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Late intensification (LI) in small cell lung cancer (SCLC)
121
status 70% (range 50-90), median age 52 years (31-68), limited disease (LD) B6, extensive disease (ED) 24, histological subgroups 28 large cell, 14 squamous cell, 8 adenocarcinoma. 21 pts (42%) achieved objective tumor response (CR+PR). LD pts: 8/26 (31%) PR following chemotherapy; 19% CR, 35% PR following additional radiotherapy. ED pts: 1/24 (4%) CR and 21% PR following chemotherapy; 4% CR, 25% PR after additional radiotherapy. Median survival of LD pts was 15.8 months, of ED pts 6.8 months (p < 0.002). Median response duration/survival of responders were 9(2-21)/16 (3-30) months. Responders survived significantly longer than on-responders (p<0.05). Side effects included myelosuppression, nausea, vomiting, and alopecia. No patient experienced persistent nephrotoxicity or severe neurotoxicity. Concerning remission rates and survival, no statistically significant differences c o u l d be demonstrated between the three vindesine schedules. In LD pts additional high-dose thoracic irradiation increased remission rates and seemed to prolong remission duration and survival.
Toxicity and Pretreatment Variables Related to Survival .in Small Cell Bronchogenic Carcinoma (SCBC) in Patients Treated With Cyclophosphamide, Methotrexate, and VP-16. Bonomi, P., Rosenberg, D., Rush Medical College, Chicago, Ii. Performance status, extent of disease, and previous weight loss have been shown to the important prognostic factors in SCBC. There is relatively little information concerning the impact of toxicity on prognosis. Fifty-six patients with SCBC were treated with cyclophosphamide 700 mgs. per square meter iv on days 1-2, methotrexate 15 mgs. per square meter orally on days 8,11,15,18,29,32,35 and 38, and VP-16 60 mg mgs per square meter iv daily on days 1 through 5 and 22 through 26. During the first cycle of therapy, doses were not modified for hematologic toxicity. Patient characteristics were the following: median age - 62 years, limited disease - 17 patients, extensive disease - 39 patients, performance status 0-i - 38, and performance status 2-18. Responses were the following: complete - 9 (16%) and partial - 28 /50%). With all patient having expired, the median survival was 28 weeks. The following toxicity was observed: WBC < 1,000 - 12(22%) with four deaths during febrile3episodes, platelet count < i00,000 per mm - 3(5%) pulmonary infiltrates - 8 (15%) with three (5%) pts dying from respiratory insufficiency, and mucositis - 24 (43%). Fortyseven patients completed induction therapy. The WBC was < 2,000/mm ~ in 25 patients. The mean survivals for patients with
WBC < 2,000 was 30,2 weeks compared to a mean survival of 49~7 weeks for patients with a WBC > 2,000/mm . Analysis of variance showed that these mean survivals were significantly different (p=0.03). Logistic regression analysis showed that pre-treatment parameters did not predict which patients would experience the greatest leukopenia (p = O . 7 8 ) . Mean survivals for patients who had dose reductions versus no dose reductions were 31.3 and 44.9 weeks respectively (p = 0.17). If these results are confirmed in a larger group of patients, the possibility of studying less toxic regimens should be considered in future SCBC trials.
Reinduction For Progressive Small Cell Lung Cancer ~SCLC) With the Induction Regimen. Postmus-, ~.E., v. Zandwi~k , N., Burghouts j, J., Bakker-, W., Splinter ~ T.~;W. ~. Dmpaztm ~ t ~ of Pulmonary Diseases, State University Groningen and 4,. Leiden. 2. Netherlands Cancer Institute Amsterdam. 3. Departments of Medical Oncology, Groot Ziekengasthuis, Den Bosch. 5. Dijkzigt Ziekenhuis Rotterdam. Despite the high initial remission rate after chemotherapy for SCLC only few patients ultimately will be long-term disease-free. Overall results are probably more dependent of the induction regimen than of the maintenance chemotherapy. With the aim of an improved quality of life several studies with short term chemotherapy have been reported, however, the optimal duration of treatment is still not defined. Retreatment after relapse is in most patients difficult due to a lack of active second line regimens with acceptable toxicity. In a phase II study we are evaluating the activity of the induction reqimen in patients with tumor progression. So far 23 patient~ received 5 c CDE (C~clophosphamide, 1 g~m doxorubicin 45 mg/m , etoposide i00 g/m day 1,3,5) and at relapse all patients received again CDE. The time between the end of induction and the retreatment was 20 weeks (median) (range 5-66). 13 patients responded (4 CR, 9PR), 6 patients had stable disease, 4 progression. These results make the use of short term chemotherapy for SCLC questionable although it is uncertain if overall survival will be different if compared with standard regimens (induction + maintenance). Regarding the high response rate, patients relapsing after short term chemotherapy are ideal candidates for phase II studies because drug-induced tumor cell resistance is apparently not yet present in the majority of the patients.
Late Intensification (LI) in Small Cell Lung Cancer (SCLC). Sculier, J.P., Klastersky, J. and the EORTC Lung Cancer Working Party, Institut J. Bordet Bruxelles, Belgium We performed three successive pilot studies of LI in SCLC: i) CAV regimen: CAV was given
122
for 2 to 3 courses2at standard dosage (SD) (cis~latin 60 mg/m dl + adri~mycine 45 mg/m dl + etoposide 120 mg/m--dl, 2,3); followed by LI (2 to 3 times SD) with autologous bone marrow transplantation (ABMT). Severe mucositis was the limiting extrahematological toxicity. 2) AVE regimen: AVE was given for 3 courses at SD (adriam~cin 45 mg/m- dl + cyc~ophosphamide 1 g/m- dl + etoposide 80 /mdl, 2,3), followed by LI (3 x SD) with ABMT. Severe mucosistis prevented further dose escalation. ABMT was not necessary. 3) VE regimen: LI with VE (cyclophosphamide 10g to 200 mg/kg + etoposide 750 to 3.5 g/m- administered over 48 hours with ABMT) was given after 3 courses of AVE or CAVE (AVE + cisplatin 60 mg/m~ dl) at SD. Severe cardiac failure appeared to be the limitant extrahemopoietic toxicity. The need for ABMT could not be clearly shown. CAV
AVE
VE
Number of patients ~ -nO-I-6 CR before LI 5 3 3 CR before LI 6 3 8 Median duration of remission (months) 7 8 9 (range) (2-57+)(8-11)(3-36+) Median Survival 8.5 19 12 time (months) (range) (2-57+) (8-27)(3-36+) 3 year disease1 1 free survival We conclude that additional complete responses have been obtained with LI, however the duration of response and survival of the LI patients were poor. EORTC 08828: Induction Versus Induction Plus Maintenance Chemotherapy (ct) In Small Cell Lung Cancer. Phase II Evaluation. Splinter I, T., McVie, J., Dalesio, O., Kirkpatrick, A., Burghouts, J., Postmus, P., Veenhof, C., Giaccone, G., Kho, G., Bakker, W., ten Velde, G., Vendrik, C., v. Zandwijk, N., Palmen, F., Rozendaal, K., v.d. Burgh, M., v. Breukelen, F., Rinaldi, M., Kleisbauer, J., Gracia, J., Wils., J., Miech, G., Festen, J. i. University Hospital Dijkzigt, Rotterdam, The Netherlands. In August 82 a randomized phase III trial was started to investigate the (disease free) survival after 5 and 12 courses of ct. Study design: after registration pts were given 5 courses of ct and restaged. All pts with CR, PR or NC were stratified according to extent of disease, CR and PR or NC, symptomatic brain mts and randomized to follow-up or 7 courses of ct. All CRpts received prophyl, brain irr. No other radiother, was given. Selection criteria: ECOG 0-3, age < 70 yrs, no previous treatment, no uncontrolled cardiac disease or infection. (Re)staging: phys. exam, biochemistry, chest x-ray, CT-scan ultra-
sound, bone-marrow biopsy, bronchoscopy+biopsy, radionuclide bone scan. Definition of LD: tumor limited to one hemithorax, contralateral hilar nodes, supraclavicular nodes both sides. CT-re 2 gimen: cyclophos~hamide i000 mg/m daY21 , doxor-~-6~icin 45 mg/m day i, Vpl6 i00 mg/m day i, 3,5. Assessment of response: according to WHO (1979). In addition CR-pts should have no abnormalities at bronchoscopy. Results till randomization: 477 pts are registered. Overall response in 288 pts: CR 35%, PR 38,5%, NC 4,5%, PD 15%, early death in 28 pts (9,5%). Survival from registration XR=X-ravs: BR=bronchoscopy: ~orall
~
ED
no. o f pts 402 147 104 med. sRank u r v . swks ~i. a a l . 43 p 60 ( O , 0 045 02
~
P~NC
1;0 141 60 p ( O . O 0 2 45
~
BR+ BR- BR+
74 11 gO 41 55p ~800,0340 39 ; ~ - XR+ %R+
Concl.: CAvpl6 is effective in SCLC with a high response rate and very acceptable med. survival in a large group of pts. with hardly any selection; bronchoscopy dose not seem to improve the restaging by radiological methods. High Dose Teniposide (VM26) in The Treatment of Non-Small Cell Lung Cancer (NSCLC). Giaccone, G., Ferrati, P., Donadio, M., Calciati, A. Medical Oncology, Ospedale S. Giovanni A.S., 10123 Torino, Italy. 17 patients (pts) wi~h advanced NSCLC were given VM26 120-180 mg/m- on days i, 3 and 5, every 3 weeks, from October 1983 to December 1984. All were males, median age 58 yrs (range 4966), median P.S. (ECOG) 1 (range 0-2), i0 squamous cell, 3 adenocarcinoma, 3 large cell, 1 poorly differentiated histology; 9 extensive disease, ii pretreated (i RT, 4 RT+CT, 3 CT, 2 surg+CT, 1 surg+RT+CT). Overall 61 cycles were administered (mean 3.6 per patient, range 1-7). Among 17 evaluable patients 1 partial response (6.2%), 9 no change, and 7 progressions were obtained. The partial response lasted 7 months and occurred in a patient with locally advanced squamous cell carcinoma, already treated by RT and cisplatin-VP-16-213. Median survival was 41 weeks. The major toxicity was marrow toxicity: leukopenia (WBC nadir < 2000/mm ) was present in i0 pts (59%) and life-threatening thrombocytopenia occurred in 3 pts. Anemia and alopecia were common. Severe vomiting in 3 pts, moderate stomatitis in 2, diarrhoea in I, melano~ermia in 1 and mild peripheral neuropathy in 1 were side effects also observed. In conclusion VM26 is rather ineffective in NSCLC at the dose and schedule that we applied, though it has been recently demonstrated to be an active drug in small cell histology. Second Line Treatment With VM 26, Doxorubicin (DXR) and BCNU For Relapsed Non Small Cell Lung Cancer (NSCLC). Araujo, C., DeMarco, H., Batagelj, E., Saporiti,
status 70% (range 50-90), median age 52 years (31-68), limited disease (LD) B6, extensive disease (ED) 24, histological subgroups 28 large cell, 14 squamous cell, 8 adenocarcinoma. 21 pts (42%) achieved objective tumor response (CR+PR). LD pts: 8/26 (31%) PR following chemotherapy; 19% CR, 35% PR following additional radiotherapy. ED pts: 1/24 (4%) CR and 21% PR following chemotherapy; 4% CR, 25% PR after additional radiotherapy. Median survival of LD pts was 15.8 months, of ED pts 6.8 months (p < 0.002). Median response duration/survival of responders were 9(2-21)/16 (3-30) months. Responders survived significantly longer than on-responders (p<0.05). Side effects included myelosuppression, nausea, vomiting, and alopecia. No patient experienced persistent nephrotoxicity or severe neurotoxicity. Concerning remission rates and survival, no statistically significant differences c o u l d be demonstrated between the three vindesine schedules. In LD pts additional high-dose thoracic irradiation increased remission rates and seemed to prolong remission duration and survival.
Toxicity and Pretreatment Variables Related to Survival .in Small Cell Bronchogenic Carcinoma (SCBC) in Patients Treated With Cyclophosphamide, Methotrexate, and VP-16. Bonomi, P., Rosenberg, D., Rush Medical College, Chicago, Ii. Performance status, extent of disease, and previous weight loss have been shown to the important prognostic factors in SCBC. There is relatively little information concerning the impact of toxicity on prognosis. Fifty-six patients with SCBC were treated with cyclophosphamide 700 mgs. per square meter iv on days 1-2, methotrexate 15 mgs. per square meter orally on days 8,11,15,18,29,32,35 and 38, and VP-16 60 mg mgs per square meter iv daily on days 1 through 5 and 22 through 26. During the first cycle of therapy, doses were not modified for hematologic toxicity. Patient characteristics were the following: median age - 62 years, limited disease - 17 patients, extensive disease - 39 patients, performance status 0-i - 38, and performance status 2-18. Responses were the following: complete - 9 (16%) and partial - 28 /50%). With all patient having expired, the median survival was 28 weeks. The following toxicity was observed: WBC < 1,000 - 12(22%) with four deaths during febrile3episodes, platelet count < i00,000 per mm - 3(5%) pulmonary infiltrates - 8 (15%) with three (5%) pts dying from respiratory insufficiency, and mucositis - 24 (43%). Fortyseven patients completed induction therapy. The WBC was < 2,000/mm ~ in 25 patients. The mean survivals for patients with
WBC < 2,000 was 30,2 weeks compared to a mean survival of 49~7 weeks for patients with a WBC > 2,000/mm . Analysis of variance showed that these mean survivals were significantly different (p=0.03). Logistic regression analysis showed that pre-treatment parameters did not predict which patients would experience the greatest leukopenia (p = O . 7 8 ) . Mean survivals for patients who had dose reductions versus no dose reductions were 31.3 and 44.9 weeks respectively (p = 0.17). If these results are confirmed in a larger group of patients, the possibility of studying less toxic regimens should be considered in future SCBC trials.
Reinduction For Progressive Small Cell Lung Cancer ~SCLC) With the Induction Regimen. Postmus-, ~.E., v. Zandwi~k , N., Burghouts j, J., Bakker-, W., Splinter ~ T.~;W. ~. Dmpaztm ~ t ~ of Pulmonary Diseases, State University Groningen and 4,. Leiden. 2. Netherlands Cancer Institute Amsterdam. 3. Departments of Medical Oncology, Groot Ziekengasthuis, Den Bosch. 5. Dijkzigt Ziekenhuis Rotterdam. Despite the high initial remission rate after chemotherapy for SCLC only few patients ultimately will be long-term disease-free. Overall results are probably more dependent of the induction regimen than of the maintenance chemotherapy. With the aim of an improved quality of life several studies with short term chemotherapy have been reported, however, the optimal duration of treatment is still not defined. Retreatment after relapse is in most patients difficult due to a lack of active second line regimens with acceptable toxicity. In a phase II study we are evaluating the activity of the induction reqimen in patients with tumor progression. So far 23 patient~ received 5 c CDE (C~clophosphamide, 1 g~m doxorubicin 45 mg/m , etoposide i00 g/m day 1,3,5) and at relapse all patients received again CDE. The time between the end of induction and the retreatment was 20 weeks (median) (range 5-66). 13 patients responded (4 CR, 9PR), 6 patients had stable disease, 4 progression. These results make the use of short term chemotherapy for SCLC questionable although it is uncertain if overall survival will be different if compared with standard regimens (induction + maintenance). Regarding the high response rate, patients relapsing after short term chemotherapy are ideal candidates for phase II studies because drug-induced tumor cell resistance is apparently not yet present in the majority of the patients.
Late Intensification (LI) in Small Cell Lung Cancer (SCLC). Sculier, J.P., Klastersky, J. and the EORTC Lung Cancer Working Party, Institut J. Bordet Bruxelles, Belgium We performed three successive pilot studies of LI in SCLC: i) CAV regimen: CAV was given
122
for 2 to 3 courses2at standard dosage (SD) (cis~latin 60 mg/m dl + adri~mycine 45 mg/m dl + etoposide 120 mg/m--dl, 2,3); followed by LI (2 to 3 times SD) with autologous bone marrow transplantation (ABMT). Severe mucositis was the limiting extrahematological toxicity. 2) AVE regimen: AVE was given for 3 courses at SD (adriam~cin 45 mg/m- dl + cyc~ophosphamide 1 g/m- dl + etoposide 80 /mdl, 2,3), followed by LI (3 x SD) with ABMT. Severe mucosistis prevented further dose escalation. ABMT was not necessary. 3) VE regimen: LI with VE (cyclophosphamide 10g to 200 mg/kg + etoposide 750 to 3.5 g/m- administered over 48 hours with ABMT) was given after 3 courses of AVE or CAVE (AVE + cisplatin 60 mg/m~ dl) at SD. Severe cardiac failure appeared to be the limitant extrahemopoietic toxicity. The need for ABMT could not be clearly shown. CAV
AVE
VE
Number of patients ~ -nO-I-6 CR before LI 5 3 3 CR before LI 6 3 8 Median duration of remission (months) 7 8 9 (range) (2-57+)(8-11)(3-36+) Median Survival 8.5 19 12 time (months) (range) (2-57+) (8-27)(3-36+) 3 year disease1 1 free survival We conclude that additional complete responses have been obtained with LI, however the duration of response and survival of the LI patients were poor. EORTC 08828: Induction Versus Induction Plus Maintenance Chemotherapy (ct) In Small Cell Lung Cancer. Phase II Evaluation. Splinter I, T., McVie, J., Dalesio, O., Kirkpatrick, A., Burghouts, J., Postmus, P., Veenhof, C., Giaccone, G., Kho, G., Bakker, W., ten Velde, G., Vendrik, C., v. Zandwijk, N., Palmen, F., Rozendaal, K., v.d. Burgh, M., v. Breukelen, F., Rinaldi, M., Kleisbauer, J., Gracia, J., Wils., J., Miech, G., Festen, J. i. University Hospital Dijkzigt, Rotterdam, The Netherlands. In August 82 a randomized phase III trial was started to investigate the (disease free) survival after 5 and 12 courses of ct. Study design: after registration pts were given 5 courses of ct and restaged. All pts with CR, PR or NC were stratified according to extent of disease, CR and PR or NC, symptomatic brain mts and randomized to follow-up or 7 courses of ct. All CRpts received prophyl, brain irr. No other radiother, was given. Selection criteria: ECOG 0-3, age < 70 yrs, no previous treatment, no uncontrolled cardiac disease or infection. (Re)staging: phys. exam, biochemistry, chest x-ray, CT-scan ultra-
sound, bone-marrow biopsy, bronchoscopy+biopsy, radionuclide bone scan. Definition of LD: tumor limited to one hemithorax, contralateral hilar nodes, supraclavicular nodes both sides. CT-re 2 gimen: cyclophos~hamide i000 mg/m daY21 , doxor-~-6~icin 45 mg/m day i, Vpl6 i00 mg/m day i, 3,5. Assessment of response: according to WHO (1979). In addition CR-pts should have no abnormalities at bronchoscopy. Results till randomization: 477 pts are registered. Overall response in 288 pts: CR 35%, PR 38,5%, NC 4,5%, PD 15%, early death in 28 pts (9,5%). Survival from registration XR=X-ravs: BR=bronchoscopy: ~orall
~
ED
no. o f pts 402 147 104 med. sRank u r v . swks ~i. a a l . 43 p 60 ( O , 0 045 02
~
P~NC
1;0 141 60 p ( O . O 0 2 45
~
BR+ BR- BR+
74 11 gO 41 55p ~800,0340 39 ; ~ - XR+ %R+
Concl.: CAvpl6 is effective in SCLC with a high response rate and very acceptable med. survival in a large group of pts. with hardly any selection; bronchoscopy dose not seem to improve the restaging by radiological methods. High Dose Teniposide (VM26) in The Treatment of Non-Small Cell Lung Cancer (NSCLC). Giaccone, G., Ferrati, P., Donadio, M., Calciati, A. Medical Oncology, Ospedale S. Giovanni A.S., 10123 Torino, Italy. 17 patients (pts) wi~h advanced NSCLC were given VM26 120-180 mg/m- on days i, 3 and 5, every 3 weeks, from October 1983 to December 1984. All were males, median age 58 yrs (range 4966), median P.S. (ECOG) 1 (range 0-2), i0 squamous cell, 3 adenocarcinoma, 3 large cell, 1 poorly differentiated histology; 9 extensive disease, ii pretreated (i RT, 4 RT+CT, 3 CT, 2 surg+CT, 1 surg+RT+CT). Overall 61 cycles were administered (mean 3.6 per patient, range 1-7). Among 17 evaluable patients 1 partial response (6.2%), 9 no change, and 7 progressions were obtained. The partial response lasted 7 months and occurred in a patient with locally advanced squamous cell carcinoma, already treated by RT and cisplatin-VP-16-213. Median survival was 41 weeks. The major toxicity was marrow toxicity: leukopenia (WBC nadir < 2000/mm ) was present in i0 pts (59%) and life-threatening thrombocytopenia occurred in 3 pts. Anemia and alopecia were common. Severe vomiting in 3 pts, moderate stomatitis in 2, diarrhoea in I, melano~ermia in 1 and mild peripheral neuropathy in 1 were side effects also observed. In conclusion VM26 is rather ineffective in NSCLC at the dose and schedule that we applied, though it has been recently demonstrated to be an active drug in small cell histology. Second Line Treatment With VM 26, Doxorubicin (DXR) and BCNU For Relapsed Non Small Cell Lung Cancer (NSCLC). Araujo, C., DeMarco, H., Batagelj, E., Saporiti,