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Cisplatin based chemotherapy with accelerated, B.I.D. radiation therapy for advanced non-small cell lung cancer (NSCLC)
‘05
CISPLATIN BASED CHEMOTHERAPY WITH ACCELERATED, B.I.D. RADIATION THERAPY FOR ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) .J.PISCH, S. MALAMDD, E. BEATTIE, B. VIKRAM. BETH ISRAEL MEDICAL CENTER, N.Y., N.Y. 10003 The purpose toxicity of interrupted Methods and
of this study was to evaluate simultaneous chemo-radiation b.i.d. irradiation. Materials: Between December
the using
efficacy accelerated
and
1988 and June 1990 20 patients with locally advanced NSCLC (4 St. IIIA + 116 St. IIIB) were entered into this study. Patients received Cisplatin (30 mg/m2 Dl-3), VP16 (80 mglm2 Dl-3), 5FU(VOO mg/m2 Dl-4). Two-hundred cGy was delivered twice a day with 6 HR time gap between the two treatments. Cycle was repeated twice for resected or for borderline resectable patient. Unresectable patients received 3 cycles and were followed by chest x-ray and CT scans. Results: Treatment was well tolerated in this patient -population (30-72 yrs. old, Median 60. M:F=13:71)Dysphagia and leukopenia were the most frequent side effects requiring 3 instead of 2 weeks rest between the 2nd and 3rd Side-effects never were serious cyc.te in 8 patients. Twelve of enough to command discontinuation of treatment. the 16 Stage IIIB patients are evaluable for response. Five of the 12 had CR (41%). 2 had PR (16%). 4 “roaressed artside the treatment ;ield-(33%). Oni pa&nt’sh&d progression in and outside the treatment field. Three of
the IIIB patients underwent surgery - 1 had pathologic CR, 1 microscopic disease and 1 patient had unresectable tumor. Median follow up for the 12 IIIB patients is 8 months. Fiw patients are clinically NED at 18-13-10-8-l months Our experience suggests that the program post treatment. is sell tolerated with moderate toxicity. The 41% CR rate
before. during and after therap>- indlcatc an integration between induction of long-lasting cell-mediated immunit! ((~‘MI: up to IO-14 years] Jnd the induction of car11 1st year rises in serum antibody humoral immunity cHI I to selected lung tumor-associated .mtigen (TAAI epitope D36h6. separated b>, a\ffinit>HI shromstograph! using TA4 monoclonsl sntlhodies. test was predlctivt: of response to therdpyisurvival at S-6 mos post-therAp)-.and test indicated that immunochemotherapy may he superior for pts with Jdenocarcinoma. In responders there was a post-therap? dhsence of immune complexes !c’Ic’i. We h:lve examined failed pts for number and ah class of hands. ag type & biochemistry. type of complement binding and size in C’IC and data suggest a specific role Cunclear! in . blocking the killing of cancer cells. The incidsnce of late non-regional metastvses in patients out past 10 yrs is consistent with the induction of quiescence by IC’Tx. and indicates a mechanism of induced dormancy-. thus justifying the usage of booster immunizations perhaps at about five years Jfter initial therspg. With further knowledge. we may improve upon the Phase 3 tri;lls results in 234 stage 1 and 2 pts with five year sut_Lival of 75% for pts on lung TAA Immunotherapy YS 49% for control pts.
seen in patients with Stage IIIB disease is most encouraging.
HIGH LOCAL RECURRENCE AND BRAIN METASTASES IN ‘JON-SMALL CELL LUNG CANCER (NSCLC) TREATED WITH CHEMO-RADIOTHERAPY. Engracio P. Cortes and Daitatreyudu Nori, Booth MemoriarMedical Center, Flushmg, NY 1355.
I
Thrty-seven prospectively lOOOmg/m’ CRT) to the
NSCLC treated 24.hr tumor
(IllAwith
contmuous bed and
4, IIIBPlatmol
33) patlent 75mglm’
Infusion x 5 days node drainine areas
were IV x
I + 5pu
+ radiotherapy withIn
I
week after the start of chemotherapy to a total dose of 32-50 Gy. Patients who relapsed were treated wth Platlnol 75mgim’ IV xl + Velban 6mglm’ IVP x I T every other month Mltomycin-C lOmg/m’ IVP x plus further RT If needed. Objertwe tumor responses were seen ,n 29 of 37 13 complete, 16 partlal. Response by patients (78%): histology: a) squamous cell, 16 of 17; b) adenocarclnoma, 8 of 14; c) large ceil, 5 of 6. Overall median survival for 37 patrznts was 11.9 months: for non-responders, 4.2 months: partial responders, Il.2 months; complete responders, 16.3 months. Of the 29 responders, recurrences were: a) local, 15 (51%); b) bran, 9 (31%); c) bones, 3 (10%). Bran metastases were seen equally ,n all lustologles. Combmed chemo-radiotherapy m Stage IIIA, IIIB NSCLC was not enough to make a major impact on palient suw~val despite Its high response rate beaux of lngh local recurrence and bran metastases. Future design of combmed chemo-radiotherapy for NSCLC must mcorporate surgery and brachytherapy + bran RT, hopmg to dlrmmsh local recurrence and brain metastases.
I
COMBINATION IMMUNO(‘HEMOTHERAP1IN PATIENTS WITH IXNG CANCER. Ariel Hollinshead. Geo.Wsshington Mzd.(‘tr..D.C.. L’S.4. Rr:search of the immune machanisms involved in solid tumor progression included B comparison of patients on chemotherspy(CTx~. immunotherapy t ITxl. immunochemotherapy(ICTx~ and controls. Me.lsurements of the humorocellulAr immune ch.mges
A Novel Membrane Protein Induced During Commitment Stage of Squamous Differentiation in Normal Human Bronchial Epitheliai Cells Mika Kakefuda, Yuk-Chor Wang, Godofredo Urbane, and Samuel D. Bernal. Section of Medical Oncology, University Hospital, Boston MA Squamous differentiation in bronchial epithelium cells is a metaplastic change that occurs primarily after chronic injury and often precedes neoplasia. Commitment is a critical stage in squamous differentiation, but there is little information on the biochemical than es associated with this stage in normal bronchial epithelium. !v e now describe a 48 kD membrane protein that is induced during the commitment stage of squamous differentiation of normal human bronchial epithelial (NBE) cells. After 24 hours of exposure to 5% fetal calf serum and 600uM calcium, approximately 40 % of NBE cells were committed to terminal differentiation. By 36 hours, more than 95 % of the cells were committed. Between 24-36 hours, expression of SQMl (a 48kD protein) was increased on the surface membrane of NBE cells. During this time, there were no changes in morphology, keratins, mvolucrin, or thymidine incorporation, although by day 8, these committed cells showed changes in these various markers consistent with terminal differentiation. The commitment stage was associated with increased adhesion of NBE cells to extracellular matrix which was inhibited by antiSQMl antibody. The cDNA sequence of the SQMl gene shows a domain homologous with several adhesion proteins of the integrin family including the human leukocyte adhesion protein, endothelial end platelet glycoprotein IIIa, and van Willebrand’s factor. In addition, SQMl expression was found to be directly correlated with the level of folate transport inlungepithelial cells. The expression of SQMl at the stage of commitment and its function related to cell adhesion and folate transport su est that SQMl may play a role in the regulation of squamous g#Ifferentiation in lung epithelial cells.
PHASE 11 TRIAL OF VERY HIGH DOSE CISPLATIN @DP) AND ETOPOSIDE (VP-16) AND MITOMYCIN-C (MITO-C) IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC). P. Caguioa, P. Hesketh, S. Tansan, W. BadueI, A. Hesketh, D. Karp, N. DiMartino, R. Elanchard, K. Zaner and D. Camey. The Univ Hosp. Boston VA Med Ctr. Boston
CISPLATIN BASED CHEMOTHERAPY WITH ACCELERATED, B.I.D. RADIATION THERAPY FOR ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) .J.PISCH, S. MALAMDD, E. BEATTIE, B. VIKRAM. BETH ISRAEL MEDICAL CENTER, N.Y., N.Y. 10003 The purpose toxicity of interrupted Methods and
of this study was to evaluate simultaneous chemo-radiation b.i.d. irradiation. Materials: Between December
the using
efficacy accelerated
and
1988 and June 1990 20 patients with locally advanced NSCLC (4 St. IIIA + 116 St. IIIB) were entered into this study. Patients received Cisplatin (30 mg/m2 Dl-3), VP16 (80 mglm2 Dl-3), 5FU(VOO mg/m2 Dl-4). Two-hundred cGy was delivered twice a day with 6 HR time gap between the two treatments. Cycle was repeated twice for resected or for borderline resectable patient. Unresectable patients received 3 cycles and were followed by chest x-ray and CT scans. Results: Treatment was well tolerated in this patient -population (30-72 yrs. old, Median 60. M:F=13:71)Dysphagia and leukopenia were the most frequent side effects requiring 3 instead of 2 weeks rest between the 2nd and 3rd Side-effects never were serious cyc.te in 8 patients. Twelve of enough to command discontinuation of treatment. the 16 Stage IIIB patients are evaluable for response. Five of the 12 had CR (41%). 2 had PR (16%). 4 “roaressed artside the treatment ;ield-(33%). Oni pa&nt’sh&d progression in and outside the treatment field. Three of
the IIIB patients underwent surgery - 1 had pathologic CR, 1 microscopic disease and 1 patient had unresectable tumor. Median follow up for the 12 IIIB patients is 8 months. Fiw patients are clinically NED at 18-13-10-8-l months Our experience suggests that the program post treatment. is sell tolerated with moderate toxicity. The 41% CR rate
before. during and after therap>- indlcatc an integration between induction of long-lasting cell-mediated immunit! ((~‘MI: up to IO-14 years] Jnd the induction of car11 1st year rises in serum antibody humoral immunity cHI I to selected lung tumor-associated .mtigen (TAAI epitope D36h6. separated b>, a\ffinit>HI shromstograph! using TA4 monoclonsl sntlhodies. test was predlctivt: of response to therdpyisurvival at S-6 mos post-therAp)-.and test indicated that immunochemotherapy may he superior for pts with Jdenocarcinoma. In responders there was a post-therap? dhsence of immune complexes !c’Ic’i. We h:lve examined failed pts for number and ah class of hands. ag type & biochemistry. type of complement binding and size in C’IC and data suggest a specific role Cunclear! in . blocking the killing of cancer cells. The incidsnce of late non-regional metastvses in patients out past 10 yrs is consistent with the induction of quiescence by IC’Tx. and indicates a mechanism of induced dormancy-. thus justifying the usage of booster immunizations perhaps at about five years Jfter initial therspg. With further knowledge. we may improve upon the Phase 3 tri;lls results in 234 stage 1 and 2 pts with five year sut_Lival of 75% for pts on lung TAA Immunotherapy YS 49% for control pts.
seen in patients with Stage IIIB disease is most encouraging.
HIGH LOCAL RECURRENCE AND BRAIN METASTASES IN ‘JON-SMALL CELL LUNG CANCER (NSCLC) TREATED WITH CHEMO-RADIOTHERAPY. Engracio P. Cortes and Daitatreyudu Nori, Booth MemoriarMedical Center, Flushmg, NY 1355.
I
Thrty-seven prospectively lOOOmg/m’ CRT) to the
NSCLC treated 24.hr tumor
(IllAwith
contmuous bed and
4, IIIBPlatmol
33) patlent 75mglm’
Infusion x 5 days node drainine areas
were IV x
I + 5pu
+ radiotherapy withIn
I
week after the start of chemotherapy to a total dose of 32-50 Gy. Patients who relapsed were treated wth Platlnol 75mgim’ IV xl + Velban 6mglm’ IVP x I T every other month Mltomycin-C lOmg/m’ IVP x plus further RT If needed. Objertwe tumor responses were seen ,n 29 of 37 13 complete, 16 partlal. Response by patients (78%): histology: a) squamous cell, 16 of 17; b) adenocarclnoma, 8 of 14; c) large ceil, 5 of 6. Overall median survival for 37 patrznts was 11.9 months: for non-responders, 4.2 months: partial responders, Il.2 months; complete responders, 16.3 months. Of the 29 responders, recurrences were: a) local, 15 (51%); b) bran, 9 (31%); c) bones, 3 (10%). Bran metastases were seen equally ,n all lustologles. Combmed chemo-radiotherapy m Stage IIIA, IIIB NSCLC was not enough to make a major impact on palient suw~val despite Its high response rate beaux of lngh local recurrence and bran metastases. Future design of combmed chemo-radiotherapy for NSCLC must mcorporate surgery and brachytherapy + bran RT, hopmg to dlrmmsh local recurrence and brain metastases.
I
COMBINATION IMMUNO(‘HEMOTHERAP1IN PATIENTS WITH IXNG CANCER. Ariel Hollinshead. Geo.Wsshington Mzd.(‘tr..D.C.. L’S.4. Rr:search of the immune machanisms involved in solid tumor progression included B comparison of patients on chemotherspy(CTx~. immunotherapy t ITxl. immunochemotherapy(ICTx~ and controls. Me.lsurements of the humorocellulAr immune ch.mges
A Novel Membrane Protein Induced During Commitment Stage of Squamous Differentiation in Normal Human Bronchial Epitheliai Cells Mika Kakefuda, Yuk-Chor Wang, Godofredo Urbane, and Samuel D. Bernal. Section of Medical Oncology, University Hospital, Boston MA Squamous differentiation in bronchial epithelium cells is a metaplastic change that occurs primarily after chronic injury and often precedes neoplasia. Commitment is a critical stage in squamous differentiation, but there is little information on the biochemical than es associated with this stage in normal bronchial epithelium. !v e now describe a 48 kD membrane protein that is induced during the commitment stage of squamous differentiation of normal human bronchial epithelial (NBE) cells. After 24 hours of exposure to 5% fetal calf serum and 600uM calcium, approximately 40 % of NBE cells were committed to terminal differentiation. By 36 hours, more than 95 % of the cells were committed. Between 24-36 hours, expression of SQMl (a 48kD protein) was increased on the surface membrane of NBE cells. During this time, there were no changes in morphology, keratins, mvolucrin, or thymidine incorporation, although by day 8, these committed cells showed changes in these various markers consistent with terminal differentiation. The commitment stage was associated with increased adhesion of NBE cells to extracellular matrix which was inhibited by antiSQMl antibody. The cDNA sequence of the SQMl gene shows a domain homologous with several adhesion proteins of the integrin family including the human leukocyte adhesion protein, endothelial end platelet glycoprotein IIIa, and van Willebrand’s factor. In addition, SQMl expression was found to be directly correlated with the level of folate transport inlungepithelial cells. The expression of SQMl at the stage of commitment and its function related to cell adhesion and folate transport su est that SQMl may play a role in the regulation of squamous g#Ifferentiation in lung epithelial cells.
PHASE 11 TRIAL OF VERY HIGH DOSE CISPLATIN @DP) AND ETOPOSIDE (VP-16) AND MITOMYCIN-C (MITO-C) IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC). P. Caguioa, P. Hesketh, S. Tansan, W. BadueI, A. Hesketh, D. Karp, N. DiMartino, R. Elanchard, K. Zaner and D. Camey. The Univ Hosp. Boston VA Med Ctr. Boston