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Patterns of failure in small cell carcinoma of the cervix
Proceedings of the 44th Annual ASTRO Meeting
Addition of CH to periaortic RT did not seem to increase the grade 3 and 4 toxicity compared to periaortic RT alone in our series. Chemoradiation should be considered in patients with periaortic lymph node metastases from cervical carcinoma.
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Patterns of Failure in Small Cell Carcinoma of the Cervix
A. Viswanathan1, A. Jhingran2, M. Deavers2, P. Ramirez2, P. Eifel2 1 Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA,2 U.T. M.D Anderson Cancer Center, Houston, TX Purpose/Objective: To analyze the sites of relapse and overall survival in women with small cell neuroendocrine carcinoma of the cervix. Materials/Methods: Women diagnosed with small cell neuroendocrine carcinomas between 1980-2000 at U. T. M.D. Anderson Cancer Center were identified from a database containing 6156 cases of cervical carcinoma. Patients who had stage IV disease, histology of small cell squamous, large or intermediate cell neuroendocrine cancer, or who did not receive a portion of their primary treatment at the MDACC were excluded. The remaining 51 women were included in this study. The median age was 48 years (range, 25-96 years). Thirty-six patients were white, 6 African-American, 5 Hispanic, and 4 Asian. FIGO stage was IA (3 patients), IB (32 patients), IIA (6 patients), IIB (3 patients), and IIIB (7 patients). For patients with stage IB disease, the tumor diameter was ⬍ 4cm in 11, 4-6cm in 16, ⬎6cm in 2, and unknown in 3 patients. The median pre-treatment hemoglobin was 12 (range, 5-15.5). Lymphovascular space invasion was noted in 13 cases. Local treatment included radical hysterectomy plus lymph node dissection alone in 11, radiation (RT) alone in 36, and radical hysterectomy followed by RT in 4 patients. All 3 of the 15 surgically treated patients who had positive lymph nodes received postoperative RT. 39 of 40 patients treated with definitive RT had a combination of external and intracavitary treatment. The median total dose to point A was 92 Gy. The median duration of external beam and intracavitary RT was 51 days (range, 16-99 days). Platinum-based chemotherapy was given to 25 patients either before RT (14), during RT (5), after RT (1), or after surgery (5). The median number of cycles was 3 (range, 2-13). The median follow-up time of surviving patients was 84 months (range, 16-227 months). Results: Twenty-eight patients relapsed. The median time to relapse was 8 months from the start of treatment (range, 3-27 months) and 25/28 relapses occurred within 24 months of treatment. Initial recurrence was confined to the pelvis in 6 cases (2 vaginal, 4 pelvic wall); 4 patients relapsed in pelvic and distant sites simultaneously; 18 patients relapsed in distant sites only, including 4 recurrences above the external beam fields in the paraaortic nodes. Two patients developed brain metastasis simultaneously with other sites of distant metastasis as a first site of failure, and 2 patients developed brain metastases following their initial failure. Of 26 patients who had local treatment only, 9 (35%) are alive; of 25 patients who had chemotherapy added to their local treatment, 10 (40%) are alive. There was no significant difference in overall survival by stage (p⫽0.17), local treatment given (p⫽0.15), by chemotherapy (p⫽0.4), or by the time in which chemotherapy was given (p⫽0.3). The 2, 3 and 5 year overall survival rates for the entire population were 50%, 41% and 36%, respectively. Conclusions: Small cell neuroendocrine carcinoma of the cervix is a rare malignancy with a poor prognosis. Most patients relapse within 2 years after diagnosis, primarily with distant metastases. Initial recurrences in the brain were uncommon, suggesting that prophylactic cranial irradiation should not play a major role in the management of these patients.
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Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF) Negatively Impact Overall Survival in Carcinoma of the Cervix
D.K. Gaffney1, D. Haslam1, A. Tsodikov2, E. Hammond3, J. Seaman3, J. Holden 4, J. Lee5, K. Zempolich6, M. Dodson6 1 Department of Radiation Oncology, University of Utah, Salt Lake City, UT, 2Department of Biostatistics, Huntsman Cancer Institute, Salt Lake City, UT, 3Department of Pathology, LDS Hospital, Salt Lake City, UT, 4Department of Pathology, University of Utah, Salt Lake City, UT, 5Department of Radiation Medicine, LDS Hospital, Salt Lake City, UT, 6 Department of Gynecologic Oncology, University of Utah, Salt Lake City, UT Purpose/Objective: Carcinoma of the cervix is responsive to radiotherapy (RT) and chemoradiotherapy (CRT). New therapeutics exist that target a variety of biomarkers. A greater description of expressed biomarkers in cervix cancer patients treated with RT or CRT may provide new therapeutic strategies. The purpose of this study is to examine a variety of biomarkers in carcinoma of the cervix to better characterize 1) the natural history of the disease, 2) response to RT and CRT, and 3) potential for new therapeutic strategies. Materials/Methods: Fifty five patients with stages I-IVA carcinoma of the cervix treated with definitive intent with RT on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Tumor blocks were obtained, and presence of tumor and histopathologic grade was verified by one pathologist. Immunohistochemistry was performed for EGFR, VEGF, CD34, topoisomerase II alpha (topo II), and cyclooxygenase-2 (COX-2). EGFR, VEGF, and COX-2 were scored for % of positive cells: 0⫽none, 1⫽⬍10%, 2⫽10-50%, 3⫽⬎50%; and for intensity of staining with a subjective score of 0-3. For EGFR, the staining was described as membranous or cytoplasmic. Topo II was scored as an index of positive staining cells, and CD34 was scored as the average number of vessels per 5 high powered fields. Univariate and multivariate cox proportional hazards modeling was performed with disease free survival (DFS) and overall survival (OS) as the endpoints. Biomarkers were evaluated for correlation between various prognostic factors. Results: In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p⬍0.001). For OS, only stage (p⬍0.0001) and membranous staining of EGFR (p⫽0.04) on univariate analysis achieved significance. On multivariate analysis for DFS, COX-2 and VEGF expression were significant (p⫽0.02 and p⫽0.01, respectively) with increased expression indicating a worse prognosis. For OS multivariate analysis revealed that VEGF (p⫽0.02), EGFR (p⫽0.03), stage (p⬍0.001) and RT dose (p⬍0.002) were significant. Significant direct correlations were identified between VEGF and CD34 (p⫽0.04), COX-2 and topo II (p⫽0.04), and tumor size and clinical stage (p⫽0.04). An inverse correlation was observed between cytoplasmic EGFR and COX-2 (p⫽0.02).
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Addition of CH to periaortic RT did not seem to increase the grade 3 and 4 toxicity compared to periaortic RT alone in our series. Chemoradiation should be considered in patients with periaortic lymph node metastases from cervical carcinoma.
65
Patterns of Failure in Small Cell Carcinoma of the Cervix
A. Viswanathan1, A. Jhingran2, M. Deavers2, P. Ramirez2, P. Eifel2 1 Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA,2 U.T. M.D Anderson Cancer Center, Houston, TX Purpose/Objective: To analyze the sites of relapse and overall survival in women with small cell neuroendocrine carcinoma of the cervix. Materials/Methods: Women diagnosed with small cell neuroendocrine carcinomas between 1980-2000 at U. T. M.D. Anderson Cancer Center were identified from a database containing 6156 cases of cervical carcinoma. Patients who had stage IV disease, histology of small cell squamous, large or intermediate cell neuroendocrine cancer, or who did not receive a portion of their primary treatment at the MDACC were excluded. The remaining 51 women were included in this study. The median age was 48 years (range, 25-96 years). Thirty-six patients were white, 6 African-American, 5 Hispanic, and 4 Asian. FIGO stage was IA (3 patients), IB (32 patients), IIA (6 patients), IIB (3 patients), and IIIB (7 patients). For patients with stage IB disease, the tumor diameter was ⬍ 4cm in 11, 4-6cm in 16, ⬎6cm in 2, and unknown in 3 patients. The median pre-treatment hemoglobin was 12 (range, 5-15.5). Lymphovascular space invasion was noted in 13 cases. Local treatment included radical hysterectomy plus lymph node dissection alone in 11, radiation (RT) alone in 36, and radical hysterectomy followed by RT in 4 patients. All 3 of the 15 surgically treated patients who had positive lymph nodes received postoperative RT. 39 of 40 patients treated with definitive RT had a combination of external and intracavitary treatment. The median total dose to point A was 92 Gy. The median duration of external beam and intracavitary RT was 51 days (range, 16-99 days). Platinum-based chemotherapy was given to 25 patients either before RT (14), during RT (5), after RT (1), or after surgery (5). The median number of cycles was 3 (range, 2-13). The median follow-up time of surviving patients was 84 months (range, 16-227 months). Results: Twenty-eight patients relapsed. The median time to relapse was 8 months from the start of treatment (range, 3-27 months) and 25/28 relapses occurred within 24 months of treatment. Initial recurrence was confined to the pelvis in 6 cases (2 vaginal, 4 pelvic wall); 4 patients relapsed in pelvic and distant sites simultaneously; 18 patients relapsed in distant sites only, including 4 recurrences above the external beam fields in the paraaortic nodes. Two patients developed brain metastasis simultaneously with other sites of distant metastasis as a first site of failure, and 2 patients developed brain metastases following their initial failure. Of 26 patients who had local treatment only, 9 (35%) are alive; of 25 patients who had chemotherapy added to their local treatment, 10 (40%) are alive. There was no significant difference in overall survival by stage (p⫽0.17), local treatment given (p⫽0.15), by chemotherapy (p⫽0.4), or by the time in which chemotherapy was given (p⫽0.3). The 2, 3 and 5 year overall survival rates for the entire population were 50%, 41% and 36%, respectively. Conclusions: Small cell neuroendocrine carcinoma of the cervix is a rare malignancy with a poor prognosis. Most patients relapse within 2 years after diagnosis, primarily with distant metastases. Initial recurrences in the brain were uncommon, suggesting that prophylactic cranial irradiation should not play a major role in the management of these patients.
66
Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF) Negatively Impact Overall Survival in Carcinoma of the Cervix
D.K. Gaffney1, D. Haslam1, A. Tsodikov2, E. Hammond3, J. Seaman3, J. Holden 4, J. Lee5, K. Zempolich6, M. Dodson6 1 Department of Radiation Oncology, University of Utah, Salt Lake City, UT, 2Department of Biostatistics, Huntsman Cancer Institute, Salt Lake City, UT, 3Department of Pathology, LDS Hospital, Salt Lake City, UT, 4Department of Pathology, University of Utah, Salt Lake City, UT, 5Department of Radiation Medicine, LDS Hospital, Salt Lake City, UT, 6 Department of Gynecologic Oncology, University of Utah, Salt Lake City, UT Purpose/Objective: Carcinoma of the cervix is responsive to radiotherapy (RT) and chemoradiotherapy (CRT). New therapeutics exist that target a variety of biomarkers. A greater description of expressed biomarkers in cervix cancer patients treated with RT or CRT may provide new therapeutic strategies. The purpose of this study is to examine a variety of biomarkers in carcinoma of the cervix to better characterize 1) the natural history of the disease, 2) response to RT and CRT, and 3) potential for new therapeutic strategies. Materials/Methods: Fifty five patients with stages I-IVA carcinoma of the cervix treated with definitive intent with RT on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Tumor blocks were obtained, and presence of tumor and histopathologic grade was verified by one pathologist. Immunohistochemistry was performed for EGFR, VEGF, CD34, topoisomerase II alpha (topo II), and cyclooxygenase-2 (COX-2). EGFR, VEGF, and COX-2 were scored for % of positive cells: 0⫽none, 1⫽⬍10%, 2⫽10-50%, 3⫽⬎50%; and for intensity of staining with a subjective score of 0-3. For EGFR, the staining was described as membranous or cytoplasmic. Topo II was scored as an index of positive staining cells, and CD34 was scored as the average number of vessels per 5 high powered fields. Univariate and multivariate cox proportional hazards modeling was performed with disease free survival (DFS) and overall survival (OS) as the endpoints. Biomarkers were evaluated for correlation between various prognostic factors. Results: In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p⬍0.001). For OS, only stage (p⬍0.0001) and membranous staining of EGFR (p⫽0.04) on univariate analysis achieved significance. On multivariate analysis for DFS, COX-2 and VEGF expression were significant (p⫽0.02 and p⫽0.01, respectively) with increased expression indicating a worse prognosis. For OS multivariate analysis revealed that VEGF (p⫽0.02), EGFR (p⫽0.03), stage (p⬍0.001) and RT dose (p⬍0.002) were significant. Significant direct correlations were identified between VEGF and CD34 (p⫽0.04), COX-2 and topo II (p⫽0.04), and tumor size and clinical stage (p⫽0.04). An inverse correlation was observed between cytoplasmic EGFR and COX-2 (p⫽0.02).
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