Small Cell Carcinoma of Lung

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  • Small Cell Carcinoma of Lung

    1. 1. Management of Small Cell Carcinoma of Lung <ul><ul><li>Moderator: Dr R Kapoor </li></ul></ul><ul><ul><li>Department of Radiotherapy </li></ul></ul><ul><ul><li>PGIMER </li></ul></ul><ul><ul><li>Chandigarh </li></ul></ul>
    2. 2. Introduction <ul><li>Accounts for approximately 20 -15% of all lung cancers. </li></ul><ul><li>30,000 new cases occur in the United States each year. </li></ul><ul><li>Important Biological and Clinical differences from NSCLC. </li></ul><ul><li>Paradoxical combination of good response and high relapse !!! </li></ul>
    3. 3. Classification: WHO 1999 Source: Brambilla et al The new World Health Organization classification of lung tumours Eur Respir J 2001; 18:1059-1068 “ SCLC presents a proliferation of small cells ( <4 lymphocytes in diameter ) with unique and strict morphological features....” Primary epithelial lung cancers Small Cell (Oat Cell Type) Non Small Cell type <ul><li>Squamous Cell carcinomas </li></ul><ul><li>Adenocarcinomas </li></ul><ul><li>Adenosquamous Carcinomas </li></ul><ul><li>Large Cell Carcinoma </li></ul><ul><li>Carcinoma with pleomorphic or sarcomatoid elements </li></ul><ul><li>Carcinoid tumors </li></ul><ul><li>Carcinoma of salivary gland type </li></ul>
    4. 4. Relevant Anatomy <ul><li>Pair of air filled sacs supplied by dual vascular system. </li></ul><ul><li>The central location of these tumors allows easy access to the mediastinal contents. </li></ul>
    5. 5. Nodal Anatomy Data from Autopsy Series Kunz et al 1985
    6. 6. Nodal Drainage
    7. 7. Epidemiology <ul><li>Accounts for 10 -20% of all lung cancers in males. </li></ul><ul><li>10-30% in women. </li></ul><ul><li>In India accounts for ~ 15% of all lung cancers. </li></ul><ul><li>Commonly in a middle aged smoker (5 th - 6 th decade in India) </li></ul>
    8. 8. Cell of Origin <ul><li>Believed to of neuroendocrine origin </li></ul><ul><li>Differs from Atypical Carcinoid in: </li></ul><ul><ul><li>Higher mitotic rate </li></ul></ul><ul><ul><li>Fewer markers of neuroendocrine differentiation </li></ul></ul><ul><ul><li>Weak /no staining with markers: Synaptophysin and chromogranin </li></ul></ul><ul><li>SCLC occupies the most high grade portion of the spectrum with max metastatic potential </li></ul>Carcinoid Atypical Carcinoid SCLC
    9. 9. Etiology <ul><li>Incidence patterns mirror the change in smoking patterns in society </li></ul><ul><li>Lag period of 20 -50 yrs noted. </li></ul><ul><li>Cause of up to 90% of cases diagnosed. </li></ul><ul><li>Interaction with other environmental carcinogens possible e.g. Asbestos </li></ul>Data from Annual Report to the Nation on the Status of Cancer, 1973-1996, With a Special Section on Lung Cancer and Tobacco Smoking Wingo et al JNCI Journal of the National Cancer Institute 1999 91(8):675-690;
    10. 10. Clinical Features: Thoracic Disease Local Symptoms Cough Dyspnea Chest Pain Mediastinal Involvement Hoarseness Retrosternal Chest pain Vocal Cord Palsy Horner's Syndrome Superior Vena Caval Syndrome Hemoptysis Post obstructive Wheezing
    11. 11. Hemaotogenous Metastasis <ul><li>SCLC is characterized by it's propensity to spread systemically. </li></ul><ul><li>Usually hematogenous metastasis is the norm. </li></ul>
    12. 12. Clinical Features: Extrathoracic <ul><li>Brain Metastasis: </li></ul><ul><ul><li>Approximately 50% of SCLC patients develop brain metastases during the course of their disease. </li></ul></ul><ul><ul><li>Presentation varies: </li></ul></ul><ul><ul><ul><li>Discreet ICSOL(s) </li></ul></ul></ul><ul><ul><ul><li>Leptomeningeal infiltration </li></ul></ul></ul><ul><ul><li>Unlike other metastasis Brain mets are symptomatic in 90% at presentation </li></ul></ul>
    13. 13. Clinical Features: Extrathoracic <ul><li>Other Common sites of Metastasis: </li></ul><ul><ul><li>Bone : </li></ul></ul><ul><ul><ul><li>Commonly lytic lesions </li></ul></ul></ul><ul><ul><ul><li>Pain: Less as compared to lesions in NSCLC </li></ul></ul></ul><ul><ul><ul><li>No elevation in Serum ALP or Ca 2+ . </li></ul></ul></ul><ul><ul><li>Adrenals / Liver : </li></ul></ul><ul><ul><ul><li>Clinically asymptomatic mets. </li></ul></ul></ul><ul><ul><ul><li>However elevation in hepatic transaminases common. </li></ul></ul></ul><ul><ul><li>Lungs : </li></ul></ul><ul><ul><ul><li>Lymphangitis carcinomatosa: Cause of dyspnea </li></ul></ul></ul>
    14. 14. Paraneoplastic Syndromes Cancer Cachexia Endocrinological Syndromes Neurological Syndromes Musculoskeletal Syndromes Dermatological Syndromes Hematological and Vascular <ul><li>SIADH </li></ul><ul><li>Cushing Syndrome </li></ul><ul><li>Gynecomastia / Galactorrhea </li></ul><ul><li>Hyperthyroidism </li></ul><ul><li>Acromegaly </li></ul><ul><li>Eaton Lambert Syndrome </li></ul><ul><li>Cerebellar Degeneration </li></ul><ul><li>Opsoclonus-Myoclonus Syndrome </li></ul><ul><li>Cancer associated Retinopathy </li></ul><ul><li>Stiff Man Syndrome </li></ul><ul><li>Hypertrophic Pulm. Osteoarthopathy </li></ul><ul><li>Dermatomyositis </li></ul><ul><li>Polymyositis </li></ul><ul><li>Acanthosis Nigricans </li></ul><ul><li>Bazex disease </li></ul><ul><li>Erythema gyratum repens </li></ul><ul><li>Scleroderma </li></ul><ul><li>Anemia </li></ul><ul><li>ITP </li></ul><ul><li>Marantic Endocarditis </li></ul><ul><li>Trousseau's Syndrome </li></ul>
    15. 15. Tit-bits on some syndromes <ul><li>SCLC is the most common cause of SIADH. </li></ul><ul><ul><li>MC presents with Hyponatremia </li></ul></ul><ul><ul><li>Diagnostic triad of : </li></ul></ul><ul><ul><ul><li>Euvolemia </li></ul></ul></ul><ul><ul><ul><li>Hyperosmalar Urine </li></ul></ul></ul><ul><ul><ul><li>Hypoosmolar Blood </li></ul></ul></ul><ul><li>In patients with SCLC, approximately 5% develop Cushing's syndrome – MC malignancy associated with Cushing's Syndrome </li></ul><ul><li>Most lung neoplasms produce large amounts of ACTH precursors – SCLC convert these into active ACTH (ectopic)!! </li></ul>
    16. 16. Neurological Syndromes <ul><li>Overall SCLC is the most common cause. </li></ul><ul><li>Origin – Autoimmune? </li></ul><ul><ul><li>Antibodies to substances produced by tumors. </li></ul></ul><ul><li>Several Types of Auto antibodies characterized: </li></ul><ul><ul><li>Anti-HU (Sensory Neuropathy, Encephalomyelitis) </li></ul></ul><ul><ul><li>Anti-Yo (Cerebellar Degeneration) </li></ul></ul><ul><ul><li>Anti-Ri (Opsoclonus Myoclonus Syndrome) </li></ul></ul><ul><ul><li>Anti-VGCC (Lambert Eaton Syndrome) </li></ul></ul><ul><ul><li>Anti-Amphiphisin (Stiff Man Syndrome) </li></ul></ul>
    17. 17. Neurological Syndromes.. <ul><li>Lambert Eaton Syndrome: </li></ul><ul><ul><li>Proximal weakness associated with aches & stiffness. </li></ul></ul><ul><ul><li>Autonomic dysfunction – dry mouth </li></ul></ul><ul><ul><li>Ptosis and opthalmoplegia milder than MG. </li></ul></ul><ul><ul><li>LEMS is usually diagnosed prior to any clinical manifestation of the tumor (2-5 yrs lag period). </li></ul></ul><ul><ul><li>2 times commoner in males </li></ul></ul><ul><ul><li>MC in ages 50 - 70 yrs. </li></ul></ul>MG LEMS
    18. 18. Neurological Syndromes <ul><li>Paraneoplastic cerebellar degeneration: </li></ul><ul><ul><li>Abrupt onset of cerebellar symptoms </li></ul></ul><ul><ul><li>Loss of Purkinje cells. </li></ul></ul><ul><ul><li>Associated with encephalomyelitis </li></ul></ul><ul><li>Sensory neuropathy: </li></ul><ul><ul><li>Pseudo-obstruction of the bowel – best characterized sensory neuropathy </li></ul></ul><ul><ul><li>Usually associated with SCLC. </li></ul></ul>
    19. 19. Investigative Workup <ul><li>To establish diagnosis: </li></ul><ul><ul><li>FOB </li></ul></ul><ul><ul><li>FNAC </li></ul></ul><ul><li>To stage the disease: </li></ul><ul><ul><li>CXR </li></ul></ul><ul><ul><li>USG </li></ul></ul><ul><ul><li>CT </li></ul></ul><ul><ul><li>MRI /PET/Bone scan </li></ul></ul><ul><li>To assess suitability for treatment: </li></ul><ul><ul><li>Hemogram </li></ul></ul><ul><ul><li>Biochemistry : RFT </li></ul></ul>
    20. 20. Evolution of pathological classification
    21. 21. Gross Pathology <ul><li>MC perihilar location (2/3 rd ) (<5% peripheral) </li></ul><ul><li>Situated in a peribronchial location </li></ul><ul><li>Infiltration of the bronchial submucosa and peribronchial tissue </li></ul><ul><li>Bronchial obstruction : Due to circumferential bronchial compression . </li></ul>
    22. 22. Microscopic pathology <ul><li>Proliferation of small cell ( < 4 lymphocytes in diameter. </li></ul><ul><li>Finely granular &quot;salt and pepper&quot; chromatin </li></ul><ul><li>Frequent nuclear molding </li></ul><ul><li>High mitotic counts </li></ul><ul><li>Azzopardi effect : hemotoxyphilic DNA crusting of the vessel walls. </li></ul>
    23. 23. Combined SCLC <ul><li>Defined when at least 10% of the tumor bulk is made of an associated non-small cell component. </li></ul><ul><li>Any cases showing at least 10% of SCLC is also diagnosed as SCLC combined, even if the tumor has a heterogeneous sarcomatous component </li></ul><ul><li>Therapeutic significance ??! Possible better prognosis of the combined variant as per recent literature. </li></ul><ul><li>Previous categories of mixed SCLC and intermediate SCLC have been dropped as they were difficult to identify and had little prognostic significance. </li></ul>
    24. 24. Chest X rays Pleural Effusion Phrenic Nerve palsy Mass Collapse
    25. 25. Radiology Miller WE: Roentgenographic manifestations of lung cancer. In Strauss MJ (ed): Lung Cancer: Clinical Diagnosis and Treatments, 2nd ed. New York, Grune and Stratton, 1983.
    26. 26. CT scan Mass Pleural Effusion Node Necrosis Mediastinal Shift
    27. 27. Staging <ul><li>The VALSG (Veterans' Administration Lung Study Group) is the most commonly used system </li></ul><ul><li>Devised by Zelen M in 1973 </li></ul><ul><li>Depends on the ABILITY to safely encompass the entire tumor in a single Radiation portal. </li></ul><ul><li>Untreated LD patients (median sur v i v al: 15.7 weeks) sur v i v ed significantly longer than ED patients (5.0 weeks). </li></ul>
    28. 28. VALSG Definition <ul><li>Limited disease patients are characterized by </li></ul><ul><li>Disease confined to one hemithorax, although local extensions may be present; </li></ul><ul><li>No extrathoracic metastases except for possible ipsilateral, supraclavicular nodes if they can be included in the same portal as the primary tumor; and </li></ul><ul><li>Primary tumor and regional nodes which can be adequately treated and totally encompassed in every portal. </li></ul><ul><li>Extensive disease patients are inoperable patients who cannot be classified as having limited disease. </li></ul>
    29. 29. VALSG vs ISALC : LD
    30. 30. Controversies in Staging <ul><li>VALSG staging system devised in the pre-CCT era. </li></ul><ul><li>With the advent of modern imaging techniques reliance on surgical staging of mediastinum probably not necessary </li></ul><ul><li>Certain factors fail to predict a poor prognosis with modern therapy: </li></ul><ul><ul><li>Ipsilateral Pleural effusion </li></ul></ul><ul><ul><li>Mediastinal adenopathy </li></ul></ul><ul><ul><li>Contralateral Supraclavicular adenopathy </li></ul></ul>
    31. 31. Prognostic Factors <ul><li>Performance status (ECOG 3 or 4) </li></ul><ul><li>Older age (> 65 years) </li></ul><ul><li>Metastatic sites: Liver, Bone marrow and bone </li></ul><ul><li>Cushing's Syndrome </li></ul><ul><li>Continued tobacco use during therapy </li></ul><ul><li>Increased pretreatment LDH (> 2 times increase) </li></ul><ul><li>CNS paraneoplastic syndromes (anti-HU antibody) </li></ul><ul><li>High VEGF/ bcl-2 / p -glycoprotein (MDR) expression </li></ul>
    32. 32. Management of SCLC
    33. 33. Treatment Outline SCLC Stage Localized Disease Extensive Disease Radiation Therapy (Curative intent ?) + Systemic Combination Chemotherapy Systemic Combination Chemotherapy + Palliative Radiation + Palliative Care and Support
    34. 34. Radiation Sensitivity Source: Radiation Biology of Lung Cancer; Sullivan et al JCB supp24
    35. 35. Radiation Biology <ul><li>Low D 0 & SF 2Gy values imply the high radiosensitivity </li></ul><ul><li>n (extrapolation number) is also low – Implies that the capacity to repair sublethal damage is limited </li></ul><ul><li>Low dose per fraction radiation schedules have potential here. </li></ul><ul><li>However due to the propensity of disseminated disease sensitivity ≠ curability </li></ul>
    36. 36. Role of Radiation therapy <ul><li>Curative : </li></ul><ul><ul><li>With Chemotherapy in localized SCLC </li></ul></ul><ul><li>Palliative : </li></ul><ul><ul><li>For palliation of symptoms due to primary growth </li></ul></ul><ul><ul><li>In SVCO </li></ul></ul><ul><ul><li>For palliation of bone mets </li></ul></ul><ul><ul><li>For palliation of brain mets </li></ul></ul><ul><li>Preventive : </li></ul><ul><ul><li>For prophylactic cranial irradiation </li></ul></ul>
    37. 37. Dose Time Fractionation <ul><li>Principle: </li></ul><ul><ul><li>Alleviate the symptoms arising due to the tumor quickly. </li></ul></ul><ul><ul><li>Integrated with Chemotherapy with minimal delay </li></ul></ul><ul><ul><li>Intent of treatment decides the TDF issues </li></ul></ul><ul><ul><ul><li>In patient with LD, good PFS and good response to CCT </li></ul></ul></ul><ul><ul><ul><ul><li>30 Gy in 10# with PCI </li></ul></ul></ul></ul><ul><ul><ul><li>In patient with ED or LD with poor response: </li></ul></ul></ul><ul><ul><ul><ul><li>Poor PFS: 600 - 800 cGy in SF </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Good PFS: 20 Gy in 5 # </li></ul></ul></ul></ul>
    38. 38. Planning RT for Localized SCLC <ul><li>Principles: </li></ul><ul><ul><li>Adequate coverage of the 1 ° tumor : 1.5 – 2 cm </li></ul></ul><ul><ul><li>Adequate margins to account for respiratory motion </li></ul></ul><ul><ul><li>Adequate coverage of draining nodes (1 st echelon) : 1 cm </li></ul></ul><ul><ul><li>Ensuring volume irradiated doesn't receive doses exceeding tolerance. </li></ul></ul><ul><li>Dose: </li></ul><ul><ul><li>30 Gy/10 # in 2 weeks preferred in our institution </li></ul></ul><ul><ul><li>Energy : Co 60 or 4-6 MV photons </li></ul></ul>
    39. 39. Palliative Radiotherapy <ul><li>Principles: </li></ul><ul><ul><li>Use high dose per fraction to achieve greatest cell kill in shortest possible time. </li></ul></ul><ul><ul><li>Use smaller number of fractions to reduce burden on facility, patient and relatives. </li></ul></ul><ul><ul><li>Use simple AP – PA portal for quick, accurate and comfortable setup </li></ul></ul><ul><ul><li>Further boost RT can be tailored individually depending upon the patients response and performance status. </li></ul></ul><ul><li>Dose schedules: </li></ul><ul><ul><li>30 Gy in 10# </li></ul></ul><ul><ul><li>20 Gy in 5# </li></ul></ul><ul><ul><li>800 cGy in 1 # </li></ul></ul>
    40. 40. Manual Marking <ul><li>Upper lobe tumors: </li></ul><ul><ul><li>Superior border is kept at the SSN </li></ul></ul><ul><ul><li>Medial border extends 3 cm across the midline on the opposite side </li></ul></ul><ul><ul><li>A field of 12 x 12 is usually used. </li></ul></ul><ul><li>Lower lobe tumors: </li></ul><ul><ul><li>Superior border is kept at the level of the nipple. </li></ul></ul><ul><li>Supraclavicular field: </li></ul><ul><ul><li>A separate supraclavicular field can be placed with a gap of 0.5 cm </li></ul></ul>
    41. 41. Guidelines for RT planning <ul><li>Upper lobe tumors: </li></ul><ul><ul><li>Ipsilateral SCF should be treated </li></ul></ul><ul><ul><li>Inferior margins kept 5-6 cm below the carina </li></ul></ul><ul><ul><li>Mediastinum should be taken into the field with 1 cm margins </li></ul></ul><ul><ul><li>A margin of 2 cm given around the primary tumor </li></ul></ul><ul><li>Lower lobe tumors: </li></ul><ul><ul><li>Lower border should encompass the lower border of mediastinum down to the level of the diaphragm </li></ul></ul><ul><ul><li>Gross mediastinal adenopathy is taken into the field but SCF can be avoided </li></ul></ul>
    42. 42. Portal arrangements Upper Lobe Middle Lobe Lower lobe
    43. 43. Critical organs and doses
    44. 44. Results of Thoracic RT <ul><li>Landmark trial by the MRC in UK(Miller et al 1969): </li></ul><ul><ul><li>144 patients selected fit for radical Sx or RT </li></ul></ul><ul><ul><li>Mean survival was 23.5 weeks for Sx and 43 weeks for RT (p = 0.03) </li></ul></ul><ul><ul><li>5 yr survival 1% in the Sx group and 5% in the radiation alone group </li></ul></ul><ul><ul><li>Sole survivor in the Sx arm had received RT. </li></ul></ul>
    45. 45. Results
    46. 46. Effect of palliative RT
    47. 47. Changing Paradigms of R x Paradigm 1 : Surgery as Standard Treatment Paradigm 2 : Thoracic radiation better than Surgery Paradigm 3 : Thoracic Irradiation with adjuvant Chemotherapy Paradigm 4 : Combination chemotherapy with adjuvant Radiotherapy Paradigm 5 : Integrated Chemotherapy and Radiation therapy
    48. 48. RT results 2 yr survival 2 yr local control
    49. 49. Is TRT needed? <ul><li>Warde et al (JCO, 1992): </li></ul><ul><ul><li>11 RCTs (published) included </li></ul></ul><ul><ul><li>Total patients 1911 </li></ul></ul><ul><ul><li>Looked at 2 yr survival, local control and toxicity </li></ul></ul><ul><ul><li>Found that: </li></ul></ul><ul><ul><ul><li>Overall benefit of adjuvant RT on OS is 5% </li></ul></ul></ul><ul><ul><ul><li>LC rate improved by 25.3% </li></ul></ul></ul><ul><ul><ul><li>1.2% increased chance of death due to Rx related toxicities </li></ul></ul></ul>
    50. 50. Is TRT needed <ul><li>Pignon metanalysis (NEJM , 1992): </li></ul><ul><ul><li>Used updated patient data from investigators </li></ul></ul><ul><ul><li>Based on 2140 patients </li></ul></ul><ul><ul><li>Assessed 3 yr survival rates and prognostic factors for survival </li></ul></ul><ul><ul><ul><li>14% reduction in the mortality rates at 3 yrs </li></ul></ul></ul><ul><ul><ul><li>Absolute benefit in OS of 5.4% </li></ul></ul></ul><ul><ul><ul><li>Twice as better local control (48% vs 23%) </li></ul></ul></ul><ul><ul><ul><li>Survival difference greater for patients aged < 50 yrs. </li></ul></ul></ul>
    51. 51. Is TRT needed <ul><li>Both meta-analysis have conclusively proved: </li></ul><ul><ul><li>Addition of thoracic RT improves the OS by approximately 5% </li></ul></ul><ul><ul><li>Reduces the risk of intrathoracic failures by 30% - 60%. </li></ul></ul><ul><li>In addition both meta-analyses used trials prior to the CE era so a more effective therapy has not been evaluated. </li></ul><ul><li>The increased incidence of toxicity related deaths is significantly reduced with modern Rx. </li></ul>Conclusion : Addition Thoracic Radiation is definitely indicated in Limited Stage SCLC both to improve LC and OS
    52. 52. ?? Controversies ?? <ul><li>Ideal treatment volume? </li></ul><ul><li>TDF issues </li></ul><ul><li>Sequencing with CCT </li></ul><ul><li>Role of PCI </li></ul>
    53. 53. Ideal Volume
    54. 54. Deciding the treatment volume <ul><li>Controversies </li></ul><ul><ul><li>How much of mediastinal / hilar nodes to be taken ? </li></ul></ul><ul><ul><li>Whether supraclavicular nodes are to included? </li></ul></ul><ul><ul><li>Whether volume of irradiation is to pre-CCT volume or post CCT volume? </li></ul></ul><ul><ul><li>Optimum portal design? </li></ul></ul>
    55. 55. Intrathoracic Volume Incorporation <ul><li>Perez et al : Reported on results of SECSG on treatment of SCLC using thoracic RT (1981) </li></ul><ul><ul><li>69% of patients treated with inadequate portals had intra thoracic failures (w.r.t. 32.5% treated with adequate portals) </li></ul></ul><ul><ul><li>Inadequate portals -> failure to include contralateral hilum or mediastinum </li></ul></ul>Conclusion : Failure to include opposite mediastinal and hilar nodes in the treatment volume can lead to significant intrathoracic failures Data from While J et al Impact of Radiation therapy quality control in LC in SCLC
    56. 56. Post CCT or Pre CCT volume? 21/5/1977 6/7/1977 26/8/1977 11/10/1977 26/10/1977
    57. 57. Pre CCT vs Post CCT volume <ul><li>Patients treated to the post-CCT tumor volume have equivalent survival </li></ul><ul><ul><li>51 weeks survival with pre CCT vol w.r.t. 46 weeks survival with post CCT vol (SWOG study ; Kies et al JCO 1987) </li></ul></ul><ul><li>Patients treated to pre CCT volumen will have same local control rates </li></ul><ul><ul><li>More than 80% of local failures were within the post CCT irradiated volume (Brodin et al Acta Oncologica 1990) </li></ul></ul><ul><li>Patients treated to the pre-CCT volume can have significant pulmonary toxicity if they survive </li></ul><ul><ul><li>Double incidence of pnuemonitis and leucopenia in patients treated to pre-CCT volumes. (SWOG study ; Kies et al JCO 1987) </li></ul></ul><ul><li>Some studies have found a lower CR rate in patients treated to pre CCT volume (? artifact) </li></ul>Conclusion : It is safe to irradiate only the post CCT volume.
    58. 58. Portal Design <ul><li>Simple AP – PA fileds are gold standard for irradiation of SCLC </li></ul><ul><li>Customizing fields not usual as: </li></ul><ul><ul><li>Most of the tumors are situated centrally so majority of peripheral lung parenchyma can be avoided. </li></ul></ul><ul><ul><li>Customizing field apertures may result in tumor miss </li></ul></ul><ul><ul><ul><li>Majority of major protocol violations in the study by white et al were due to inappropiate shielding </li></ul></ul></ul><ul><ul><ul><li>Difficulty in compensating for complex respiratory motion </li></ul></ul></ul><ul><ul><li>Customization probably too time consuming an effort for patients who are unlikely to be cured </li></ul></ul>Conclusion : Customized portal designing is unlikely to add to control
    59. 59. Time, Dose & Fractionation
    60. 60. Dose and Fractionation of Radiation <ul><li>Dose, time and fractionation choice depend upon: </li></ul><ul><ul><li>Tumor size and bulk </li></ul></ul><ul><ul><li>Nature of symptoms </li></ul></ul><ul><ul><li>Severity of symptoms </li></ul></ul><ul><ul><li>Patient performance status </li></ul></ul><ul><ul><li>Expected survival </li></ul></ul><ul><ul><li>Possibility of complications </li></ul></ul><ul><ul><li>Logistical factors </li></ul></ul><ul><ul><li>Patient supportive care available </li></ul></ul>
    61. 61. Dose of Radiotherapy <ul><li>NCI reported a clear dose response: </li></ul><ul><ul><li>25 Gy in 10 # </li></ul></ul><ul><ul><li>37.5 Gy in 15 # </li></ul></ul><ul><ul><li>Higher dose associated with a significant gain in PFS </li></ul></ul><ul><li>Arrigada et al did a trial on LD with 3 dose schedules given by split course: </li></ul><ul><ul><ul><li>45 Gy: 5 yr survival 16% </li></ul></ul></ul><ul><ul><ul><li>55 Gy: 5 yr survival 16% </li></ul></ul></ul><ul><ul><ul><li>65 Gy: 5 yr survival 20% (p = N.S.) </li></ul></ul></ul>
    62. 62. Altered Fractionation Conclusion : Altered fractionation with split course is not effective
    63. 63. Continuous AF schemes Conclusion : Sadly Continuous AF is too toxic for routine use !!!
    64. 64. Sequencing with CCT
    65. 65. Sequencing with CCT <ul><li>Several techniques of sequencing possible: </li></ul><ul><ul><li>Concurrent </li></ul></ul><ul><ul><li>Sequential </li></ul></ul><ul><ul><li>Alternating </li></ul></ul><ul><li>Controversies that exist are: </li></ul><ul><ul><li>Is concurrent better than the other models </li></ul></ul><ul><ul><li>What is the ideal time of giving RT with CCT </li></ul></ul>
    66. 66. CRT protocols <ul><li>Concurrent: </li></ul><ul><ul><li>Radiation is started along with 1 st CCT cycle typically between the D1 or D2 of CCT. </li></ul></ul><ul><ul><li>CCT administered as scheduled. </li></ul></ul><ul><ul><li>Weekly chemoradiation is not used as full therapeutic doses of CCT need to be delivered. </li></ul></ul><ul><li>Sequential: </li></ul><ul><ul><li>RT is administered after completion of 3 -4 cycles of chemotherapy. CCT is not delivered during RT </li></ul></ul><ul><ul><li>Additional cycles of CCT may be given after RT </li></ul></ul><ul><li>Alternating: </li></ul><ul><ul><li>RT is usually given in a split course and CCT is administered between the treatment breaks. </li></ul></ul>
    67. 67. Concurrent vs Sequential CCT <ul><li>Generally accepted that concurrent chemoradiation is better than sequential chemoradiation. </li></ul><ul><li>Takada et al (2002): JCOG </li></ul><ul><ul><li>Used CE </li></ul></ul><ul><ul><li>RT dose 45 Gy in 30# @ 1.5 Gy per fraction bid over 3 weeks </li></ul></ul><ul><ul><li>Median survival improved from 19 months to 27 months </li></ul></ul>
    68. 68. Why not Concurrent CRT? <ul><li>Controversy still exists about relative superiority of CCRT </li></ul><ul><li>Impairment in delivery of both modalities a frequent problem </li></ul><ul><li>Most of patients will present with ED </li></ul><ul><li>Even patients with LD will have: </li></ul><ul><ul><li>Poor performance scores </li></ul></ul><ul><ul><li>Bulky disease </li></ul></ul><ul><ul><li>Poor pulmonary functions </li></ul></ul><ul><ul><li>Several co-morbidities </li></ul></ul><ul><ul><li>Incompliance with an aggressive regimen </li></ul></ul><ul><li>CCRT has a high in treatment mortality ( 7 -10%) in various series </li></ul>
    69. 69. Alternating Chemoradiation <ul><li>Popularized in the 1980s due to the toxicity of then available CCT agents precluding concomitant / sequential approach </li></ul><ul><li>Largest trial by Gregor et al (ECOG/LCCG)1997 (n = 349) </li></ul><ul><li>Poor local control and severe acute hematotoxicity in the study arm </li></ul><ul><li>Most patients failed within the portal </li></ul>Conclusion : Alternate CRT is inferior to sequential CRT
    70. 70. Early vs Late Thoracic RT <ul><li>Early better : </li></ul><ul><ul><li>Reduce chances of systemic metastasis </li></ul></ul><ul><ul><li>Reduce chances of appearance of chemoresistant clones </li></ul></ul><ul><ul><li>Lower probability of radioresistance </li></ul></ul><ul><ul><li>Diminished accelerated repopulation </li></ul></ul><ul><li>Late Better : </li></ul><ul><ul><li>Allows shrinkage of portals to a reduced tumor volume </li></ul></ul><ul><ul><li>Reversible resistance (Kinetic and epigenetic resistance.) </li></ul></ul>
    71. 71. Timing of RT
    72. 72. Timing of RT <ul><li>Two meta-analyses have also been published on this topic : </li></ul><ul><ul><li>Fried et al : </li></ul></ul><ul><ul><ul><li>Defined late RT as after 9 weeks after starting CCT </li></ul></ul></ul><ul><ul><ul><li>OS benefit of 5% at 2 yrs with early RT (p = 0.03) </li></ul></ul></ul><ul><ul><ul><li>Benefit with the use of Platinum based regimens only and with the use of hyperfractionated regimens </li></ul></ul></ul><ul><ul><li>Cochrane review : </li></ul></ul><ul><ul><ul><li>Early RT defined as that started within 30 days of CCT </li></ul></ul></ul><ul><ul><ul><li>No significant benefit at 2 or 3 yrs with the use of early or late CCT </li></ul></ul></ul><ul><ul><ul><li>But found a significant advantage in 5 yrs survival with the use of early thoracic radiotherapy with the use of cisplatin based CCT ; OR of 0.62 (p = 0.02) </li></ul></ul></ul>
    73. 73. Timing of RT Conclusion : Early Start of RT does lead to a better outcome
    74. 74. Role of PCI
    75. 75. Role of PCI <ul><li>Dr Heine Hansen suggested possible role of PCI in 1973 extrapolating experience from Leukemias </li></ul><ul><li>Role believed to exist as: </li></ul><ul><ul><li>SCLC has aggressive behavior like leukemia </li></ul></ul><ul><ul><li>It is very chemosensitive </li></ul></ul><ul><ul><li>Development of new CCT regimens in 70's lead to increased expectations of cure </li></ul></ul><ul><ul><li>Development of brain mets was thought to be the most important cause of failures if chemotherapy was to be successful. </li></ul></ul><ul><ul><li>BBB was expected to be a impediment for disease eradication from the CNS (sanctuary) </li></ul></ul>
    76. 76. Benefit from PCI <ul><li>In order for PCI to be integrated with the regimen it should fulfill certain basic requirements: </li></ul><ul><ul><li>Solitary CNS relapse should be a significant clinical problem </li></ul></ul><ul><ul><li>Systemic control should be maintained for a prolonged period of time </li></ul></ul><ul><ul><li>Side effects from PCI should not overcome any survival benefit </li></ul></ul><ul><ul><li>PCI should be effective in eliminating sub clinical metastatic disease in the CNS </li></ul></ul><ul><ul><li>Demonstrable survival benefit should be present </li></ul></ul>
    77. 77. Meta-analysis <ul><li>A meta-analysis was published in BMC by Meert et al (2001) </li></ul><ul><li>12 trials included; 1547 patients </li></ul><ul><ul><li>5 trials evaluated the role of PCI in patients who had attained CR </li></ul></ul><ul><ul><li>5 trials included only LD stages </li></ul></ul>
    78. 78. Toxicity of PCI <ul><li>Long term neurological toxicity difficult to evaluate </li></ul><ul><li>Jhosnson et al reported on 20 patients with median F/U of 6 yrs </li></ul><ul><ul><li>15 of 20 patients had some neurological complaints and abanormalities </li></ul></ul><ul><li>Another study by Laukkanen et al reported memory loss in 60% of long term survivors of SCLC who had received PCI </li></ul>
    79. 79. Practice Guidelines <ul><li>PCI should be given in: </li></ul><ul><ul><li>Patients with LD stage with radiological CR </li></ul></ul><ul><ul><li>Documented absence of brain mets ( pre PCI CT) </li></ul></ul><ul><ul><li>Good performance status to merit further treatment </li></ul></ul><ul><li>Dose of PCI: </li></ul><ul><ul><li>20 - 24 Gy in 10 – 12 # is the recommended dose schedule </li></ul></ul><ul><li>Timing: </li></ul><ul><ul><li>Should be administered 2-3 weeks after completion of chemotherapy </li></ul></ul><ul><li>How given: </li></ul><ul><ul><li>Parallel opposing fields with energy of 4-6 MV / Co 60 </li></ul></ul>
    80. 80. Summary <ul><li>Ideal RT volume: </li></ul><ul><ul><li>Incorporate B/L mediastinal nodes </li></ul></ul><ul><ul><li>Post CCT volume can be irradiated safely </li></ul></ul><ul><ul><li>Extensive portal customizations can backfire </li></ul></ul><ul><li>TDF issues: </li></ul><ul><ul><li>Conventional once daily RT is of choice </li></ul></ul><ul><li>Integration with CCT: </li></ul><ul><ul><li>Early start of RT is better </li></ul></ul><ul><ul><li>Concomitant CRT is more effective but also highly toxic </li></ul></ul><ul><li>Role of PCI: </li></ul><ul><ul><li>Can improve survival in small subgroup of patients </li></ul></ul>
    81. 81. Chemotherapy
    82. 82. Chemotherapy <ul><li>The chemosensitivity of SCLC was first identified 50 years ago with the recognition that CCNU could effect tumor regression in 50% patients </li></ul><ul><li>Several agents have single agent activity </li></ul><ul><li>However: </li></ul><ul><ul><li>Complete remissions are relatively infrequent </li></ul></ul><ul><ul><li>Remission durations tend to be brief </li></ul></ul><ul><ul><li>Combination therapy is known to produce superior survival** </li></ul></ul>
    83. 83. Single Agent Chemotherapy
    84. 84. Standard CCT regimens
    85. 85. Cisplatin based CCT <ul><li>CE is considered standard regimen. </li></ul><ul><li>CR rates </li></ul><ul><ul><li>20-45% in LD </li></ul></ul><ul><ul><li>10-25% in ED </li></ul></ul><ul><ul><li>ORR 60- 70% </li></ul></ul><ul><ul><li>Median survival 10 – 12 months </li></ul></ul><ul><li>Carboplatin is equivalent in therapeutic efficacy as shown by a HCOG study (Median survival 11.8 months with ORR of 70 -80%) </li></ul>
    86. 86. Alternative CCT regimens <ul><li>Single agent Topotecan: </li></ul><ul><ul><li>One phase III trial reported by Shiller et al compared Topotecan to CAV (n = 188) </li></ul></ul><ul><ul><li>Same ORR (21% & 15%) and survival (5.8 & 5.5 mo) </li></ul></ul><ul><ul><li>Better symptom control – however greater hematological toxicity </li></ul></ul><ul><li>However it has also been shown in a RCT by same author that 4 cycles of Topotecan after 4 cycles of PE is not superior to observation. </li></ul>Conclusion : Single agent Topotecan fails to improve results over those obtained by PE regimen in SCLC when used as 1 st line approach
    87. 87. Alternative Chemotherapy
    88. 88. Combination CCT <ul><li>Active regimens yield objective response rates in the range of 80% to 90% </li></ul><ul><li>Complete remissions occurring in 30 to 50% of patients </li></ul><ul><li>Median survival: </li></ul><ul><ul><li>7 to 9 months in extensive-stage patients (3 yr OS ~ 1%) </li></ul></ul><ul><ul><li>20 months in patients with limited disease.(3 yr OS ~ 20%) </li></ul></ul><ul><li>Best survival is achieved in good performance status patients who present with limited-stage disease and who receive combined modality therapy with chemotherapy plus thoracic radiotherapy . </li></ul>
    89. 89. Toxicity of CCT <ul><li>Most common complication is severe myelosuppression, which occurs in 25% to 30% </li></ul><ul><ul><li>Rates increased to 75% with CRT </li></ul></ul><ul><ul><li>Cyclophosphamide-based therapy associated with the highest incidence of neutropenia </li></ul></ul><ul><ul><li>Cisplatin plus etoposide generally represents the least myelosuppressive regimen </li></ul></ul><ul><li>Late complications (heard of but not seen!!) </li></ul><ul><ul><li>Pulmonary fibrosis </li></ul></ul><ul><ul><li>Cardiac toxicity </li></ul></ul>
    90. 90. More intensive CCT <ul><li>The concept of MDTI is analogous to that of TCP/NTCP </li></ul><ul><li>It defines the maximum tolerated dose intensity </li></ul><ul><li>dose intensity refers to dose in mg/m 2 /week </li></ul><ul><li>The plateauing of the curve is important </li></ul>
    91. 91. Alternative Strategies <ul><li>Dose intensification </li></ul><ul><li>Weekly Chemotherapy </li></ul><ul><li>Alternating Chemotherapy </li></ul>
    92. 92. Dose intensification Conclusion : Dose intensification by 25 – 50% over the standard doses fails to improve the survival but increases toxicity significantly
    93. 93. Weekly Chemotherapy Conclusion : Dose intensification by giving weekly CCT fails to improve the survival but increases toxicity significantly
    94. 94. Alternating CCT <ul><li>3 major trials have appeared: </li></ul><ul><ul><li>Fukuoka et al (JNCI 1991) </li></ul></ul><ul><ul><li>Roth et al -SECSG (JCO 1992) </li></ul></ul><ul><ul><li>Evans et al – NCI (AIM 1987) </li></ul></ul><ul><li>All the 3 trials failed to show any significant advantage of alternate CAV/EP vs EP alone but did show that CAV alone was inferior. (OS with CAV/EP 16.8 mo, EP alone 11.6 mo and CAV 8.0 mo) </li></ul>Conclusion : Alternating non cross resistant CCT regimens failed to improve results as compared to standard regimens
    95. 95. Chemotherapy for recurrence <ul><li>Selected patients may be treated provided: </li></ul><ul><ul><li>Good performance status </li></ul></ul><ul><ul><li>Symptomatic relapse </li></ul></ul><ul><ul><li>Local control maintained </li></ul></ul><ul><ul><li>Time of relapse > 6 months </li></ul></ul><ul><ul><li>Desires further treatment </li></ul></ul><ul><li>Response rates: </li></ul><ul><ul><li>Vinorelbine: 14% </li></ul></ul><ul><ul><li>Irinotecan: 33% </li></ul></ul><ul><ul><li>Topotecan: 19% </li></ul></ul><ul><ul><li>Paclitaxel: 25% </li></ul></ul>
    96. 96. SVCO in SCLC
    97. 97. SVCO <ul><li>Seen in 6-10% patients at presentation </li></ul><ul><li>60 -70% of the patients are non ambulatory with poor performance scores </li></ul><ul><li>60- 70% have extensive disease </li></ul><ul><li>60 -70% have extrathoracic extension of disease </li></ul><ul><li>80% patients have moderate to severe SVCO </li></ul><ul><li>20% will die within 2 weeks of presentation </li></ul>
    98. 98. Management of SVCO <ul><li>Principle: </li></ul><ul><ul><li>SVCO is a oncologic urgency but a medical emergency. </li></ul></ul><ul><ul><li>The 1 st goal is hemodynamic stabilization of the patient to allow the patient to lie down in the treatment couch. </li></ul></ul><ul><ul><li>Radiotherapy should be given in large doses per fraction as: </li></ul></ul><ul><ul><ul><li>Fast debulking is needed </li></ul></ul></ul><ul><ul><ul><li>Most patients have poor general condition – cant tolerate fractionated regimens </li></ul></ul></ul><ul><ul><ul><li>Patients are suitable for palliative treatment alone. </li></ul></ul></ul>
    99. 99. Management of SVCO <ul><li>Step 1: Initial workup </li></ul><ul><ul><li>Patient should be nursed in a sitting position as most have orthopnea with Type I hypoxia </li></ul></ul><ul><ul><li>Anxiety allayed through proper explanation and medications </li></ul></ul><ul><ul><li>To alleviate respiratory distress: </li></ul></ul><ul><ul><ul><li>Moist O 2 inhalation – high flow </li></ul></ul></ul><ul><ul><ul><li>Nebulization with β agonists + Steroids: Reduces bronchospasm </li></ul></ul></ul><ul><ul><ul><li>Injectable Deriphyllin: Reduces bronchospasm </li></ul></ul></ul><ul><ul><ul><li>Injectable loop diuretics: Reduce edema, promotes diuresis and relieves pulmonary congestion </li></ul></ul></ul><ul><ul><ul><li>Injectable steroids: Reduces airway edema. </li></ul></ul></ul><ul><ul><ul><li>Injectable antibiotics: In event of fever of significant cough </li></ul></ul></ul>
    100. 100. Management of SVCO <ul><li>Step 2: Monitoring </li></ul><ul><ul><li>Regular checking of </li></ul></ul><ul><ul><ul><li>Pulse </li></ul></ul></ul><ul><ul><ul><li>BP </li></ul></ul></ul><ul><ul><ul><li>Respiratory rates </li></ul></ul></ul><ul><ul><ul><li>Arterial O2 saturation (where available) </li></ul></ul></ul><ul><ul><li>Patient assessment: </li></ul></ul><ul><ul><ul><li>Reduction in edema </li></ul></ul></ul><ul><ul><ul><li>Ability to lie down </li></ul></ul></ul><ul><ul><ul><li>Reduced respiratory distress </li></ul></ul></ul><ul><ul><li>Biochemical and hematological evaluation </li></ul></ul><ul><ul><li>Radiological assessment of disease as permitted by patient's condition </li></ul></ul>
    101. 101. Management of SVCO <ul><li>Further management in the event of the HP S/O SCLC can be: </li></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Radiotherapy </li></ul></ul><ul><li>Chemotherapy can be used initially in patients who are: </li></ul><ul><ul><li>Young </li></ul></ul><ul><ul><li>Good performance status </li></ul></ul><ul><ul><li>Good response to medical therapy </li></ul></ul><ul><ul><li>XRT planned as a adjuvant in the subsequent treatment. </li></ul></ul>
    102. 102. Radiotherapy in SVCO <ul><li>Position: Supine with head turned to opposite side </li></ul><ul><ul><li>Superior border: Encompasses the ipsilateral SCF upto the crico-thyroid junction </li></ul></ul><ul><ul><li>Inferior border: Taken 2 -4 cm below the carina </li></ul></ul><ul><ul><li>Medial border: 1 cm beyond the mediastinal shadow on opposite side </li></ul></ul><ul><ul><li>Lateral border: 1.5 -2 cm margin from the lateral most extent of tumor </li></ul></ul><ul><li>Doses: </li></ul><ul><ul><li>800 cGy in single fraction </li></ul></ul><ul><ul><li>2000 cGy in 5 fractions </li></ul></ul><ul><ul><li>3000 cGy in 10 fractions – least commonly used </li></ul></ul>
    103. 103. Response to RT
    104. 104. Radiotherapy in SVCO <ul><li>Radiotherapy alone can result in: </li></ul><ul><li>Immediate subjective improvement (< 3 d) in 60% patients of SCLC </li></ul><ul><li>Early improvement in 90% patients </li></ul><ul><li>70% patients will respond to RT alone </li></ul><ul><li>Addition of CCT doesn't improve response or survival </li></ul><ul><li>CCT by itself results in a slight delay in response </li></ul>
    105. 105. Investigational Agents <ul><li>Matrix Metalloproteinase Inhibitors ( Marimastat ) </li></ul><ul><ul><li>Important in cancer cell invasion, metastasis, and angiogenesis. </li></ul></ul><ul><ul><li>Two phase III studies </li></ul></ul><ul><ul><ul><li>NCI and EORTC </li></ul></ul></ul><ul><ul><ul><li>No difference in survival </li></ul></ul></ul><ul><ul><ul><li>Adversely impacted the quality of life </li></ul></ul></ul><ul><li>Tyrosine Kinase Inhibitors: ( Imatinib mesylate ) </li></ul><ul><ul><li>Phase II study </li></ul></ul><ul><ul><ul><li>19 patients treated : No observed responses !! </li></ul></ul></ul>
    106. 106. Other agents <ul><li>Antibody based therapy </li></ul><ul><li>Anti sense BCL-2 oligonucleotide ( Genasense ) </li></ul><ul><ul><li>BCL-2 inhibits apoptosis and might contribute to chemotherapy resistance. </li></ul></ul><ul><ul><li>Anti sense oligonucleotides inhibit the translation of mRNA </li></ul></ul><ul><ul><ul><li>Rudin treated 12 patients with refractory SCLC </li></ul></ul></ul><ul><ul><ul><li>No objective responses were observed </li></ul></ul></ul><ul><ul><ul><li>2 of the 12 patients had stable disease. </li></ul></ul></ul>
    107. 107. Follow up Goals <ul><li>To detect symptomatic* progression of disease. </li></ul><ul><li>Gathering outcome data </li></ul><ul><li>Providing reassurance and psychological support. </li></ul>
    108. 108. Follow up Goals <ul><li>To detect symptomatic* progression of disease. </li></ul><ul><li>Gathering outcome data </li></ul><ul><li>Providing reassurance and psychological support. </li></ul>
    109. 109. Follow Up Protocol <ul><li>History and Physical Examination*: </li></ul><ul><ul><li>Every 3 months for 1 -2 years </li></ul></ul><ul><ul><li>Every 6 months for the next 5 years </li></ul></ul><ul><ul><li>Annually thereafter </li></ul></ul><ul><li>Investigations Suggested: </li></ul><ul><ul><li>Chest X-rays </li></ul></ul><ul><ul><li>Other expensive investigations are not cost effective. </li></ul></ul>
    110. 110. Follow up: Other Issues <ul><li>Detection of residual disease is not required after complete radiological response to 1 ° therapy – due to lack of effective R x in this scenario. </li></ul><ul><li>Smoking cessation useful in the small subset who get complete response: </li></ul><ul><ul><li>Can potentially delay recurrence </li></ul></ul><ul><ul><li>Can reduce 2 nd cancers </li></ul></ul>
    111. 111. Conclusions <ul><li>Despite its sensitivity to radiation SCLC is extremely frustrating to treat </li></ul><ul><li>The systemic nature of disease and fast growth make it one of the most aggressive malignancies known </li></ul><ul><li>Radiation therapy is an important part of the therapeutic armamentarium </li></ul><ul><li>Systemic combination chemotherapy is the mainstay of treatment but ineffective in the long run. </li></ul>
    112. 112. Thank You

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