STEROID.
  47. 47. Etiliogy …..  Infection  Oncogenic viruses  HPV DNA has been detected in lung squamous cell carcinoma tissues.  (EBV) which is associated with Burkitt lymphoma and nasopharyngeal carcinoma, has been strongly associated with lymphoepithelioma like carcinoma (LELC), a rare form of lung cancer in Asian patients.  Chlamydia pneumoniae  Pulmonary tuberculosis  HIV. 
  48. 48. Electrical smoking  An electronic cigarette is a battery-operated device that emits doses of vaporized nicotine, or non- nicotine solutions, for the user to inhale.
  49. 49. Here are some key points about e-cigarettes.  E-cigarettes aim to resemble cigarettes, but without burning tobacco.  They are sold as aids to reduce or quit smoking, and some people find them helpful for this.  However, research shows that they may have a negative impact on health.  Health authorities are trying to tighten up regulations to discourage young people from using e-cigarettes.
  50. 50. Clinical pictures  Clinical features:  • Major complaints are  - Cough (50-75%),  - Weight loss (40%),  - Chest pain (40%),  - Dyspnea (20%) and  - Haemoptysis.
  51. 51. pulmonary  Cough 75% of SCC & SCLC Any new variant cough in smoker Ix  Haemoptysise which is coug.blood ,asphyxia  Its more in central lesion  Chest pain more in young ,usually dull ache pain.
  52. 52. pulmonary  Dyspnea .by itself not cause dysp.but indirectly by causing pneu.atelac.ple.effu.,pneum.&lym.spread  Hoarseness of voice/ LN involvment  Pleu.eff.may be serous,serosangeose and bloody Bloody .indicate MGNT effus. Benign may 2nd.pneumnities,atel,or lymphatic spre.
  53. 53. pulmonary  SVCO  (SVC) vulnerable to extrinsic compression .  The thin vessel wall coupled with low intravascular pressure and surr. LN  Ca bron. 46 to 75% of all cases of SVC
  54. 54.  Svco .  SVC obstruction may get complicated with jugular venous and cerebrovascular thrombosis Pulmonary facial edema prominent veins SCLC>NSCLC Stent Radiotherapy Chemothereapy
  55. 55.  Pancoats tumor thoracic outlet syndrome Horner syndrome Miosis Anhydrosis Ptosis MAP NSCLC
  56. 56. Paranewplastic
  57. 57.  A 62-y. man 6-week hx cough, hemoptysis, and SOB.  Prior to this, he reports feeling well except for some difficulty rising out of a chair.  Hx 50-pac-y,no PMHx & no medications.  O/E,vital N., SPo2 90%; BMI is 30.  CV and chest exam. are unremarkable.  Neur. Ex., symme. proxi. muscle weakness in UL&LL.  There is no LAP,CXR Rt hil.mass CT 8 CM hil.mass adjacent to the mediastinum with bulky bilateral mediastinal lymphadenopathy.
  58. 58. Which of the following is the most likely diagnosis? A Adenocarcinoma of the lung B Atypical bronchial carcinoid tumor C Small cell lung cancer D Squamous cell carcinoma of the lung
  59. 59. Which of the following is the most likely diagnosis? A Adenocarcinoma of the lung B Atypical bronchial carcinoid tumor C Small cell lung cancer D Squamous cell carcinoma of the lung
  60. 60.  Hypertrophic pulmonary osteoarthropathy (HPOA).  clubbing  This is a tender painful periostitis of the distal end of bones  arthralgia  X-rays reveal subperiosteal new bone formation.  SCC
  61. 61. Paranewplastic syndrome Hypercalcemia(SCC) ,PTHrP, cytokines,metas. poor progn. Usually indicate stage 3 or 4  SIADH (SCLC), hypo Na. cerebral edema, Patient suffer from anorexia ,nausea &vomiting usually seen after starting chemo.
  62. 62.  Cushing syndrome  Ectopic adrenocorticotrophic hormone secretion  SCLC
  63. 63. Paranewplastic syndrome
  64. 64. Paranewplastic syndrome Eatn lambort syndrome
  65. 65. Feature 2ndary to metastasis >AD
  66. 66. Diagnosis
  67. 67. Diagnosis The main aims of investigation are 1-to confirm the diagnosis, 2-establish the histological cell type 3-define the extent of the disease. IX 1-Ix to confirm disease 2-Ix to assess the stage 3-Ix to assess fitness for the treatment
  68. 68. Establishing a Diagnosis  For the lesions with  lower likelihood of malignancy, a tissue diagnosis can be pursued with sputum cytology or bronchoscopy if the lesion is located centrally  Transthoracic Needle Aspiration (TTNA) if the lesion is peripheral.
  69. 69.  literature, sensi. and spec. of sputum cytology were 66% and 99%, respectively  In the same study, sensitivity of FOB  central tumors 88%, compared with 69% for peripheral tumors.  Among the bronchoscopic techniques, endo. Biop. were associated with high.sen. (74%), brushings (59%) and washings (48%).
  70. 70.  peripheral lesions >2 cm, TTNA had a sensitivity of 62% as compared to 33% <2 cm  Comp. of TTNA  1-pneumothrax 27%  2-haemoptesis 5%  3-local bleeding 11%
  71. 71.  Pleu.effusion  The sensitivity of pleural fluid cytology is only 60%, which increases to 80% with three separate fluid specimens and therefore a minimum of three samples should be evaluated by an experienced cytologist  Pleural biopsy is > sensitive
  72. 72.  If the lesion is high.suspecious  The mentioned modalities are useful in confirming the diagnosis, the false-negative rate for all three has not been well defined, or remains too high to rule out the diagnosis effectively  Autofluorescence Bronchoscopy (AFB) and electromagnetic navigation.
  73. 73. Diagnosis imaging
  74. 74. IMMUNOHISTOCHEMISTRY 1-IHC may be used to verify neuroendcrine diferentiation within a tumor  neuron-specific enolase (NSE), CD56 or NCAM, synaptophysin, chromogranin, and Leu7.  2-in diferentiating primary from metastatic AD  thyroid transcription factor-1 ( TTF-1)
  75. 75. IMMUNOHISTOCHEMISTRY 3-in diferentiating different hist.type within lung AD +NAP,+TTF1 SCC - NAP,-TTF1 SCLC -NAP,+TTF1
  76. 76. Molecular biology terminology Onco-gene: “A gene that is a mutated (changed) form of a gene involved in normal cell growth” Tumor suppressor gene: “A type of gene that makes a protein called a tumor suppressor protein that helps control cell growth. Also called anti-oncogene”
  77. 77. MOLECULAR BIOLOGY  Several genetic alterations have been observed in lung cancer  The main molecular mechanisms observed in its pathogenesis include 1-abnormalities in growth-stimulatory signaling pathways, 2-abnormalities in tumor suppressor gene pathways, 3-evasion of apoptosis 4- epigenetic changes
  78. 78. KRAS Most common mutation: ~25% of all adenocarcinoma Exclusive to smoker Mutation has lack of therapeutic efficacy shorter survival No targeted therapy established so far Non-Small Cell Lung Cancer, NCCN Guidelines Version7.2015 https://sangakukan.jp/journal/journal_contents/2013/01/articles/-1301 02-1/1301-02- 1_tmlh.eiclrtea
  79. 79. EGFR Mutation cause receptor deregulation or over expression Overall frequencies in NSCLC = 10-15% Most common forms: Deletions in exon 19 and exon 21 [sensitizing EGFR mutation] Sensitive to small molecule tyrosine kinase inhibitor TKI Erlotinib, Gefitinib, Afatnibe Non-Small Cell Lung Cancer, NCCN Guidelines Version7.2015 Brambilla E. et al. Eur Respir J.2009;33(6):1485–1497 Erlotinib
  80. 80. EML4-ALK Estimates 2-7% of patients with NSCLC and common in young men (median: 52 years) Due to inversion in chromosome 2 that links EML4 to ALK cancer cell proliferation Does not occur concurrently with EGFR or KRAS Sensitive to TKI Crizotinib,ceritnib Non-Small Cell Lung Cancer, NCCN Guidelines Version7.2015
  81. 81.  Genetic mutation testing ,biomarker,moleculartesting  To perform it the sample is taken ----entire tumour is removed or part of it is collected biopsy  Genetic DNA is then removed from tum.sample and then tested for gen.mut.  10-14 test result avail.
  82. 82.  If no enough sample. For multiple mutation  Then it priorised based on 1-which mut.patient may have 2-mut. Most likely to be treatable with aproved target thearpy –e.g for NSCLC EGFR &ALK gen.muta.
  83. 83. Indica. for ALK &EGFR testing  1-stage 4 AD ,AD that has returned after initial Dx of stage1,2,3 LC  2-Patient with stage1,2,3 AD at the time of Dx  3-Dx.ing SCC & SCLC from specimen comes from small biopsy
  84. 84.  patient with CT thorax report :  "There is a mass arising from the left main bronchus, 1.5 cm from the carina and not directly involving the carina. It is causing almost complete obstruction of the left main bronchus, and is likely to represent a primary lung tumour.  There are several left hil. LN, the largest measuring 2 cm. The TNM staging is T3N1MX."
  85. 85.  What is the TNM staging A-T1N1MX B-T2N1MX C-T2N2MX D-T3N1MX E- T3N2MX
  86. 86.  What is the TNM staging A-T1N1MX B-T2N1MX C-T2N2MX D-T3N1MX E- T3N2MX
  87. 87. Using the above information what is the staging? A-IB B-IIB C-IIIA D-IIIB D-IV
  88. 88. Using the above information what is the staging? A-IB B-IIB C-IIIA D-IIIB D-IV
  89. 89. Screening and prevention  The surgeon general first exposed the link between smoking and lung cancer in a report that was released in 1964  Until a former smoker is past fifteen years smoke-free, they are considered to be at approximately the same risk factor as patients who are currently smoking
  90. 90. Screening and prevention
  91. 91. NCCN and USPSTF  The National Comprehensive Cancer Network (NCCN) is a collaboration of twenty-five highly regarded cancer centers  They routinely issue consensus-based clinical practice guidelines on how to most effectively diagnose and treat various forms of cancer  NCCN has recommended screening for high risk individuals but only recently has any momentum begun  The United States Preventative Services Task Force (USPSTF) helped move the fight forward in July 2013, endorsing low-dose CT screening for those at the highest risk of developing lung cancer
  92. 92. ELCAP  The Early Lung Cancer Action Program (ELCAP) is an organization formed in 1992, consisting of a group of physicians from Cornell University Medical Center and other specialists to establish research parameters to positively impact lung cancer detection  This design utilized both chest radiography and low-dose chest CT  Baseline scanning was established followed by repeat annual screening  This research forged the way for others to build upon  ELCAP was scrutinized for not randomizing the trial
  93. 93. Management
  94. 94.  treatment For Stage I and II NSCLC is Surgical resection  Operative MR patients rese. by thoracic or cardiothoracic than those removed by general surgeons  SR in patients who undergo resection in a facilities with a high surgical volume compared with those performing fewer than 70 procedures per year
  95. 95.  In patients with stage IA NSCLC, lobecotomy is superior to wedge resection with respect to rates of local recurrence
  96. 96.  In patients with co morbidities, compromised pulmonary reserve & small peripheral lesions limited resection,wedge resection, and segmentectomy (potentially by VATS) may be reasonable surgical option.  Pneumonectomy is reserved for patients with central tumors
  97. 97.  5-y SR 60–80% I NSCLC 40–50% II NSCLC  the therapeutic benefit of nodal dissection versus nodal sampling is contraversial  A pooled analysis of three trials involving patients with stages I to IIIA NSCLC demonstrated a superior 4-year survival in patients undergoing resection and a complete mediastinal lymph node dissection compared with lymph node sampling
  98. 98.  Radiation Therapy in Stages I and II NSCLC  No role for post operative radiation  I and II disease who either refuse or are not suitable candidates for surgery should be considered for radiation therapy with curative intent .  (SBRT ) Stereotactic body radiation therapy is new technique in tre.pulm.nodule (≤5 cm)
  99. 99.  studies, disease control rates are >90%, and 5- y. SR 60% SBRT  SR range from 13 to 39% in I or II NSCLC treated with external beam RT  Cryoablation .used to treat small (≤3 m) little data exist on long-term outcomes with this technique.
  100. 100. Chemotherapy in Stages I and II NSCLC  a landmark MA of cisplatin-based adjuvant chemotherapy trials in patients with resected stages I to IIIA NSCLC (the Lung Adjuvant Cisplatin Evaluation [LACE] Study) demonstrated a 5.4% improve. in 5-SR for ACT compared to surgery alone, SR benefit was seemingly confined to II or III  survival was worsened in IA with ACT  IB, there was a modest improvement in survival of questionable clinical significance.
  101. 101.  ACT was also detrimental in patients with poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status = 2)  data suggest ACT is best applied in patients with res. stage II or III NSCLC  There is no apparent role for ACT in patients with rese. stage IA or IB NSCLC  exception is the stage IB patient with a rese. lesion ≥4 cm
  102. 102.  If a decision is made to proceed with ACT,, treatment should be initiated 6–12 weeks after surgery, assuming the patient has fully recovered,  administered for no more than 4 cycles  cisplatin-based CTH is preferred treatment regimen  carboplatin can be substituted  Platinum plus vinorelbine is most commonly used
  103. 103. NACT  With the exception superior sulcus tumors, the role of NACT in stage I to III disease is not welldefined  However, a MA 15 randomized controlled trials involving more than 2300 patients with stage I to III NSCLC  suggested 5-year survival benefit (i e , ~5%) that is virtually identical to the survival benefit achieved with postoperative chemo therapy
  104. 104.  patients with resected NSCLC are at high risk recurrence, 18–24 months of surgery  Based on the timing of most recurrences, some guidelines recommend a C CT 6 months for the first 3 years after surgery, followed by yearly CT scans without contrast thereafter.
  105. 105. MANAGEMENT OF STAGE III NSCLC  Management patients usually requires a combined-modality  Many aspects of therapy patients with stage III NSCLC remain controversial, and the optimal treatment strategy has not been clearly defined
  106. 106. Role of the traditional treatment modalities in different stages of non-small cell lung cancer RadiotherapyChemotherapySurgeryStage* Yes (post-operative)Yes(adjuvant or neoadjuvant) YesIIIA (non- bulky) Yes (sequential or concurrent) YesNot routinelyIIIA (bulky) Yes (sequential or concurrent) YesNoIIIB (without pleural effusion) Only for palliationYesNoIIIB (with pleural effusion)and IV
  107. 107.  E.g patients with limited stage IIIA disease  where involved mediastinal lymph nodes can be completed resected, initial surgery followed by post operative CHT (with or without RT)  patients with Clinically evident bulky mediastinal LN, treatment is concurrent CRT , in some cases, the latter group patients may be candidates for surgery following CRT
  108. 108.  Superior Sulcus Tumors (Pancoast Tumors)  distinctive subset stage III disease  tumors should undergo the same staging procedures as all patients with stage II and III NSCLC  NAC or combined CRT followed by surgery is reserved for those without N2 involvement. This approach yields excellent survival out comes (>50% 5-year survival )
  109. 109.  Patients with N2 disease are less likely to benefit from surgery and can be managed with CRT alone  Patients presenting with metast. disease can be treated with RT (with or without CTH.) for symptom palliation
  110. 110. MANAGEMENT OF METASTATIC  NSCLC 40% IV disease  median SR (4–6 m ) and a 1-year survival 10% when managed with BSC alone  signif. Num. patients who 1st presented with early stage NSCLC will eventually relapse with distant disease  Patients who have recur.disease have a better prognosis than those presenting with meta. disease at the time diagnosis quality
  111. 111.  Standard medical management, the judicious use of pain medications, and use RT and CTH forms the cornerstone of mang.  CTH palliates symptoms, improves the life, and improves survival in patients with stage IV NSCLC, particularly in patients with good performance status.
  112. 112.  optimal CTH regimen for advanced NSCLC  majority randomized trials showed no major survival improvement with any one regimen versus another  An ongoing debate about duration of platinum-based CTH  large phase III randomized trials have failed to show benefit for increasing the duration of platinum-based doublet CTH beyond 4to6 cycle
  113. 113.  longer duration CTH has been associated with increased toxicities and impaired quality of life
  114. 114. Maintenance therapy following initial platinum based therapy  in a landmark randomized phase III trial, patients with  non SCC were found to have an improved survival when treated with cisplatin and pemetrexed  By contrast, patients with squamous  carcinoma had an improved survival when treated with cisplatin and gemcitabine
  115. 115. Target therapy  Targeted therapy is a class of drug, it stops the action of molecules that are key to the growth of cancer cells. so not like chemotherapy it affects cancer cells more than normal cells.
  116. 116. FDA approved specific targeted therapies Erlotinib: EGFR positive mutation Crizotinib: EML4-ALK positive mutation Bevacizumab*: if neither positive
  117. 117.  Bevacizumab, MC Ab against VEGF  improve response rate, progression-free survival, and overall survival in patients with advanced disease when combined with CTH  However, bevacizumab cannot be given to patients with SCC because their tendency to experience serious hemorrhagi efects
  118. 118.  currently carboplatin/paclitaxel and bevacizumab or carboplatin/pemetrexed and bevacizumab are appropriate regimens for first-line treatment for stage IV nonsquamus NSCLC patients
  119. 119. Erlotinib (Tarceva ®( Small molecule TKI used as: First-line: patient with EGFR mutation Second line: locally advanced/metastatic NSCLC after progression on at least one prior chemotherapy Dose: 150 mg by mouth daily until disease progression or unacceptable toxicity Drug-drug interaction: strong CYP3A4 (inducers/inhibitors); proton pump inhibitors
  120. 120. Side effects: Dermatologic: skin rash (49% to 85%; grade 3:  5% to 13%; grade 4: <1%; median onset: 8 days) Gastrointestinal: diarrhea (20% to 62%; grade 3: 2% to 6%; grade 4: <1%; median onset: 12 days) Respiratory: Cough (33% to 48%), dyspnea  (41% to 45%; grades 3/4: 8% to 28%
  121. 121. Dose Adjustments: Toxicity Discontinuation of therapy: Bullous, blister or exfoliative GI perforation Corneal perforation or severe ulceration Withhold and reinitiate with 50 mg dose reduction: Severe rash Dehydration due to diarrhea Acute or worsening ocular toxicities or keratitis
  122. 122. Landmark Trials Trial Study Design Patient Population Results OPTIMAL n =83 Multicenter, open-label, randomized, phase III. Oral erlotinib (150mg/d) vs. chemotherapy (GEM+CIS) Adults >18years with confirmed Stage IIIB or IV NSCLC+ EGFR positive mutation Median progression-free survival (PFS): 13.1months vs.4.6 months; p<0.0001. Grade3and4side effects were less in erlotinib group EURTAC n =174 Multicenter, multinational, open- label, randomized, phase III. Oral erlotinib (150 mg/d) vs. chemo (DTX+CIS) Adults >18years with confirmed Stage IIIB or IV NSCLC+ EGFR positive mutation Median PFS:9.7months vs.5.2 months; p<0.0001. Grade3&4hematologic toxicity was higher in chemo group (22%vs. none), whereas, erlotinib has higher rash (13%), and ↑ of LFTs (2%)
  123. 123. Crizotinib (Xalkori ®) Small molecule tyrosine kinase inhibitor of c-MET, ALK, or ROS 1 and indicated for: ALK-positive metastatic NSCLC Dose: 250 mg orally twice daily, continue treatment until disease progression or unacceptable toxicity Drug-drug interaction: strong CYP3A4 inhibitors/inducers Ingnateus SH. et al. Drug Design, Development and Therapy 2011:5471–485
  124. 124. Side effects: Cardiovascular: edema (28% to 39%), bradycardia (5% to 11%) Metabolic: hypophosphatemia (28%), hypokalemia (18%) Gastrointestinal: Diarrhea (43% to 60%), nausea (51% to 55%),  vomiting (40% to 47%) Hematologic: lymphocytopenia (51%; grades 3/4: 9% to 11%),  neutropenia (49%; grades 3/4: 5% to 12%) Hepatic: Increased serum ALT (13% to 76%; grades 3/4: 5% to17%), AST (9% to 61%; grades 3/4: 2% to 9%) Ophthalmic: Visual disturbance (55% to 62%; onset: <2 weeks)
  125. 125. Dose Adjustments: Toxicity Discontinuation of therapy: Pulmonary toxicity: Interstitial lung disease (any grade) Grade 4 hematologic toxicity despite lowest dose (250 mg once daily) QTc >500 msec or ≥60 msec change from baseline with life-threatening symptoms Erlotinib. Lexi-Drugs Multinational [Internet]. Accessed: June 062015
  126. 126. Dose reduction necessary, if patient develops grade 3 or 4 cardiac, hematologic, and hepatotoxicity Dose reduction scheme:  Step1: reduce dose to 200 mg orally twice daily; if not  tolerable  Step2: reduce to 250 mg once daily. If not tolerable  Step3: reduce to 250 mg once daily
  127. 127.  A randomized phase III trial in SCLC is underway To validate these data

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