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Prognostic factors in 400 patients with invasive bladder cancer treated by a combined modality bladder-sparing protocol
Proceedings of the 42nd Annual ASTRO Meeting
Materials and Methods: CN706 was constructed by deleting E3 from an Ad5 adenovirus and adding a minimal promoterenhancer construct of the human PSA gene 5' of E1A resulting in regulation of E1A expression and, thus, regulated replication. All patients had biopsy-proven locally-recurrent PCa with biochemical failure as defined by the ASTRO criteria or a PSA > 10 ng/ml on 2 successive occasions. Other entry criteria included: normal serum testosterone, no evidence of metastatic disease on bone and CT scans. Dose escalation method: single administration of 1XI011 to IX1013 viral particles divided in 20-80, 0.1 cc deposits injected with 10-40 needles. Pre-treatment planning was performed using a modified 3-D prostate brachytherapy treatment planning system. Toxicity was graded using the NCI CTC. Serial post-treatment biopsies were obtained at multiple intervals to assess for treatment effect, alteration in PSA staining and evidence of viral replication. Serial urine and serum samples were also obtained to assist in pharmacodynanfic measurements. Results: Twenty patients were treated over 5 dose levels. Treatment has been well tolerated. Adverse events consistently noted included: Day 1. Grade 2 fever (treated with antipyretics), perineal bruising/edema/pain, urinary irritation (in large part due to indwelling Foley catheter use required in Phase I). Two patients had Grade 1 liver transaminase elevation. No clinicallysignificant alteration in hematologic profiles or coagulation studies noted. There were 3 reversible Grade 3 toxicities ( 1 patient with hypertension, 2 patients with blood clots in urine). No significant adverse events were noted. Four evaluable patients at the time of this abstract exhibited a PR (>50% reduction in PSA) for at least 4 weeks. Note that all responders occurred in final 2 dose levels, i.e. 4/7 evaluable patients. 60% of day 22 biopsies exhibited a significant reduction in PSA staining. Viral replication confirmed by electron microscopy of post-treatment biopsy samples. Conclusions: CN706, administered by a modified prostate brachytherapy technique, exhibits an acceptable safety profile with both biochemical and histologic evidence of antitumor activity in patients with prostate cancer which is locally-recurrent following radiation. In vivo replication has also been established in these patients. Continued study with the next generation of virus (CV787) is on-going in a Phase l-ll trial. Supported by NIH S.P.O.R.E. in Prostate Cancer, N1H GCRC Johns Hopkins and a clinical research agreement only with Calydon, 1no.
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Prognostic factors in 400 patients with invasive bladder cancer treated by a combined modaUty bladdersparing protocol
C. R6deL l G. G. Grabenbauer, 1 R. K??hn,2 P. Martus, 3 J. I)unst,4 K. M. Schrott, -~ R. Sauer, L
1Dep. ~["Radiation Oncology, Erlangen, Germany, :Dep. of" Urology, Erlangen, Germany, ~Dep. of Medical It~)rmatics, Erhmgen, Germany, 4Dep. of Radiation Oncology, Halle, Germany Purpose: Clinical and pathologic factors were analysed in patients treated in a prospective bladder-preserving protocol consisting of transurethral resection (TUR), radiotherapy (RT) with or without concomitant platin-based chemotherapy (RCT). The aim of this study was to identify the patients most suitable for this type of treatment. Patients and Methods: The prognostic value of age, gender, clinical stage, histologic grade, presence of tumor-associated carcinoma in situ (CIS), lymphatic invasion, multifocality of the tumor, completeness of TUR, type of treatment (radiotherapy versus radiochemotherapy) has been studied in 400 patients, who received bladder sparing treatment in the period from 1982 and 1999:137 patients were treated by RT alone (54 to 59,4 Gy to the bladder and 45 to 50 Gy to the regional lymph nodes), 263 patients by concomitant RCT. CT was applied in the first and fifth week of RT and consisted of cisplatin (25 mg/sqrrdd) in 127 patients, carboplatin (65 mg/sqm/d) in 92 patients and cisplatin (20 mg/sqm/d) combined with 5-FU (600 mg/sqm/d) in 44 patients. Cystectomy was recommended only for patients with residual invasive disease at restaging-TUR. Results: Five-year disease-specific survival was 52% for the whole group of patients. Of all surviving patients, 80 % maintained their bladder. An independent prognostic value was confirmed for completeness of TUR (p = 0.0001), clinical stage (p 0.003), grading (p = 0.02) and RCT versus RT alone (p - 0.04, with the combination of 5-FU and Cisplatin being most efficacious: 5-year-DSS 77%). In univariate analysis also gender (5-year DSS in women: 41%, in male 57%. p - 0.(/4) and lymphatic invasion (5-y-DSS 43% with and 62% without lymphatic invasion, p = 0.//07) achieved statisitical significance, whereas CIS and multifocality of the tumor were not related to DSS. Conclusion: Clinical and pathologic criteria helpful in determining patients for bladder preservation include such variables as small tumor size with a histologic low grade and a possible complete TUR prior to radiochemotherapy. The combination of cisplatin and 5-FU is most promising. Interestingly, CIS and multiibcality of the tumor were not associated with a poor prognosis.
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Predictors of xerostomia following parotid-sparing irradiation (RT) of head and neck cancer
A. Eisbruch, H. M. Kim, J. E. Terrell, L. H. Marsh, L. A. Dawson, J. A. Ship
University ~f Michigan, Ann Arbor, MI Purpose: Parotid gland-sparing RT techniques for patients with head and neck cancer have been developed and implemented, resulting in partial preservation of the salivary output post-RT (previously reported). The exact benefit regarding xerostomia symptoms is not known. The purpose of this study was to devise an instrument for measuring patient-reported xerostomia, and to use this instrument to assess how much saliva needs to be retained and which other factors affect the severity of xerostomia following parotid gland-sparing RT. Methods: The study included 124 patients with head and neck cancer irradiated between 1994-1999 with conformal and multisegmental intensity modulated RT aiming to spare parotid gland tissue. 77 patients received bilateral neck RT (group 1), and 47 with smaller, lateralized tumors received unilateral neck RT (group 2). An 8-question xerostomia questionnaire using an 11-point Likert scale ranging from 0 to 10 was devised, with higher scores indicating worse xerostomia. The summary scores were standardized to range between 0 and 100. Validation of the questionnaire included: high test-retest correlation coefficient (r = 0.82), high internal consistency (Cronbach alpha 0.72-0.94 at different time points), and high correlation with the scores of a previously validated questionnaire developed for Sjogren's syndrome.
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Materials and Methods: CN706 was constructed by deleting E3 from an Ad5 adenovirus and adding a minimal promoterenhancer construct of the human PSA gene 5' of E1A resulting in regulation of E1A expression and, thus, regulated replication. All patients had biopsy-proven locally-recurrent PCa with biochemical failure as defined by the ASTRO criteria or a PSA > 10 ng/ml on 2 successive occasions. Other entry criteria included: normal serum testosterone, no evidence of metastatic disease on bone and CT scans. Dose escalation method: single administration of 1XI011 to IX1013 viral particles divided in 20-80, 0.1 cc deposits injected with 10-40 needles. Pre-treatment planning was performed using a modified 3-D prostate brachytherapy treatment planning system. Toxicity was graded using the NCI CTC. Serial post-treatment biopsies were obtained at multiple intervals to assess for treatment effect, alteration in PSA staining and evidence of viral replication. Serial urine and serum samples were also obtained to assist in pharmacodynanfic measurements. Results: Twenty patients were treated over 5 dose levels. Treatment has been well tolerated. Adverse events consistently noted included: Day 1. Grade 2 fever (treated with antipyretics), perineal bruising/edema/pain, urinary irritation (in large part due to indwelling Foley catheter use required in Phase I). Two patients had Grade 1 liver transaminase elevation. No clinicallysignificant alteration in hematologic profiles or coagulation studies noted. There were 3 reversible Grade 3 toxicities ( 1 patient with hypertension, 2 patients with blood clots in urine). No significant adverse events were noted. Four evaluable patients at the time of this abstract exhibited a PR (>50% reduction in PSA) for at least 4 weeks. Note that all responders occurred in final 2 dose levels, i.e. 4/7 evaluable patients. 60% of day 22 biopsies exhibited a significant reduction in PSA staining. Viral replication confirmed by electron microscopy of post-treatment biopsy samples. Conclusions: CN706, administered by a modified prostate brachytherapy technique, exhibits an acceptable safety profile with both biochemical and histologic evidence of antitumor activity in patients with prostate cancer which is locally-recurrent following radiation. In vivo replication has also been established in these patients. Continued study with the next generation of virus (CV787) is on-going in a Phase l-ll trial. Supported by NIH S.P.O.R.E. in Prostate Cancer, N1H GCRC Johns Hopkins and a clinical research agreement only with Calydon, 1no.
122
Prognostic factors in 400 patients with invasive bladder cancer treated by a combined modaUty bladdersparing protocol
C. R6deL l G. G. Grabenbauer, 1 R. K??hn,2 P. Martus, 3 J. I)unst,4 K. M. Schrott, -~ R. Sauer, L
1Dep. ~["Radiation Oncology, Erlangen, Germany, :Dep. of" Urology, Erlangen, Germany, ~Dep. of Medical It~)rmatics, Erhmgen, Germany, 4Dep. of Radiation Oncology, Halle, Germany Purpose: Clinical and pathologic factors were analysed in patients treated in a prospective bladder-preserving protocol consisting of transurethral resection (TUR), radiotherapy (RT) with or without concomitant platin-based chemotherapy (RCT). The aim of this study was to identify the patients most suitable for this type of treatment. Patients and Methods: The prognostic value of age, gender, clinical stage, histologic grade, presence of tumor-associated carcinoma in situ (CIS), lymphatic invasion, multifocality of the tumor, completeness of TUR, type of treatment (radiotherapy versus radiochemotherapy) has been studied in 400 patients, who received bladder sparing treatment in the period from 1982 and 1999:137 patients were treated by RT alone (54 to 59,4 Gy to the bladder and 45 to 50 Gy to the regional lymph nodes), 263 patients by concomitant RCT. CT was applied in the first and fifth week of RT and consisted of cisplatin (25 mg/sqrrdd) in 127 patients, carboplatin (65 mg/sqm/d) in 92 patients and cisplatin (20 mg/sqm/d) combined with 5-FU (600 mg/sqm/d) in 44 patients. Cystectomy was recommended only for patients with residual invasive disease at restaging-TUR. Results: Five-year disease-specific survival was 52% for the whole group of patients. Of all surviving patients, 80 % maintained their bladder. An independent prognostic value was confirmed for completeness of TUR (p = 0.0001), clinical stage (p 0.003), grading (p = 0.02) and RCT versus RT alone (p - 0.04, with the combination of 5-FU and Cisplatin being most efficacious: 5-year-DSS 77%). In univariate analysis also gender (5-year DSS in women: 41%, in male 57%. p - 0.(/4) and lymphatic invasion (5-y-DSS 43% with and 62% without lymphatic invasion, p = 0.//07) achieved statisitical significance, whereas CIS and multifocality of the tumor were not related to DSS. Conclusion: Clinical and pathologic criteria helpful in determining patients for bladder preservation include such variables as small tumor size with a histologic low grade and a possible complete TUR prior to radiochemotherapy. The combination of cisplatin and 5-FU is most promising. Interestingly, CIS and multiibcality of the tumor were not associated with a poor prognosis.
123
Predictors of xerostomia following parotid-sparing irradiation (RT) of head and neck cancer
A. Eisbruch, H. M. Kim, J. E. Terrell, L. H. Marsh, L. A. Dawson, J. A. Ship
University ~f Michigan, Ann Arbor, MI Purpose: Parotid gland-sparing RT techniques for patients with head and neck cancer have been developed and implemented, resulting in partial preservation of the salivary output post-RT (previously reported). The exact benefit regarding xerostomia symptoms is not known. The purpose of this study was to devise an instrument for measuring patient-reported xerostomia, and to use this instrument to assess how much saliva needs to be retained and which other factors affect the severity of xerostomia following parotid gland-sparing RT. Methods: The study included 124 patients with head and neck cancer irradiated between 1994-1999 with conformal and multisegmental intensity modulated RT aiming to spare parotid gland tissue. 77 patients received bilateral neck RT (group 1), and 47 with smaller, lateralized tumors received unilateral neck RT (group 2). An 8-question xerostomia questionnaire using an 11-point Likert scale ranging from 0 to 10 was devised, with higher scores indicating worse xerostomia. The summary scores were standardized to range between 0 and 100. Validation of the questionnaire included: high test-retest correlation coefficient (r = 0.82), high internal consistency (Cronbach alpha 0.72-0.94 at different time points), and high correlation with the scores of a previously validated questionnaire developed for Sjogren's syndrome.
173