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neu expression and drug resistance for non-small cell lung cancer
Chemotherapy
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Phase II trial of MTA (Alimta TM) and cisplatin in patients with advanced Non-Small Cell Lung Cancer (NSCLC)
F.A. Shepherd, A. Arnold, A. Neville, J. Dancey, J. Rusthoven, B. Fisher, E. Eisenhauer. National Cancer Institute of Canada-Clinical
Trials Group, Kingston, ON, Canada, Eli Lilly and Company, Indianapolis, IN, USA MTA (Alimta TM, pemetrexed disodium, LY231514) is a multi-targeted anti-folate agent that inhibits enzymes in the folate pathway including thymidylate synthase, dihydrofolate reductase and GAR*formyl transferase. Phase II trials showed single-agent response rates of 16% and 23% in untreated pts with NSCLC. This study was undertaken to determine the response to MTA given with cisplatin. Previously untreated Stage IIIB or IV, PS 0-2 lOtSwere eligible if they had adequate hematology and biochemistry and bi-dimensionally measurable lesions. Pts with prior malignancy, brain mets, neuropathy > Grade 2 were excluded. MTA, 500 mg/m2 given over 10 mins and cisplatin 75 mg/m2 with hydration and mannitol diuresis were administered day 1 q 21 days. Dexamethasone 4 mg was taken orally q 12 hrs starting 24 hrs before and continuing for 6 doses after treatment. Treatment was given as an outpatient. Response was evaluated q 2 cycles. From 5/98-6/99 31 pts were treated: 20 male, 11 female; median age 60 yrs (35-75 yrs); 8 Stage IIIB, 23 Stage IV, 26 PS 0, 1 and 5 PS 2. In 30 evaluable pts, there were 1 CR and 12 PRs (ORR 43%, C1:26%63%), median duration 5.8 mos (2.3-9.1 mos). Three of four evaluable PS 2 pts achieved PR and 10 of 22 Stage IV pts responded (1 CR and 9 PR, ORR 45.5% in Stage IV). Median survival is 8.2 mos (1-15 mos). A total of 149 courses were delivered (median 4 for cisplatin and 5 for MTA). Grade 3/4 anemia was seen in 5/1 pts and Grade 3/4 neutropenia in 7/3 pts respectively. Grade 3 vomiting occurred in only 2 pts, Grade 3/4 diarrhea in 3 pts, and 1 pt had Grade 3 motor neuropathy. Nine pts had Grade 2 infections and there was 1 case of febrile neutropenia. In summary, MTA and cisplatin is an active welltolerated, out-patient regimen. It deserves further study to compare it to other regimens for NSCLC.
Phase II study of docetaxel (DOC) and carboplatin (CP)
as second-line treatment in patients (pts) with advanced non-small cell lung cancer (NSCLC) J.W.G. van Putten, D.J. Slebos, H.J.M. Groen. Dept. of Pulmonary Diseases, University Hospital, Groningen, The Netherlands Chemotherapy in pts with advanced NSCLC who failed, or relapsed after previous treatment is rather disappointing. Administered in secondline setting DOC seems to have promising activity and improve survival and quality of life. In this phase II trial we studied the effects of the combination of DOC 75 mg/m 2 and CP AUC 6 mg/ml.min administered in a 21-day cycle as second-line treatment in NSCLC. A maximum of 5 cycles (cy) were administered. Pts were included with a diagnosis of NSCLC, stage IIIb/IV, previous treatment with chemo- or radiotherapy, PS below 2, adequate bone marrow reserve, and liver and renal function. Toxicity was scored on day 1, 12 and 22 of each cycle. In 1999 28 pts were included: 16 male and 12 female, median age was 56 yrs (range 30-73), stage IIIb/IV; 5/23 pts, PS 0/1/2; 7/18/3 pts, histology adeno/squamous/large cell; 10/15/3 pts, prior treatment; gemcitabine in 1 pt, epirubicin/gemcitabine in 17 pts, cisplatin/gemcitabine in 6 pts, and thoracic radiotherapy (60 Gy) in 4 pts, median interval from prior treatment was 24 wks (range 2-100). 28 pts are evaluable for toxicity and 27 for tumor response. Median number of cycles 4 (range 1-5). Reasons to stop treatment earlier were progression in 9 pts, own request after 4 cy in 2 pts, hematological toxicity in 2 pts, nonhematological toxicity in 2 pts, toxic death in 2 pts. Hematological toxicity in a total of 93 cy was CTC grade 3/4 (%cy); leukocytopenia 37/14, granulocytopenia 40/30, thrombocytopenia 6/6. Febrile neutropenia occurred in 3 pts after 1, 2 and 4 cy, of whom 2 pts died. Non-hematological toxicity CTC grade 3/4 (number of pts); nausea 0/0, fatigue 4/1, polyneuropathy 0/0, muscle and joint pain in 4 pts, nail alterations in 4 pts. Delay next cycle for 1 or 2 wks was necessary in 10 and 2 cy, resp. Dose reductions of DOC to 75% after first cy in
13
3 pts. Blood transfusions were given in 9 pts, no platelet transfusions were necessary. Best tumour responses were: 10 PR, 8 SD, 7 PD, 2 NE. Overall response rate 37%. Median time to progression is 15 wks, median survival is 32 wks (95%CI 16-47), median survival after PR is 41 wks (95%CI 29-52). Quality of Life was scored, but has to be analyzed. Conclusion: The combination of docetaxel and carboplatin is active in second-line treatment in pts with NSCLC.
Tuesday, 12 September 2000
4:00-5:00 pm
ORAL SESSION
Chemotherapy relationship between HER2/neu expression and drug [31313•The resistance for non-smaU cell lung cancer K. Matsuyama, S. Oura, 1". Yoshimasu, T. Sakurai, T. Nakamura, Y. Kokawa, H. Ohta, Y. Naito. Wakeyama Medical College,
Wakayama, Japan Background: HER2/neu is a well-known growth factor receptor which exists in many kinds of tumors, and HER2/neu positive case has been associated with a lower response to chemotherapy. A recent study reported that administration of anti-HER2/neu agent increases the effect of chemotherapy, so HER2/neu may be correlated with drug resistance in itself. Purpose: The purpose of this study was to investigate the relationship between HER2/neu expression and the results of an in vitro drug response testing in non-small cell lung cancer (NSCLC), and to clarify whether HER2/neu is a drug resistant factor of NSCLC. Materials and Methods: We analyzed the tissue expression of HER2/neu in 85 NSCLC cases, who underwent surgical resection and had neither induction nor adjuvant chemotherapy. Formalin-fixed, paraffin-embedded tumor specimens were stained immunohistochemically to characterize HER2/neu expression. According to HER2/neu expression, this series was divided into two groups; HER2/neu positive cases (Group HER2/neu(+), n = 36) and HER2/neu negative cases (Group HER2/neu(-), n = 49). We performed an in vitro drug response testing by the formazan-based MTT assay (Histoculture Drug Response Assay; HDRA) with CDDP, 5-FU, ADM, MMC, VP-16 and SN38, and the inhibition rate (IR) was applied to evaluate sensitivity. We compared IR and overall survival among these two groups. Results: There was no significant difference in IR between two groups. IR for CDDP, 5-FU, MMC, ADM, VP-16 and SN38 were 36 +- 19%, 44 +- 18%, 62 +- 17%, 51 +- 23%, 34 +- 22%, 42 +- 22% in Group HER2/neu(+), and 38 +- 19%, 47 +- 23%, 62 +- 19%, 42 +- 23%, 32 +- 23%, 33 +- 26% in Group HER2/neu(-), respectively. However, survival rates of HER2/neu(+) (87.7%; 1 year, 70.3%; 2 year) was significantly inferior to those of HER2/neu(-) (100%; 1 year, 100%; 2 year). Conclusions: It was clarified that HER2/neu was not a drug resistant factor of NSCLC in itself, and was associated with poor prognosis. It was concluded that poor prognosis under chemotherapy does not mean drug resistance in patients with HER2/neu positive lung cancer.
[~
Increased activity of the cisplatin to UCN-01 treatment sequence is associated with M-phase and p53-independent induction of p27/Kip 1 in Non-Small Cell Lung Carcinoma (NSCLC) cells P.H. Gurnerlock, P.C. Mack, A.H. Lau, D.R. Gandara. University of California, Davis Cancer Center, Sacramento, California, USA
The cyclin-dependent kinase (Cdk) inhibitor 7-hydroxystaurosporine (UCN-01)(U) has anticancer activity, induces a p53-independent, RBdependent G1 arrest, and potentiates the DNA damaging agent cisplatin (C) by abrogating the G2 checkpoint arrest. We previously
F•
Phase II trial of MTA (Alimta TM) and cisplatin in patients with advanced Non-Small Cell Lung Cancer (NSCLC)
F.A. Shepherd, A. Arnold, A. Neville, J. Dancey, J. Rusthoven, B. Fisher, E. Eisenhauer. National Cancer Institute of Canada-Clinical
Trials Group, Kingston, ON, Canada, Eli Lilly and Company, Indianapolis, IN, USA MTA (Alimta TM, pemetrexed disodium, LY231514) is a multi-targeted anti-folate agent that inhibits enzymes in the folate pathway including thymidylate synthase, dihydrofolate reductase and GAR*formyl transferase. Phase II trials showed single-agent response rates of 16% and 23% in untreated pts with NSCLC. This study was undertaken to determine the response to MTA given with cisplatin. Previously untreated Stage IIIB or IV, PS 0-2 lOtSwere eligible if they had adequate hematology and biochemistry and bi-dimensionally measurable lesions. Pts with prior malignancy, brain mets, neuropathy > Grade 2 were excluded. MTA, 500 mg/m2 given over 10 mins and cisplatin 75 mg/m2 with hydration and mannitol diuresis were administered day 1 q 21 days. Dexamethasone 4 mg was taken orally q 12 hrs starting 24 hrs before and continuing for 6 doses after treatment. Treatment was given as an outpatient. Response was evaluated q 2 cycles. From 5/98-6/99 31 pts were treated: 20 male, 11 female; median age 60 yrs (35-75 yrs); 8 Stage IIIB, 23 Stage IV, 26 PS 0, 1 and 5 PS 2. In 30 evaluable pts, there were 1 CR and 12 PRs (ORR 43%, C1:26%63%), median duration 5.8 mos (2.3-9.1 mos). Three of four evaluable PS 2 pts achieved PR and 10 of 22 Stage IV pts responded (1 CR and 9 PR, ORR 45.5% in Stage IV). Median survival is 8.2 mos (1-15 mos). A total of 149 courses were delivered (median 4 for cisplatin and 5 for MTA). Grade 3/4 anemia was seen in 5/1 pts and Grade 3/4 neutropenia in 7/3 pts respectively. Grade 3 vomiting occurred in only 2 pts, Grade 3/4 diarrhea in 3 pts, and 1 pt had Grade 3 motor neuropathy. Nine pts had Grade 2 infections and there was 1 case of febrile neutropenia. In summary, MTA and cisplatin is an active welltolerated, out-patient regimen. It deserves further study to compare it to other regimens for NSCLC.
Phase II study of docetaxel (DOC) and carboplatin (CP)
as second-line treatment in patients (pts) with advanced non-small cell lung cancer (NSCLC) J.W.G. van Putten, D.J. Slebos, H.J.M. Groen. Dept. of Pulmonary Diseases, University Hospital, Groningen, The Netherlands Chemotherapy in pts with advanced NSCLC who failed, or relapsed after previous treatment is rather disappointing. Administered in secondline setting DOC seems to have promising activity and improve survival and quality of life. In this phase II trial we studied the effects of the combination of DOC 75 mg/m 2 and CP AUC 6 mg/ml.min administered in a 21-day cycle as second-line treatment in NSCLC. A maximum of 5 cycles (cy) were administered. Pts were included with a diagnosis of NSCLC, stage IIIb/IV, previous treatment with chemo- or radiotherapy, PS below 2, adequate bone marrow reserve, and liver and renal function. Toxicity was scored on day 1, 12 and 22 of each cycle. In 1999 28 pts were included: 16 male and 12 female, median age was 56 yrs (range 30-73), stage IIIb/IV; 5/23 pts, PS 0/1/2; 7/18/3 pts, histology adeno/squamous/large cell; 10/15/3 pts, prior treatment; gemcitabine in 1 pt, epirubicin/gemcitabine in 17 pts, cisplatin/gemcitabine in 6 pts, and thoracic radiotherapy (60 Gy) in 4 pts, median interval from prior treatment was 24 wks (range 2-100). 28 pts are evaluable for toxicity and 27 for tumor response. Median number of cycles 4 (range 1-5). Reasons to stop treatment earlier were progression in 9 pts, own request after 4 cy in 2 pts, hematological toxicity in 2 pts, nonhematological toxicity in 2 pts, toxic death in 2 pts. Hematological toxicity in a total of 93 cy was CTC grade 3/4 (%cy); leukocytopenia 37/14, granulocytopenia 40/30, thrombocytopenia 6/6. Febrile neutropenia occurred in 3 pts after 1, 2 and 4 cy, of whom 2 pts died. Non-hematological toxicity CTC grade 3/4 (number of pts); nausea 0/0, fatigue 4/1, polyneuropathy 0/0, muscle and joint pain in 4 pts, nail alterations in 4 pts. Delay next cycle for 1 or 2 wks was necessary in 10 and 2 cy, resp. Dose reductions of DOC to 75% after first cy in
13
3 pts. Blood transfusions were given in 9 pts, no platelet transfusions were necessary. Best tumour responses were: 10 PR, 8 SD, 7 PD, 2 NE. Overall response rate 37%. Median time to progression is 15 wks, median survival is 32 wks (95%CI 16-47), median survival after PR is 41 wks (95%CI 29-52). Quality of Life was scored, but has to be analyzed. Conclusion: The combination of docetaxel and carboplatin is active in second-line treatment in pts with NSCLC.
Tuesday, 12 September 2000
4:00-5:00 pm
ORAL SESSION
Chemotherapy relationship between HER2/neu expression and drug [31313•The resistance for non-smaU cell lung cancer K. Matsuyama, S. Oura, 1". Yoshimasu, T. Sakurai, T. Nakamura, Y. Kokawa, H. Ohta, Y. Naito. Wakeyama Medical College,
Wakayama, Japan Background: HER2/neu is a well-known growth factor receptor which exists in many kinds of tumors, and HER2/neu positive case has been associated with a lower response to chemotherapy. A recent study reported that administration of anti-HER2/neu agent increases the effect of chemotherapy, so HER2/neu may be correlated with drug resistance in itself. Purpose: The purpose of this study was to investigate the relationship between HER2/neu expression and the results of an in vitro drug response testing in non-small cell lung cancer (NSCLC), and to clarify whether HER2/neu is a drug resistant factor of NSCLC. Materials and Methods: We analyzed the tissue expression of HER2/neu in 85 NSCLC cases, who underwent surgical resection and had neither induction nor adjuvant chemotherapy. Formalin-fixed, paraffin-embedded tumor specimens were stained immunohistochemically to characterize HER2/neu expression. According to HER2/neu expression, this series was divided into two groups; HER2/neu positive cases (Group HER2/neu(+), n = 36) and HER2/neu negative cases (Group HER2/neu(-), n = 49). We performed an in vitro drug response testing by the formazan-based MTT assay (Histoculture Drug Response Assay; HDRA) with CDDP, 5-FU, ADM, MMC, VP-16 and SN38, and the inhibition rate (IR) was applied to evaluate sensitivity. We compared IR and overall survival among these two groups. Results: There was no significant difference in IR between two groups. IR for CDDP, 5-FU, MMC, ADM, VP-16 and SN38 were 36 +- 19%, 44 +- 18%, 62 +- 17%, 51 +- 23%, 34 +- 22%, 42 +- 22% in Group HER2/neu(+), and 38 +- 19%, 47 +- 23%, 62 +- 19%, 42 +- 23%, 32 +- 23%, 33 +- 26% in Group HER2/neu(-), respectively. However, survival rates of HER2/neu(+) (87.7%; 1 year, 70.3%; 2 year) was significantly inferior to those of HER2/neu(-) (100%; 1 year, 100%; 2 year). Conclusions: It was clarified that HER2/neu was not a drug resistant factor of NSCLC in itself, and was associated with poor prognosis. It was concluded that poor prognosis under chemotherapy does not mean drug resistance in patients with HER2/neu positive lung cancer.
[~
Increased activity of the cisplatin to UCN-01 treatment sequence is associated with M-phase and p53-independent induction of p27/Kip 1 in Non-Small Cell Lung Carcinoma (NSCLC) cells P.H. Gurnerlock, P.C. Mack, A.H. Lau, D.R. Gandara. University of California, Davis Cancer Center, Sacramento, California, USA
The cyclin-dependent kinase (Cdk) inhibitor 7-hydroxystaurosporine (UCN-01)(U) has anticancer activity, induces a p53-independent, RBdependent G1 arrest, and potentiates the DNA damaging agent cisplatin (C) by abrogating the G2 checkpoint arrest. We previously