ABSTRACT
PURPOSE: We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32. RESULTS: Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment. CONCLUSIONS: Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.
Subject(s)
Adenoviridae/genetics , Adenoviridae/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Genes, p53 , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Tumor Suppressor Protein p53/metabolism , Aged , Aged, 80 and over , Apoptosis , Carcinoma, Non-Small-Cell Lung/metabolism , Combined Modality Therapy , Female , Gene Transfer Techniques , Genetic Therapy , Genetic Vectors , Humans , Lung Neoplasms/metabolism , Male , Middle Aged , RNA, Messenger/metabolism , Radiotherapy , Reverse Transcriptase Polymerase Chain Reaction , Time FactorsABSTRACT
OBJECTIVE: To assess the evolution of treatment and outcome for resected esophageal cancer at a single institution. SUMMARY BACKGROUND DATA: Strategies for optimizing the treatment of resected esophageal cancer continue to evolve over time. The outcomes of these evolving treatments in the context of improved diagnostic staging and changing epidemiology have not been carefully analyzed in a single institution. METHODS: One thousand ninety-seven consecutive patients with primary esophageal cancer underwent surgery during the period 1970 to 2001. Nine hundred ninety-four patients underwent curative esophagectomy and were analyzed for changing demographics. Eight hundred seventy-nine patients who did not have systemic metastases and survived the perioperative period were assessed by multivariate analysis for factors associated with long-term survival. RESULTS: During the study period the overall median survival increased from 17 to 34 months, and combined hospital and 30-day mortality decreased from 12% to 6%. The R0 resection rate increased from 78 to 94%, and adenocarcinoma replaced squamous cell carcinoma as the predominant histology (83% vs. 17%). No change in survival with time was noted for patients treated with surgery alone having the same postoperative pathologic stage (pTNM). An increased proportion of patients had preoperative chemoradiation in the last 4 years of the study (59% vs. 2%). Preoperative chemoradiation was associated with a longer survival and increased likelihood of achieving a complete resection. Multivariate analysis showed that long-term survival was associated with a complete resection and the preoperative staging strategy used, while the use of preoperative chemoradiation was the most significant factor associated with ability to achieve an R0 esophageal resection. CONCLUSIONS: This study shows favorable trends in the survival of patients with resected esophageal cancer over time. The increased use of preoperative chemoradiation, better preoperative staging, and other time-dependent factors may have contributed to the observed increase in survival.
