Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA LUNG CANCER. VIII. THERAPY. V. SMALL CELL LUNG CANCER Prof.

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1 Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA LUNG CANCER. VIII. THERAPY. V. SMALL CELL LUNG CANCER Prof. Alberto Riccardi

2 SMALL CELL LUNG CARCINOMA Summary of treatment approach * limited stage (good performance status) = combination CT + chest RT; * extensive stage (good performance status) = combination CT; - complete responders (all stages): prophylactic cranial RT; * poor - performance - status pts (all stages): - modified - dose combination CT; - palliative RT

3 TREATMENT OF SMALL CELL LUNG CARCINOMA. I. * SCLC = chemotherapy - sensitive disease; - with limited stage disease response rates = 60-80%, with 10-30% complete response); - with extensive disease response rates = 50%, usually partial responses; - tumor regressions usually quick, within first 2 cycles of treatment, providing rapid palliation of tumor - related symptoms

4 TREATMENT OF SMALL CELL LUNG CARCINOMA. II. * chemotherapy significantly prolongs survival; * untreated pts with limited - stage SCLC median survival = 12 wks; - with chemotherapy, median survival = 18 mos and long - term (> 3 yr) survival = 30-40%; - median survival of extensive - stage pts = 9 mos and < 5% of pts survive 2 yrs; although initially responsive, most pts relapse (due to emergence of chemotherapy resistance)

5 INFLUENCE OF M ODERN C O M BIN A TI ON CHE M OTHER A PY ON SURVIV A L OF PTS WITH SCLC era sur v i v al li m it e d dise a se exten s ive dise a se pre c he m ot h erapy s u p p or t ive car e ( m e d i a n) 3 m os 1,5 m os sur g ery ( 5 yr) < 1% - rad i o t her a py ( 5 yr) 1-3 % - che m o t her a py si ng le a g e nt (m e di a n) 6 m os 4 m os co m b i na ti o n me d ian m os 7-11 m os 5 yr 2-8 % 0-1 % che m o t her a py + R T me d ian m os m os

6 I. Combination chemotherapy * goal of treatment = obtaining complete clinical response - regression (after 6-12 wks, by repeating initial positive staging procedures, especially fiberoptic bronchoscopy with washings and biopsies); * quality of initial response predicts both median and long - term survivals and potential cure; - complete responders survive longer (with > 3 yrs response, some pts are cured) than partial responders (tumor > 50% of visible disease) and of no responders

7 II. Combination chemotherapy * pts with both limited or extensive disease evaluated as physiologically able or not able to tolerate combination chemotherapy (or chemo - radiotherapy); * mortality ~ 1-5% even in able pts (as for pulmonary resection = need for physiologic staging) and kept low by attention to day by day management through initial 6-12 wks

8 III. Combination chemotherapy * reserved to ambulatory pts with no prior CT or RT, no other major medical problems, and adequate heart, liver, renal, lung and bone marrow functions; - arterial P O2 on room air > 6.6 kpa (50 mmhg), without CO 2 retention; * chemotherapy modified (to prevent undue toxicity) in pts with some health limitations; * in all pts, treatment coupled with supportive care (for infectious, hemorrhagic and other complications)

9 IV. Combination chemotherapy * most widely combination chemotherapy used = etoposide plus cisplatin or carboplatin (/ 3 wks, on outpatient basis for 4-6 cycles)

10 V. Combination chemotherapy * other combination chemotherapy regimens (effective with adequate drug dose and schedules) include etoposide + cisplatin + paclitaxel, irinotecan + etoposide ( median survival, but > toxic than etoposide + cisplatin), given / 3 wks for 4-6 courses; - dose intensity chemotherapy adds toxicity without clear survival benefit; * on other hand, oral single agent etoposide of clinical benefit in initial treatment of pts who are elderly or with very poor performance status

11 VI. Combination chemotherapy * appropriate supportive care (antiemetic therapy, fluid and saline boluses with cisplatin, monitoring blood counts and chemistries, attention for bleeding or infection, and, as required, administration of erythropoietin and granulocyte colony - stimulating factors, CSFs); * adjustment of chemotherapy doses from nadir granulocyte counts [initial chemotherapy often results in moderate / severe granulocytopenia (i.e., granulocytes < / µl, respectively) and thrombocytopenia (platelets < 50, ,000 / µl)

12 VII. Combination chemotherapy * following initial 4-6 courses, restaging for complete clinical remission (= complete disappearance of all clinically evident lesions and paraneoplastic syndromes), or partial remission, or no response, or tumor progression (10-20% of pts); - chemotherapy stopped in responding pts (continuing CT not of value

13 VIII. Combination chemotherapy * complete remission in ~ 50 and 30% of pts with limited - and extensive - stage, respectively. and partial response in 90-95% of all pts

14 IX. Combination chemotherapy * responses median survival from 2-4 mos for untreated pts to and mos for limited and extensive stage for pts, respectively; * potential cure = 30-20% and 5-1% for limited and extensive stage SCLC, respectively; - for most pts, improvement of symptoms and performance status (physician be able at administering out - pt chemotherapy with avoiding undue therapeutic toxicity)

15 IX. Combination chemotherapy * poor prognosis for pts who relapse; - patients who relapse > 3 mos since completion of initial chemotherapy ( chemosensitive disease ) median survival = 4-5 months; - pts not responding to initial chemotherapy or relapsing within 3 mos ( chemorefractory disease) median survival of 2-3 months; - pts with chemosensitive disease may be retreated with initial regimen (topotecan = modest activity as 2nd - line therapy; pts be entered onto clinical trials testing new agents)

16 COMBINED - MODALITY CHEMORADIOTHERAPY FOR LIMITED STAGE SCLC. I. * radiation therapy to thorax associated with small but significant in long - term survival for pts with limited - stage SCLC (5% at 3 yrs); - chemotherapy given concurrently with thoracic radiation > effective than sequential chemoradiation but associated with significantly more esophagitis and hematologic toxicity

17 COMBINED - MODALITY CHEMORADIOTHERAPY FOR LIMITED STAGE SCLC. II. * in one randomized study, twice - daily hyperfractionated radiation compared with once - daily schedule (both administered concurrently with 4 cycles of cisplatin and etoposide) - survival significantly higher with twice - daily regimen (median = 23 vs 19 mos; 5 - yr survival = 26 vs 16%), with twice - daily regimen giving > G3 esophagitis and pulmonary toxicity = pts be carefully selected for concurrent chemoradiation therapy based on good performance status and pulmonary reserve

18 COMBINED - MODALITY CHEMORADIOTHERAPY FOR LIMITED STAGE SCLC. III. * selection criteria = limited - stage disease + PS initial good pulmonary function: - CT full dose RT given without sacrificing too much lung function; * from some studies twice - daily radiation fractions toxic and improve survival (compared to once - daily treatment)

19 COMBINED - MODALITY CHEMORADIOTHERAPY FOR LIMITED STAGE SCLC. IV.

20 . XIV. COMBINED - MODALITY CHEMORADIOTHERAPY FOR EXTENSIVE STAGE SCLC * initial chest RT usually not indicated; * however, addition of chest RT to CT considered for favorable pts (PS good pulmonary function + only one site of extensive disease); * radiotherapy survival in pts with chemotherapy - induced complete remission; * for all pts, radiotherapy added if chemotherapy inadequate to relieve local tumor symptoms

21 COMBINED - MODALITY CHEMORADIOTHERAPY * cured ~ 20-30% pts with limited - and 1-5% pts with extensive - stage, respectively: * complete remission in 50% with limited - and in 30% pts with extensive - stage disease (90-95% pts have complete or partial responses); - responses median survival by mos for pts with extensive and by mos for pts with limited - stage disease (as compared 2-4 mos for untreated pts); - in addition, relief of tumor - related symptoms and of performance status in most pts (however, maintenance of good performance status in pts receiving outpatient chemotherapy requires judgment and skill to avoid undue therapeutic toxicity)

22 TREATMENT OF SMALL CELL LUNG CARCINOMA Prophylactic cranial irradiation in limited - stage disease * prophylactic cranial irradiation (PCI) significantly development of brain metastases (occuring in ~ 2 / 3 of pts not receiving PCI) and results in small survival benefit (~5%) in pts who obtained complete response to induction chemotherapy; - deficits in cognitive ability following PCI uncommon and often difficult to sort out from effects of chemotherapy or normal aging

23 Radiation therapy for palliation * palliative radiation therapy = important component of management of SCLC; - with symptomatic, progressive lesions in chest or at other critical sites, be administered in full doses (e.g., 40 Gy to chest tumor mass, if radiotherapy not yet been given to these areas)

24 TREATMENT OF SMALL CELL LUNG CARCINOMA Radiation therapy for palliation * high - dose radiotherapy (40 Gy) to whole brain when documented brain metastases or symptomatic progressive lesions in chest or other critical sites

25 Surgery and adjuvant chemotherapy * surgical resection not routinely recommended for SCLC; - occasional pts meet usual requirements for resectability (stage I or II with negative mediastinal nodes); - often histologic diagnosis made in some pts only on review of resected surgical specimen they should receive standard SCLC chemotherapy; * from retrospective series, high cure rates (> 25%) with surgery + adjuvant combination chemotherapy (although unclear what outcome would be with chemoradiation therapy alone, given relatively low bulk disease)

26 New treatments * only in context of approved clinical protocol: - new drug combinations; - very intensive initial or "reinduction" therapy with autologous peripheral stem cell infusion ( bone marrow transplantation ) and - novel ways of combining chemotherapy, radiotherapy, and surgery

27 METASTATIC PULMONARY TUMORS

28 METASTASES TO LUNG

29 METASTATIC PULMONARY TUMORS. I. * lung as frequent site of metastases from primary cancers outside lung; - metastatic disease considered incurable, except in two special situations

30 METASTATIC PULMONARY TUMORS. II. 1. Solitary pulmonary nodule on chest x - ray in pt with known extrathoracic neoplasm * metastasis or a new primary LC?; * nodule can be surgically resected (= treated as primary LC) because: - natural history of LC usually worse than that of other primary tumors; - especially in smoker pt > 35 yrs, and - no other sites of active cancer found

31 METASTATIC PULMONARY TUMORS. III. 2. Multiple unilateral pulmonary nodules. I. * resectable with curative intent if, after careful staging: - pt can tolerate pulmonary resection; - primary tumor definitively and successfully treated, and - all known metastatic disease encompassed by projected pulmonary resection

32 METASTATIC PULMONARY TUMORS. IV. 2. Multiple pulmonary nodules. II * key = excluding uncontrolled primary tumors and extrapulmonary metastases; * primary tumors with curatively resected pulmonary metastases include osteogenic and soft tissue sarcomas, colon, rectal, uterine, cervix and corpus tumors, head and neck, breast, testis, salivary gland cancers, melanoma, bladder and kidney tumors; % 5 yr survival rates in carefully selected pts, especially with osteogenic sarcomas (where resection of pulmonary metastases is becoming a standard treatment approach)