sclc - Introduction SMALL CELL LUNG CANCER Current...

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Unformatted text preview: Introduction SMALL CELL LUNG CANCER Current Controversies & Update in Management Dr. Zia Hashim October 29,2004 Small cell lung cancer (SCLC) was initially recognized Small as an entity distinct from other types of lung cancer by pathologic examination in 1926 by Dr. Barnard Most malignant tumors of lung Most 20-25% of cases. Recent data suggests that incidence 20of SCLC is falling 14%(Proc Am Soc Clin Oncol 2002 WHO classification: 3 types WHO Small/oat cell Intermediate cell type less regular shape more cytoplasm some large cell + more resistant to chemo Combined subgp: <1% subgp: managed as small cell same prognosis Photomicrograph of SCLC Usually arise from central bronchi Usually At presentation 2/3rd have evidence of At extensive disease (rapid growth; early metastasis) Frequent sites: Liver, CNS and bone Frequent Other sites: abdominal lymph nodes, Other adrenals 1 Approach Any new onset cough that persists for more than 2 wks Any in smoker more than 40 yrs old Hemoptysis Hemoptysis Clubbing Clubbing On CXR cavitation is not a feature On Sputum cytology has a role because SCLC are central Sputum yield from one sample 40% repeated samples 80% false +ve <1% +ve Brochoscopy: histological confirmation and extent of Brochoscopy: disease PROGNOSTIC FACTORS PROGNOSTIC Stage: limited vs exensive Stage: Histologic subclassification: poor if large cells are involved Histologic subclassification: Metastasis Metastasis Tumors with c-myc: more aggressive course Tumors myc: more N-myc: poor response to chemo myc: poor p-53 Ab no correlation ?  survival ! (cf NSCLC) (cf Serum NSE: inversely related to survival algorithm: Serum PI = zNSE + z(stage) + 2zPS, where PI represents the prognostic index, and z represents the regression coefficient. This algorithm segregated the patients into four groups with clearly different prognoses. Cyfra 21-1 level over 3.6 ng/mL or a tissue polypeptidespecific antigen level over 140 U/Lsignificantly indicated a poor survival rate. Serum chromogranin level: poor prognosis Staging Initially proposed by VA gp Presently International Association for study of Lung Cancer (IASLC) recommends (IASLC) Limited disease: 30% Corresponds to I-IIIB Corresponds Iconfined to one hemithorax & regional lymph nodes (including mediastinal, C/L hilar & ipsilateral supraclavicular) supraclavicular) depends on, whether known tumor can be encompassed within one radiotherapy port ipsilateral pleural effusion C/L supraclavicular, rec laryngeal nv and SVC can all supraclavicular, be part of it Extensive disease: 70% exceeding beyond boundaries of limited ds cardiac tamponade, malignant pleural effusion and tamponade, B/L parenchymal involvemaent Recommendation medical history and physical examination, complete blood medical counts, comprehensive chemistry panels, CT scans of the chest and abdomen, a CT scan or MRI of the brain, and a bone scan. PET scanning is not recommended; grade of recommendation, PET D Host related prognostic factors CERTAIN: performance status CERTAIN wt loss LDH Probable: QOL and depressed mood Probable sex: females do better alkaline phosphatase Hb serum albumin Possible: age, socioeconomic status, TLC, Possible bicarbonate level, platelet count, soluble IL-2 R IL- 2 TREATMENT Before 1970 surgery & RT were the most Before common form of treatment Appreciation of frequency & extent of Appreciation metastases coupled with the sensitivity of SCLC to CT has led to the CENTRAL ROLE OF CT 5X  survival 5X Long term disease free survival of more than 3 Long yrs in 5-10% as a whole and 15-20% of limited 515stage ds Cytotoxic agents for SCLC Alkylating agents: Cyclophosphamide 1500 mg/m2 IV q 3wk Alkylating IV Ifosfamide 5000 mg/m2 IV day 1 q 3wk IV hexamethylmelamine Lomustine Vinca alkaloids: Vincristine 2 mg IV q 3 wk Vinca Vincristine Vindesine Epipodophyllotoxin: Etoposide 80 mg/m2 IV d1-3 q 3wk Epipodophyllotoxin: Etoposide IV d1Teniposide 2 IV q 3wk, day 1 Platinum analogues: Cisplatin 80 mg/m IV Platinum Cisplatin Carboplatin 300 mg/m2 day 1 q 3 wk day Miscellaneous: Doxorubicin 40 mg/m2 IV q 3 wk Miscellaneous: Doxorubicin IV Methotrexate 3rd generation drugs: ironotecan, topotecan, paclitaxel ironotecan, Which combination Which Earliest drug used was cyclophosphamide Earliest survival without any drug 2 mo cyclophosphamide prolonged it to 5 mo (1960) Single drug or combination ? Single Combination therapy was introduced in 1970 and survival touched 5 yrs CAV was earliest; still the SCLC was fatal in 95% cases CAV was earliest; still the SCLC was fatal in CAV 95% cases Cisplatin+etoposide(PE): Cisplatin+etoposide(PE): Less toxicity to lung and heart When combined with RT: 2-year survival rates of 40% Cp was sometimes used instead of P in combination with E (CpE), having a similar response and survival as PE but with less nephro- and ototoxicity 3 Other improvement efforts For how long? In the past, one of the frequently For practiced approaches was to treat patients for the duration of their life only one study demonstrated a survival advantage for LD patients (in sharp contrast to numerous studies that showed no advantage at all/detrimental) no survival benefit was seen for eight cycles of CEV compared with four cycles Intergroup 0096 study produced convincing results with only four cycles of PE and local TRT The current standard treatment protocol is four (to six) cycles of a platinum-based regimen + TRT. The dismal fate of a high recurrence rate was the impetus for investigating other approaches such as rapid alternation, dose intensification, and testing the Introduction of ‘‘third-generation’’ drugs such as irinotecan, topotecan, and paclitaxel The mathematic model of Goldie and Coldman indicated that rapid alteration of non–cross-resistant CHT should improve survival in SCLC. Tested and confirmed in practice this approach demonstrated an improvement in survival by adding CAV and PE in a sequential protocol (Fukoka 1991). Dose intensification: slight increase in survival much more  in toxicity idea dropped Third generation drugs Why combination with RT Irinotecan was combined with P and compared with PE. A significant survival advantage for the irinotecan/P arm was observed Disadvantage: high grade diarrhea Topotecan was initially shown to be effective in relapsed SCLC. So used for maintainence after PE With the addition of topotecan, progression-free survival was improved but no impact on survival Taxanes: only modest benefit some studies showing increased no of treament related deaths and toxicities not a part of usual practice With chemotherapy alone intrathoracic With failure occurs in 80% (median survival 101014 mo) Addition of TRT resulted in an increase in Addition the 3-year survival rate from 8.9 to 314.3%, an absolute improvement of 5%, and a relative improvement of nearly 50% (Meta-analyses by Warde and Payne;& MetaPignon et al) 4 Sequencing and Timing of Thoracic Radiation and Chemotherapy Murray and Coldman meta-analysis: best results were Murray metaseen with TRT beginning 3 to 5 weeks from the start of chemotherapy. As radiation was further delayed, the benefit decreased and survival approached that seen with chemotherapy alone. Trials with alkylating agents: no improvement with RT Trials Trials with platinum-etoposide: concurrent Trials platinum- etoposide: chemotherapy-TRT is superior to sequential TRT, where chemotherapyTRT is administered after chemotherapy the data are divergent as to whether early TRT (ie, in the week 1) is better than delayed TRT (ie, week 6 or week 13). ROLE OF SURGERY ROLE abandoned after the British Medical Counsel(1973) abandoned published the results of their study comparing primary radiation therapy with surgery in patients with resectable SCLC with a 10-year follow-up 10followsubsequent reports published in the 1970s and early subsequent 1980s showed long-term survival in patients who had longbeen treated with surgery alone who had very earlyearlystage disease Best for T1-2N0 Best T1May be followed by postop CT. Medistinoscopy is May required in all patients undergoing surgical resection. PCI may be recommended if CR is achieved Role of surgery in node positive? Lung Cancer Study Role Group: 5 cycles of CAV+ RT± surgery: no difference in survival Radiation dose: retrospective analysis of patients Radiation treated at the Massachusetts General Hospital: improvement in local control as radiation doses were increased from 30 to 50 Gy Fractionation: The North American Intergroup trial Fractionation 0096 compared doses of 45 Gy administered in 25 fractions for > 5 weeks to the investigational arm of doses of 45 Gy administered in 30 fractions for > 3 45 weeks. Chemotherapy consisted of four cycles of cisplatin-etoposide. The accelerated regimen cisplatin- etoposide. The resulted in improved local control (intrathoracic failure: accelerated therapy arm, 36%; standard therapy arm, 52%) and long-term survival, which was 26% for longthe twice-daily regimen and 16% for the standard twiceregimen. There was an increased rate of grade 3 esophagitis (26% vs 11%, respectively), but there were no other significant differences in toxicity EXTENSIVE DISEASE Meta-analysis by Pujol et al in Br J Cancer: patients Metarandomized to a regimen containing cisplatin had a significant increase in the probability of response and survival with no significant increase in toxicity use of cisplatin and/or etoposide offered a significant survival use advantage to patients with SCLC Berghmans et al In a meta-analysis by Chute et al: 2-month prolongation in In meta2median survival was demonstrated in patients with extensiveextensivestage SCLC independently associated with both cisplatincisplatinbased therapy and in the improvement of best supportive care Carboplatin vs cisplatin: carboplatin plus etoposide is as Carboplatin cisplatin: effective as cisplatin plus etoposide but is less toxic (except for increased myelosuppression) Brahmer and Ettinger myelosuppression) Brahmer The Hellenic Oncology Group phase III trial :patients with The both limited-stage and extensive-stage disease, the median limitedextensivesurvival time was 11.8 months for cisplatin plus etoposide and 12.5 months for carboplatin plus etoposide. The difference etoposide. was not statistically significant, although the study was not powered to show equivalence 5 MAINTENANCE TREATMAENT MAINTENANCE recent Japanese trial compared cisplatin and irinotecan with recent cisplatin and etoposide. Patients randomized to the etoposide. cisplatin/irinotecan arm did (statistically) significantly better than the group that was randomized to the cisplatin/etoposide arm (median survival time, 420 vs 300 days, respectively). 3rd drug ? Hoosier Oncology Group evaluated the addition of ifosfamide to cisplatin and etoposide in a phase III trial of 171 patients with extensive-stage disease. At the expense of increased extensivetoxicity, the 2-year survival rate increased from 5 to 13% with the 2addition of ifosfamide Mavroudis et al compared the use of paclitaxel, etoposide, and Mavroudis etoposide, platinum (TEP) with the use of etoposide and platinum. The study was terminated early, secondary to a higher number of toxic deaths deaths in the TEP arm. Despite a statistically significant improvement in the time to progression for TEP, there was no difference in overall survival. phase III intergroup trial (Cancer and Leukemia Group B 9732) was phase reported comparing cisplatin and etoposide with or without paclitaxel in patients with extensive-stage SCLC. No significant extensivesurvival advantage was seen with the addition of paclitaxel to cisplatin and etoposide in this study. On the other hand, there was an increased incidence of deaths from toxicities in the paclitaxel paclitaxel arm. Role of PCI It was frequently practiced in complete response (CR) and occasionally in good partial response (PR) patients, it was not unequivocally proved to produce superior survival Fear of toxicity: decline in neurocognitive function The issue was taken by meta-analysis by Perez et al(1981): ↓ relative risk of death absolute  in 3yr survival by 5.4% absolute  in ds free survival by 8.8% ↓cumulative risk for CNS metastasis issue of toxicity was clearly discarded The current approach is to administer PCI at the time of achieving CR, but its timing becomes important to avoid administration concurrently with CHT, and thus more CNS toxicity Several randomized trials have demonstrated that 4 to 6 Several months of treatment is equal to prolonged treatment when survival is considered as the end point. In the meta-analysis reported by Sculier et al, 13 In metapublished randomized trials were included. One showed a statistically significant difference in survival in favor of maintenance therapy, 5 studies showed survival advantage in subgroups of patients, 1 study showed significantly shorter survival times with maintenance therapy, and 6 studies showed no difference. The Eastern Cooperative Oncology Group (ECOG) The conducted a phase III trial in which patients showing a response to therapy or patients whose disease stabilized after receiving four cycles of cisplatin and etoposide were randomized to observation alone or to four cycles of topotecan therapy. Despite an improvement in progression-free survival, there was no difference in progressionoverall survival between the two groups. anti-GD3 immunization as maintenance treatment. antiMetalloproteinase inhibitors and inhibitors of angiogenesis also are being investigated in this fashion angiogenesis TREATMENT OF RELAPSED OR REFRACTORY SCLL Despite high initial response rates to chemotherapy (ie, 45 to 75% CRs) Despite CRs) reported in patients with limited-stage disease and 20 to 30% CRs in limitedpatients with extensive-stage disease, the response duration is usually short extensivewith a progression-free survival time of approximately 4 months for patients progressionwith extensive-stage disease and 12 months for patients with limited-stage extensivelimiteddisease. Most patients are destined to relapse, and the prognosis of this prognosis group of relapsed patients is poor. Patients who relapse < 3 months after months first-line therapy are commonly called refractory, and patients who relapse refractory first3 months after therapy are called sensitive. Patients with late relapses sensitive Patients after receiving initial therapy may be retreated with the same induction regimen used initially. von Pawel et al compared cyclophosphamide, adriamycin, and vincristine von cyclophosphamide, adriamycin, (CAV) with topotecan as a single agent in patients who relapsed at least 60 days after the completion of initial therapy. that topotecan was at least topotecan as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms. However, toxicity rates toxicity were high in both arms of the study, and alternative dose schedules of schedules topotecan are currently being evaluated 6 TREATMENT OF ELDERLY Approximately 25% of patients with SCLC are > 70 years Approximately of age performance status and the physiologic status of the performance patient should guide treatment decisions rather than the patient’s chronologic age good performance status (ECOG level 0 or 1) and normal good organ function should be treated with optimal chemotherapy (and with radiotherapy, if indicated) as in their younger counterparts age did not appear to impact the delivery, tolerance, or age efficacy of thoracic irradiation in the combined-modality combinedmanagement of patients with limited-stage SCLC. limitedGreater myelosuppression is to be expected since equivalent exposure to a drug will lead to more myelosuppression in the elderly compared to their younger counterparts Elderly patients with poor performance status or with Elderly compromised organ function may be offered singlesingleagent chemotherapy or polychemotherapy in attenuated doses doses Palliative treatment Palliative Identification of patients with poor prognosis: anatomic, Identification performance status The Manchester Prognostic Score: (tumor stage,performance status, The serum sodium, alkaline phosphatase, and serum lactate phosphatase, dehydrogenase One approach has been to maintain dose intensity but decrease One toxicity by using a low-dose high-frequency regimen. lowhighIn one study, the high-frequency arm showed similar response rates In highbut significantly more myelosuppression compared with the standard regimen of alternating cyclophosphamide, doxorubicin, cyclophosphamide, plus vincristine and cisplatin plus etoposide. The quality-of-life etoposide. quality- ofassessment in a subset of patients in the high frequency treatment treatment arm, however, showed an improvement in general wellbeing,activity, and anorexia. wellbeing,activity, At present, a standard therapy for patients with poor-prognosis small cell lung cancer is a combination of carboplatin plus etoposide; for those with very poorprognosis (eg, 20% survival at 1 year), a standard therapy is single-agent carboplatin. A number of newer drugs that may play a role in the management of these patients are currently being investigated, including taxanes, gemcitabine, topotecan, and vinorelbine TREATMENT OF ELDERLY such "gentler" chemotherapy is inferior to optimal combination such chemotherapy oral etoposide for 14 days combined with carboplatin on day 1 every 28 days ; abbreviated chemotherapy with CAV in full full doses followed 3 weeks later by chemotherapy with cisplatin and etoposide in optimal doses ; or chemotherapy with platinum, adriamycin, vincristine, and etoposide in reduced doses adriamycin, vincristine, A recently reported phase III trial compared carboplatinrecently carboplatingemcitabine therapy with cisplatin-etoposide therapy in patients cisplatinwith SCLC who had poor prognoses, with carboplatin-gemcitabine carboplatintherapy exhibiting a more favorable overall toxicity profile at the expense of increased myelotoxicity. myelotoxicity. Another phase III trial compared the use of single-agent carboplatin Another singlewith CAV, with carboplatin producing response rates, relief of tumor-related symptoms, and survival similar to that seen with CAV. tumorThere was a lower risk of life-threatening sepsis and less need for lifehospitalization in the group that received carboplatin. carboplatin. SPECIAL TREATMENT CNS metastasis: concurrent RT must as cytotoxic drugs have CNS poor penetration in CNS Leptomeningeal metastasis: I/T MTX or high dose I/V Leptomeningeal Etoposide Spinal cord compression: ~3% Acute therapy required Spinal either RT or laminecomy role of steroids ? Steroids are recommended during RT for cord cord compression SVC obstruction: systemic chemotherapy alone produces SVC sufficient relief. If the effect of CT is not observed in few days days palliative RT is advocated 10 Gy in one fr or 30 Gy in 3-10 fr 3Paraneoplastic syndromes: hyponatremia at the time of Paraneoplastic diagnosis poor prognostic factor treatment is fluid restriction RT may be used when there is poor response to chemo/sigificant RT chemo/sigificant toxicity 7 TOXICITY OF TREATMENT Haematologic toxicity The use of cisplatin and etoposide, currently the base of SCLC The etoposide, treatment, normally shows a medium level of myelosuppression, myelosuppression, with a nadir of 7 to 14 days and an approximate recovery of 21 days. GM-CSF ?The systematic review of 12 randomized studies that GMincluded 2107 patients to evaluate the effectiveness of granulocyte granulocyte and granulocyte macrophage colony-stimulating factors in the colonytreatment of SCLC concerning survival, the rate of response, toxicity, and frequency of infection or neutropenic fever concluded that their effectiveness was not demonstrated in terms of a their better rate of response or survival. Moreover, a harmful effect of the use of this cytokine before chemotherapy was observed in patients patients with LD who had received concomitant treatment with chemotherapy and radiotherapy prophylactic use of ciprofloxacin plus roxitromycin during prophylactic ciprofloxacin chemotherapy reduced the incidence of leukopenic fever, chemotherapy fever, number of infections, the use ofantibiotics, and number infections, ofantibiotics, hospitalizations due to this fever by 50%, in addition to hospitalizations reducing infection-related mortality reducing infectionr-HuEPO decreases the degree of anemia and the need for blood transfusion in patients with SCLC (de Campos et al ) Esophageal toxicity Rapid cell replacement of the mucosa cells in a normal Rapid esophagus makes this organ particularly sensitive to radiation-induced damage that at first appears to be an radiationinflammatory response. On administration of isolated fractionated radiotherapy, a On certain degree of acute esophagitis may be observed with symptoms that resolve easily within 7 to10 days and that are rarely severe with less than 50 Gy. Depending on the size of Gy. esophagus irradiated, severe esophagitis may appear after 60 Gy, which may evolve occasionally to stenosis. Gy, stenosis. prophylaxis against esophagitis in SCLC may be the use of prophylaxis amiphostine. in a recent phase II study in 34 patients with amiphostine SCLC treated with amiphostine and with the aforementioned combined treatment, no benefits were observed in the control of esophageal toxicity contrary to the positive results reported in NSCLC transdermic fentanyl (Durogesic) at a dose of 25 mg/72 hours transdermic Durogesic) in patients with grade 2 and 3 esophagitis Pulmonary Toxicity radiotherapy particularly affects endothelial capillary cells radiotherapy and type I epithelial cells so that acute histologic changes are characterized by alterations in small vessels, with the subsequent development of vascular congestion and an increase in permeability. An exudate rich in fibrin is produced in the alveolar spaces, leading to hyaline hyaline membranes. In the chronic phase of fibrosis, an increase in the thickness of the alveolar walls is found as fibrosis of the subintimal layer of the vessels, with their consequent stenosis. stenosis. Pentoxifylline reduces the production of proinflammatory Pentoxifylline cytokines, particularly tumor necrosis factor–alpha (TNFfactor– (TNFa), in response to harmful stimuli and may, protect against the cellular damage mediated by cytokines and produced by irradiation. CARDIAC TOXICITY CARDIAC Light pericardial effusion post irradiation has Light been reported which is of little clinical significance On rare occasion large pericarditis may appear On requiring pericardiocentesis Ischemic coronary artery disease secondary to Ischemic radiation may be present Neuropathy of Cisplatin: tricyclic antidepressants Neuropathy Cisplatin: and vitamin E 8 CELL SURVIVAL PATHWAY CELL MODULTORS NOVEL APPOACHES… Signal induction pathway: Agent Target Agent No. of pts GRP 2A11 12 CR 1 SD 4 CD117kit-tk CD117kit- Imatinib 19 Retinoid ATRA, 22 cisplatin, cisplatin, etoposide Fenretinide 19 No response CR 1 PR 9 Target No of pts Response Oblimersan bcl-2 bcl+ Paclitaxel 12 SD 2 Oblimersan bcl-2 bcl+carboplati n/etoposid e 16 PR 12/14 CCI-779 CCI- 16 SD 1 Response Retinoid SD 5 Angiogenesis Inhibitors Immunotherapy Agent Target Fucosyl GM1 vaccine Polysialic acid agent No of pts 15 I-SCLC RFS>11 mo Fucosyl GM1 13 NCAM 13 BEC2-BCG GD3 BEC2- Phase mTOR response target No of pts phase response Marimastat Matrix 555 metalloprot ease III I-SCLC BAY 12129566 III TTP↓ I-SCLC Thalidomid angiogenes 26 e+ is carboplatin /cisplatin II CR 2/23 PR13/23 SD5/23 Matrix 700 metalloprot ease 9 Is small cell lung cancer Is diagnosis a sentence of death ? …....answer is probably “no” but still we have miles to go….. miles 10 ...
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This note was uploaded on 12/03/2011 for the course MEDICINE 350 taught by Professor Dr.aslam during the Winter '07 term at Medical College.

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