- Email: [email protected]
Synergistic effect of ONYX-015 and chemotherapy on lung cancer cell lines and primary cultures
124
Combined Modality Therapy
nuclei staining with DAPI followed by fluorescence microscopy. Both of 14-member macrolides enhanced chemotherapeutic agent-induced apoptosis of wild type (wt) p53 carrying NSLC cells whereas 16member macrolides did not. Fourteen-member macrolides increased the level of p53 in NSLC cells with wt p53 whereas these agents decreased the level of bcl-2 in the cells. On the contrary, in p53 null H358 cells, neither anticancer agent alone nor combination of 14member macrolide and anticancer agent induced apoptosis. Then we evaluated the effect of macrolide antibiotics on the expression of CD95 in NSLC cells. Chemotherapeutic agents induced the cell surface CD95 and CD95 mRNA expression in wt p53 NSLC cells. Combination treatment of 14-member macrolide and anticancer agent enhanced these effects. Pretreatment with antagonistic anti-CD95 antibody did not inhibit the 14-member macrolide plus anticancer agent-induced apoptosis in wt p53 NSLC cells. Finally, we evaluated the effect of p53 antisense oligonucleotide on the apoptosis enhanced by the combined treatment, and we observed that the enhanced apoptosis was inhibited by pretreatment with p53 antisense oligonucleotide. These results indicate that 14-member macrolides enhance the anticancer agent-induced apoptosis in NSLC cells by p53 dependent, CD95independent fashion.
complications of surgery were related only after major surgical interventions (pneumonectomy) and are in the range of an accepted international standard (6.8%) and frequency of postoperative complications was significantly correlated with exploratory thoracotomy and pneumonectomy as compared with Iobectomy. Survival: with a median follow-up of 15 months [2-60], overall survival was 40% at 23 months. Prognostic factors for survival (univariate analysis) were: weight loss (<5% vs. >5%: 60% vs. 12%), performance status (0-1 vs. 2: 62% vs. y 22%), clinical stage (I vs. II vs. IIh 60% vs. 56% vs. 32%), pathological stage (I vs. II vs. IliA vs. IIIB: 93% vs. 56% vs. 16% vs. 10%), histology (carcinoid vs. squamous vs. large cell vs. adenocarcinoma: 71% vs. 48% vs. 32% vs. 20%), residual disease (R0 vs. R1 vs. R2: 55% vs. 21% vs. 0%) and treatment strategy for stage III patients (neoadjuvant chemotherapy surgery vs. initial surgery: 51% vs. 17%). Conclusion: Our results confirm the improvement of prognosis in NSCLC in the last 5 years in Cluj (median survival 21 months, in 161 resected patients), mainly due to a better quality of the surgical act and a more effective pluridisciplinary approach.
14-•
A.H.K. Djang. Jamestown, New York 14701, USA
High frequency electrical knife through fibrebronchoscope in treatment of tracheal tumor with large airway obstruction
G.Q. Wang, M.J. Xie, F. Chi, Y. He. Guangzhou Institute of Respiratory Disease, Guangzhou, P.R. China From May 1985 to June 1999, high frequency electrical knife (HFEK) Through fibrobronchoscope was used to treat the large airway obstruction by tracheal tumor in 28 patients (Cystuc adenoid carcinoma: 17, Squamous cell carcinoma: 8. Undifferentiated small cell carcinoma: 1. and neurinoma: 2). Most of the tracheal tumors were Inoperable because of extensive lesions or poor lung function. Olympus B F B B3R, B F p 30 Type or Pentax B F 15 P Type fibrobronchoscope, Olympus UES or PSD-10 high frequent electricity producer with a home-made electrical and CD-5P knife were used. After 81 time of HFEK cautery of tracheal tumors, all patients showed remakable improvement in lung function and exertional dyspnea. HFEK is valuable in relieving dyspnea in patients with large airway obstruction by tracheal tumor. After endoscopic cautery to release the tumor obstruction of trachea, it is often necessary to add radiotherapy and chemotherapy (26 malignant cases used) to get betteer results. In our series 5 patients had stents inserted to maintain the potency of trachea.
[4•1
Integration of surgery in the pluridisciplinary approach of non-small cell cancer patients improves the outcome
A. loan, T. Ciuleanu, T. Guttman, N. Ghilezan. Oncological Institute CIuj-Napoca, Romania Purpose: To assess the results obtained in stage I to III NSCLC patients, treated with surgery alone or integrated in a pluridisciplinary approach, following the decision taken by the Lung Committee of the Oncological Institute CIuj (OIC). Endpoints: correspondence between clinical and pathological staging, complications of surgery, survival, prognostic factors. Methods and Materials: From January 1994 through December 1998 a prospective nonrandomized study was carried on at OIC, on 161 operated NSCLC patients. The TNM system advocated by the AJCC was used and was determined on CT findings. Although more than half (57%) patients had clinical Iocoregional advanced disease clinical stage Ill-A), surgery was initially performed at 125 pts. and 36 pts. received neoadjuvant chemotherapy (platinum containing regimen) followed by surgical resection. 109 pts. underwent complete surgical resection (R0) and depending on pTN pT3-T4 or/and pN1N2) they received adjuvant therapy. Results: Correspondence between clinical and pathological staging was 70%, with regard to the T category, the agreement between cT vs. pT reached 78% and to the N category, 80%. Lethal
•4-•
Oncolyn causes clinical remission of diffuse malignant pulimonary imesothelioma and other solid tumors in man*
Median survival of malignant diffuse thoracic mesothelioma is less than 6 months. From the time of definitive pathology diagnosis, approximately 90% of the patients are dead within a period of one year. Treatment with surgery, radiation, chemotherapy and a combination of methods has been attempted but is usually unsuccessful Oncolyn is a formulated combination of extracts from three edible plants (US patent) composed mainly of bioflavonoids and polyphenols. It was demonstrated to be clinically effective against cancers of the breast, lung, colon and prostate in mouse and man. In 1999, we used Oncolyn for one terminal pulmonary mesothelioma patient and achieved a clinical remission in 6 months. A terminal disseminated intraosseous lymphoma patient also achieved clinical remission in 6 months with Oncolyn therapy. Both patients are functioning well and working full time as of January 2000. To date, six plant derived anticancer medications (taxol, vinblastine, vincristine, topotecan, etoposide and teniposide) are used extensively in the United States. Others such as camptothecin are evaluated in clinical trials world-wide. Oncolyn was imtially evaluated with the mouse subrenal capsule assay technique for its anticancer activity by itself or in combination with standard chemotherapeutic agents such as Cytoxan, 5FU and Methotrexate. The present poster will depict experiences with Oncolyn for malignant mesothelioma, disseminated intraosseous lymphoma, seminoma with embryonal carcinoma component and carcinomas of the breast, prostate, lung and colon. Illustrative surgical pathology, CT, MRI, nuclear scan, clinical data with tumor markers and photomicrographs will be on display. 6 references and 15 illustrations. *supported in part by a grant from Sante International, USA
•
Synergistic effect of ONYX-015 and chemotherapy on lung cancer cell lines and primary cultures
L. You, C. Yang, C. Clare-Macy, D.M. Jablons. University of California, San Francisco, San Francisco, CA 94115, USA ONYX-015, the mutant adenovirus which has a deletion in the E1B region, has shown tumor-specific cytolysis effect in tumor cells with non-functional p53. In this study, we carried out cytopathic effect (CPE) assays using ONYX-015 on five lung cancer cell lines with known p53 status and seven primary lung cancer cultures. In 6-well plates, cells were infected with either ONYX-015 or with wild-type adenovirus at increasing multiplicities of infection (MOI). For the synergistic effect, the viruses were applied right after chemotherapeutic agents. The plates were stained with crystal violet and then analyzed. Five non-small cell lung cancer (NSCLC) cells were all lysed by ONYX-015. Synergistic
Combined Modality Therapy effect with chemotherapeutic agents (paclitaxel and cisplatin) were clearly shown. Furthermore, we tested the cytolytic effect of ONYX015 on a panel of primary cultures freshly made from 7 patients with lung cancer. ONYX-015 can lyse primary cultures and the synergistic effect was also shown. Our data demonstrates that ONYX-015 can work synergistically with chemotherapeutic agents in lung cancer cell lines and primary cultures. This study suggests that ONYX-015 can be used, in combination with conventional chemotherapy, for the treatment of patients with lung cancer.
•1--•
Pulsed paclitaxel radiosensitization for thoracic malignancy: A therapeutic approach based on preclinical research of human lung cancer cells
Y. Chen, K. Pandya, P. Okunieff, R. Feins, P. Keng, T. Smudzin, R. Raubertas, J. Rosenblatt. University of Rochester, Rochester, New
York, USA Background: A phase 1/11clinical trial for thoracic malignancy was conducted based on pre-clinical laboratory data of cell cycle effects of paclitaxel on human lung cancer cells. Taxanes have been shown to enhance radiation sensitivity of tumor cells by either G2/M arrest of cell cycle, which is the most radiosensitivity phase of the cell cycle, or by improving reoxygenation of radioresistant hypoxic cells. The theoretical advantages of our trial design are to enhance radiation cell kill by optimally integrating the timing of paclitaxel treatments with irradiation, and to decrease treatment related toxicity using low dose pulsed paclitaxel. Methods: Patients with inoperable/unresectable non-small cell carcinoma or mesothelioma were eligible. Pulsed paclitaxel was delivered three times per week in the morning of Mondays, Wednesdays, and Fridays with a starting dose of 15 mg/m2. Daily thoracic radiotherapy was delivered with 60-64 Gy to gross disease. Timing of radiotherapy was designed to allow for a minimum of 5 to 24 hours for cell cycle progression. Results: 22 patients have enrolled and 15 completed treatments (6 at 15 mg/m2; 5 at 20 mg/m2; and 4 at 25 mg/m2). One patient is starting treatment and 6 patients did not complete protocol treatments due to (1) acute allergic reactions in 2; (2) distant disease spread during therapy in 3, and (3) an incidental pneumonia which was outside of the radiation fields associated with bacteremia without neutropenia. Stage distribution of non-small cell carcinoma for patients completed therapy was: 2 stage I, 1 stage II, 3 stage IliA, and 8 stage IIIB. One patient with mesothelioma has stage II disease. Results: Average primary tumor shrinkage at approximately 1 month post-therapy was 83% + 8% (95% C.I.). Overall Iocoregional tumor response rate was 100% [22% (2/15) CR and 78% (13/15) PR]. There was no treatment interruption from acute side effects of therapy. Dose limiting toxicity included 1/15 grade 3 pneumonitis and 3/15 grade 3 esophagitis. There was no grade 4 pneumonitis and esophagitis. There were no grade 3/4 neutropenia, thrombocytopenia, neuropathy or cardiac arrhythmia. Non-dose limiting toxicity included 2/15 transient hyperglycemia from steroid pre-medication, 1/15 skin reaction from electron radiation, and 15/15 grade 3 lymphocytopenia. Conclusions: Pulsed paclitaxel radiosensitization for thoracic malignancy showed early and remarkable Iocoregional tumor response rates, including a mesothelioma histology which is known to be resistant to both radiotherapy and chemotherapy. Concurrent pulsed paclitaxel and radiotherapy schedule was well tolerated with low rates of dose-limiting toxicity.
125
response to combined medality treatment, and more specifically the risk of brain failure so as to evaluate the need for cerebral prophylaxis. Methods: Data from 3 consecutive studies performed between 1983 and 1996 were collected: 1°) the CEBI 138, a phase III trial comparing thoracic radiotherapy (TRT) to sequential combination of chemotherapy (CT) and TRT (353 pts); 2°) the CEBI 140, a phase II trial evaluating concomitant hyperfractionated TRT and CT (33 pts) and finally the CEBI 142, a phase II trial evaluating an induction treatment with TRT and CT before surgery (40 pts). Only pts with local control were analysed (165 out of 426 pts). Median age was 58. Sex ratio was: 154 men for 11 women. Distribution according to stage was: 17 Stage II, 88 Stage Ilia and 60 Stage IIIB pts. All pts except 4 had TRT, 104 pts had CT and 28 pts had surgery. Results: The 5-year disease free survival rate was 12% and the overall survival rate was 15%. The 5-year cumulative incidence of first events was 29% for intercurrent death (52 pts), 28% for extracerebral distant metastases (46 pts), 20% for local relapse (34 pts) and finally 11% only for brain metastases (19 pts). The 5-year brain metastasis rate as first site of failure according to treatment was: 11% both in pts who had and did not have CT; 4% in pts who had surgery and 13% in pts who had no surgery (p < 0.16). There was no difference according to stage or histology. Conclusion: The risk of brain failure as first event was only 11% in pts with LANSCLC so that prophylactic cranial irradiation does not seem warranted in such a population of pts. PCI could be evaluated in pts who receive combined modality treatment including surgery.
•7]
Introduction of resistance to ONYX-015 by re-expressing p 14ARF in human mesothelioma cells: Implications for therapy
C. Yang, L. You, J. Song, DM. Jablons. University of California, San
Francisco, San Francisco, CA 94115, USA To test if ONYX-015 can be used as a potential therapeutic agent for mesotheliomas. In previous studies, a mutant adenovirus ONYX015 has been shown to lyse cervical carcinoma, colon adenocarcinoma, glioblastoma, and pancreatic adenocarcinoma cell lines with abnormalities in p53 genes. However, previous report has also shown the cytolytic effect of this adenovirus on tumor cell lines with normal sequences in exons 5 to 9 of p53 gene. The p14ARF protein encoded from the INK4a/ARF locus functions to promote MDM2 degradation and thus prevents MDM2is neutralization of p53. Homozygous deletions of the INK4a/ARF locus was reported to be a predominant event at a frequency of over 70% in mesothliomas, in which might result in loss of p14ARF and functional inactivation of p53. Such an inactivation of p53 might thus make mesothelioma a potential target for ONYX015 adenovirus therapy. In the present study, we evaluated the ability of ONYX-015 adenovirus to lyse mesothelioma cells, and elucidate the possible mechanism involved in this effect. ONYX-015 lysed H28 and 211H cells effectively, but not MS-1 cells. Immunoblotting assay revealed that absence of p 14ARF expression in H28 cell line, while p 14ARF expression was found in MS-1 cells. Transfection with Adp14 resulted in an increase in the amount of p53 expression in the H28 and 211H cell lines, and these cells with tranfected P14 become more resistant to the virus. Our results indicate that mesothelioma may be a potential target for ONYX-015 adenoviral therapy.
•
Pulmonary biastoma- 11 years experience
A. Zaidi, J. Barry, F.R. Macbeth, N. Kulatilake. University Hospital of
•1-•
Brain relapse in patients with locally advanced non small cell lung cancer (LANSCLC): Is there a place for prophylactic cranial irradiation (PCI)?
C. Le Pechoux, A. Laplanche, J.J. Bretel, M. Tarayre, P. Girard, D. Grunenwald, P. Ruffi~, 12 Le Chevalier. Institut Gustave Roussy,
94805, Villejuif,, France Purpose: To estimate by a competing risks approach, the failure rates of patients (pts) with LANSCLC who had a complete or a partial
Wales, Cardiff, Wales; Velindra Hospital, Cardiff, Wales, UK Objective: To evaluate the clinical features and management of patients presenting with pulmonary blastoma. Methods: Patients with a diagnosis of pulmonary blastoma were identified from the period 1988 to 1999 via the regional pathology laboratory. Specimens were obtained from bronchoscopy, FNA, trucut biopsy and thoracotomy. Results: Six cases of pulmonary blastoma were identified out of 2720 pulmonary malignancies (0.2%). Sex ratio was equal, with a
Combined Modality Therapy
nuclei staining with DAPI followed by fluorescence microscopy. Both of 14-member macrolides enhanced chemotherapeutic agent-induced apoptosis of wild type (wt) p53 carrying NSLC cells whereas 16member macrolides did not. Fourteen-member macrolides increased the level of p53 in NSLC cells with wt p53 whereas these agents decreased the level of bcl-2 in the cells. On the contrary, in p53 null H358 cells, neither anticancer agent alone nor combination of 14member macrolide and anticancer agent induced apoptosis. Then we evaluated the effect of macrolide antibiotics on the expression of CD95 in NSLC cells. Chemotherapeutic agents induced the cell surface CD95 and CD95 mRNA expression in wt p53 NSLC cells. Combination treatment of 14-member macrolide and anticancer agent enhanced these effects. Pretreatment with antagonistic anti-CD95 antibody did not inhibit the 14-member macrolide plus anticancer agent-induced apoptosis in wt p53 NSLC cells. Finally, we evaluated the effect of p53 antisense oligonucleotide on the apoptosis enhanced by the combined treatment, and we observed that the enhanced apoptosis was inhibited by pretreatment with p53 antisense oligonucleotide. These results indicate that 14-member macrolides enhance the anticancer agent-induced apoptosis in NSLC cells by p53 dependent, CD95independent fashion.
complications of surgery were related only after major surgical interventions (pneumonectomy) and are in the range of an accepted international standard (6.8%) and frequency of postoperative complications was significantly correlated with exploratory thoracotomy and pneumonectomy as compared with Iobectomy. Survival: with a median follow-up of 15 months [2-60], overall survival was 40% at 23 months. Prognostic factors for survival (univariate analysis) were: weight loss (<5% vs. >5%: 60% vs. 12%), performance status (0-1 vs. 2: 62% vs. y 22%), clinical stage (I vs. II vs. IIh 60% vs. 56% vs. 32%), pathological stage (I vs. II vs. IliA vs. IIIB: 93% vs. 56% vs. 16% vs. 10%), histology (carcinoid vs. squamous vs. large cell vs. adenocarcinoma: 71% vs. 48% vs. 32% vs. 20%), residual disease (R0 vs. R1 vs. R2: 55% vs. 21% vs. 0%) and treatment strategy for stage III patients (neoadjuvant chemotherapy surgery vs. initial surgery: 51% vs. 17%). Conclusion: Our results confirm the improvement of prognosis in NSCLC in the last 5 years in Cluj (median survival 21 months, in 161 resected patients), mainly due to a better quality of the surgical act and a more effective pluridisciplinary approach.
14-•
A.H.K. Djang. Jamestown, New York 14701, USA
High frequency electrical knife through fibrebronchoscope in treatment of tracheal tumor with large airway obstruction
G.Q. Wang, M.J. Xie, F. Chi, Y. He. Guangzhou Institute of Respiratory Disease, Guangzhou, P.R. China From May 1985 to June 1999, high frequency electrical knife (HFEK) Through fibrobronchoscope was used to treat the large airway obstruction by tracheal tumor in 28 patients (Cystuc adenoid carcinoma: 17, Squamous cell carcinoma: 8. Undifferentiated small cell carcinoma: 1. and neurinoma: 2). Most of the tracheal tumors were Inoperable because of extensive lesions or poor lung function. Olympus B F B B3R, B F p 30 Type or Pentax B F 15 P Type fibrobronchoscope, Olympus UES or PSD-10 high frequent electricity producer with a home-made electrical and CD-5P knife were used. After 81 time of HFEK cautery of tracheal tumors, all patients showed remakable improvement in lung function and exertional dyspnea. HFEK is valuable in relieving dyspnea in patients with large airway obstruction by tracheal tumor. After endoscopic cautery to release the tumor obstruction of trachea, it is often necessary to add radiotherapy and chemotherapy (26 malignant cases used) to get betteer results. In our series 5 patients had stents inserted to maintain the potency of trachea.
[4•1
Integration of surgery in the pluridisciplinary approach of non-small cell cancer patients improves the outcome
A. loan, T. Ciuleanu, T. Guttman, N. Ghilezan. Oncological Institute CIuj-Napoca, Romania Purpose: To assess the results obtained in stage I to III NSCLC patients, treated with surgery alone or integrated in a pluridisciplinary approach, following the decision taken by the Lung Committee of the Oncological Institute CIuj (OIC). Endpoints: correspondence between clinical and pathological staging, complications of surgery, survival, prognostic factors. Methods and Materials: From January 1994 through December 1998 a prospective nonrandomized study was carried on at OIC, on 161 operated NSCLC patients. The TNM system advocated by the AJCC was used and was determined on CT findings. Although more than half (57%) patients had clinical Iocoregional advanced disease clinical stage Ill-A), surgery was initially performed at 125 pts. and 36 pts. received neoadjuvant chemotherapy (platinum containing regimen) followed by surgical resection. 109 pts. underwent complete surgical resection (R0) and depending on pTN pT3-T4 or/and pN1N2) they received adjuvant therapy. Results: Correspondence between clinical and pathological staging was 70%, with regard to the T category, the agreement between cT vs. pT reached 78% and to the N category, 80%. Lethal
•4-•
Oncolyn causes clinical remission of diffuse malignant pulimonary imesothelioma and other solid tumors in man*
Median survival of malignant diffuse thoracic mesothelioma is less than 6 months. From the time of definitive pathology diagnosis, approximately 90% of the patients are dead within a period of one year. Treatment with surgery, radiation, chemotherapy and a combination of methods has been attempted but is usually unsuccessful Oncolyn is a formulated combination of extracts from three edible plants (US patent) composed mainly of bioflavonoids and polyphenols. It was demonstrated to be clinically effective against cancers of the breast, lung, colon and prostate in mouse and man. In 1999, we used Oncolyn for one terminal pulmonary mesothelioma patient and achieved a clinical remission in 6 months. A terminal disseminated intraosseous lymphoma patient also achieved clinical remission in 6 months with Oncolyn therapy. Both patients are functioning well and working full time as of January 2000. To date, six plant derived anticancer medications (taxol, vinblastine, vincristine, topotecan, etoposide and teniposide) are used extensively in the United States. Others such as camptothecin are evaluated in clinical trials world-wide. Oncolyn was imtially evaluated with the mouse subrenal capsule assay technique for its anticancer activity by itself or in combination with standard chemotherapeutic agents such as Cytoxan, 5FU and Methotrexate. The present poster will depict experiences with Oncolyn for malignant mesothelioma, disseminated intraosseous lymphoma, seminoma with embryonal carcinoma component and carcinomas of the breast, prostate, lung and colon. Illustrative surgical pathology, CT, MRI, nuclear scan, clinical data with tumor markers and photomicrographs will be on display. 6 references and 15 illustrations. *supported in part by a grant from Sante International, USA
•
Synergistic effect of ONYX-015 and chemotherapy on lung cancer cell lines and primary cultures
L. You, C. Yang, C. Clare-Macy, D.M. Jablons. University of California, San Francisco, San Francisco, CA 94115, USA ONYX-015, the mutant adenovirus which has a deletion in the E1B region, has shown tumor-specific cytolysis effect in tumor cells with non-functional p53. In this study, we carried out cytopathic effect (CPE) assays using ONYX-015 on five lung cancer cell lines with known p53 status and seven primary lung cancer cultures. In 6-well plates, cells were infected with either ONYX-015 or with wild-type adenovirus at increasing multiplicities of infection (MOI). For the synergistic effect, the viruses were applied right after chemotherapeutic agents. The plates were stained with crystal violet and then analyzed. Five non-small cell lung cancer (NSCLC) cells were all lysed by ONYX-015. Synergistic
Combined Modality Therapy effect with chemotherapeutic agents (paclitaxel and cisplatin) were clearly shown. Furthermore, we tested the cytolytic effect of ONYX015 on a panel of primary cultures freshly made from 7 patients with lung cancer. ONYX-015 can lyse primary cultures and the synergistic effect was also shown. Our data demonstrates that ONYX-015 can work synergistically with chemotherapeutic agents in lung cancer cell lines and primary cultures. This study suggests that ONYX-015 can be used, in combination with conventional chemotherapy, for the treatment of patients with lung cancer.
•1--•
Pulsed paclitaxel radiosensitization for thoracic malignancy: A therapeutic approach based on preclinical research of human lung cancer cells
Y. Chen, K. Pandya, P. Okunieff, R. Feins, P. Keng, T. Smudzin, R. Raubertas, J. Rosenblatt. University of Rochester, Rochester, New
York, USA Background: A phase 1/11clinical trial for thoracic malignancy was conducted based on pre-clinical laboratory data of cell cycle effects of paclitaxel on human lung cancer cells. Taxanes have been shown to enhance radiation sensitivity of tumor cells by either G2/M arrest of cell cycle, which is the most radiosensitivity phase of the cell cycle, or by improving reoxygenation of radioresistant hypoxic cells. The theoretical advantages of our trial design are to enhance radiation cell kill by optimally integrating the timing of paclitaxel treatments with irradiation, and to decrease treatment related toxicity using low dose pulsed paclitaxel. Methods: Patients with inoperable/unresectable non-small cell carcinoma or mesothelioma were eligible. Pulsed paclitaxel was delivered three times per week in the morning of Mondays, Wednesdays, and Fridays with a starting dose of 15 mg/m2. Daily thoracic radiotherapy was delivered with 60-64 Gy to gross disease. Timing of radiotherapy was designed to allow for a minimum of 5 to 24 hours for cell cycle progression. Results: 22 patients have enrolled and 15 completed treatments (6 at 15 mg/m2; 5 at 20 mg/m2; and 4 at 25 mg/m2). One patient is starting treatment and 6 patients did not complete protocol treatments due to (1) acute allergic reactions in 2; (2) distant disease spread during therapy in 3, and (3) an incidental pneumonia which was outside of the radiation fields associated with bacteremia without neutropenia. Stage distribution of non-small cell carcinoma for patients completed therapy was: 2 stage I, 1 stage II, 3 stage IliA, and 8 stage IIIB. One patient with mesothelioma has stage II disease. Results: Average primary tumor shrinkage at approximately 1 month post-therapy was 83% + 8% (95% C.I.). Overall Iocoregional tumor response rate was 100% [22% (2/15) CR and 78% (13/15) PR]. There was no treatment interruption from acute side effects of therapy. Dose limiting toxicity included 1/15 grade 3 pneumonitis and 3/15 grade 3 esophagitis. There was no grade 4 pneumonitis and esophagitis. There were no grade 3/4 neutropenia, thrombocytopenia, neuropathy or cardiac arrhythmia. Non-dose limiting toxicity included 2/15 transient hyperglycemia from steroid pre-medication, 1/15 skin reaction from electron radiation, and 15/15 grade 3 lymphocytopenia. Conclusions: Pulsed paclitaxel radiosensitization for thoracic malignancy showed early and remarkable Iocoregional tumor response rates, including a mesothelioma histology which is known to be resistant to both radiotherapy and chemotherapy. Concurrent pulsed paclitaxel and radiotherapy schedule was well tolerated with low rates of dose-limiting toxicity.
125
response to combined medality treatment, and more specifically the risk of brain failure so as to evaluate the need for cerebral prophylaxis. Methods: Data from 3 consecutive studies performed between 1983 and 1996 were collected: 1°) the CEBI 138, a phase III trial comparing thoracic radiotherapy (TRT) to sequential combination of chemotherapy (CT) and TRT (353 pts); 2°) the CEBI 140, a phase II trial evaluating concomitant hyperfractionated TRT and CT (33 pts) and finally the CEBI 142, a phase II trial evaluating an induction treatment with TRT and CT before surgery (40 pts). Only pts with local control were analysed (165 out of 426 pts). Median age was 58. Sex ratio was: 154 men for 11 women. Distribution according to stage was: 17 Stage II, 88 Stage Ilia and 60 Stage IIIB pts. All pts except 4 had TRT, 104 pts had CT and 28 pts had surgery. Results: The 5-year disease free survival rate was 12% and the overall survival rate was 15%. The 5-year cumulative incidence of first events was 29% for intercurrent death (52 pts), 28% for extracerebral distant metastases (46 pts), 20% for local relapse (34 pts) and finally 11% only for brain metastases (19 pts). The 5-year brain metastasis rate as first site of failure according to treatment was: 11% both in pts who had and did not have CT; 4% in pts who had surgery and 13% in pts who had no surgery (p < 0.16). There was no difference according to stage or histology. Conclusion: The risk of brain failure as first event was only 11% in pts with LANSCLC so that prophylactic cranial irradiation does not seem warranted in such a population of pts. PCI could be evaluated in pts who receive combined modality treatment including surgery.
•7]
Introduction of resistance to ONYX-015 by re-expressing p 14ARF in human mesothelioma cells: Implications for therapy
C. Yang, L. You, J. Song, DM. Jablons. University of California, San
Francisco, San Francisco, CA 94115, USA To test if ONYX-015 can be used as a potential therapeutic agent for mesotheliomas. In previous studies, a mutant adenovirus ONYX015 has been shown to lyse cervical carcinoma, colon adenocarcinoma, glioblastoma, and pancreatic adenocarcinoma cell lines with abnormalities in p53 genes. However, previous report has also shown the cytolytic effect of this adenovirus on tumor cell lines with normal sequences in exons 5 to 9 of p53 gene. The p14ARF protein encoded from the INK4a/ARF locus functions to promote MDM2 degradation and thus prevents MDM2is neutralization of p53. Homozygous deletions of the INK4a/ARF locus was reported to be a predominant event at a frequency of over 70% in mesothliomas, in which might result in loss of p14ARF and functional inactivation of p53. Such an inactivation of p53 might thus make mesothelioma a potential target for ONYX015 adenovirus therapy. In the present study, we evaluated the ability of ONYX-015 adenovirus to lyse mesothelioma cells, and elucidate the possible mechanism involved in this effect. ONYX-015 lysed H28 and 211H cells effectively, but not MS-1 cells. Immunoblotting assay revealed that absence of p 14ARF expression in H28 cell line, while p 14ARF expression was found in MS-1 cells. Transfection with Adp14 resulted in an increase in the amount of p53 expression in the H28 and 211H cell lines, and these cells with tranfected P14 become more resistant to the virus. Our results indicate that mesothelioma may be a potential target for ONYX-015 adenoviral therapy.
•
Pulmonary biastoma- 11 years experience
A. Zaidi, J. Barry, F.R. Macbeth, N. Kulatilake. University Hospital of
•1-•
Brain relapse in patients with locally advanced non small cell lung cancer (LANSCLC): Is there a place for prophylactic cranial irradiation (PCI)?
C. Le Pechoux, A. Laplanche, J.J. Bretel, M. Tarayre, P. Girard, D. Grunenwald, P. Ruffi~, 12 Le Chevalier. Institut Gustave Roussy,
94805, Villejuif,, France Purpose: To estimate by a competing risks approach, the failure rates of patients (pts) with LANSCLC who had a complete or a partial
Wales, Cardiff, Wales; Velindra Hospital, Cardiff, Wales, UK Objective: To evaluate the clinical features and management of patients presenting with pulmonary blastoma. Methods: Patients with a diagnosis of pulmonary blastoma were identified from the period 1988 to 1999 via the regional pathology laboratory. Specimens were obtained from bronchoscopy, FNA, trucut biopsy and thoracotomy. Results: Six cases of pulmonary blastoma were identified out of 2720 pulmonary malignancies (0.2%). Sex ratio was equal, with a