- Email: [email protected]
A phase I-II study of pre-operative radiotherapy and escalating doses of oral UFT for rectal cancer
Proceedings of the 44th Annual ASTRO Meeting
(median dose: 54 Gy; range: 50 to 60 Gy) was given to 36 out of 97 patients (37%). The two group of patients (early vs. delayed RT) were well balanced in respect to extent of surgery and other main clinical prognostic factors. PFS and DSS were estimated for all eligible patients using the Kaplan-Meier method, and tested for equality with log-rank test. Uni- and multivariate analyses of treatment related and clinical prognostic factors were performed using the Cox proportional hazards model. Results: At a median follow-up of 79 months (range: 28 to 154 months) the 5- and 10-year PFS was 52.2 % and 30.7% with early RT and 39.5% and 12.4% with delayed RT (p ⬍ 0.04; RR: 0.60). Univariate analysis demonstrated that only extent of surgery, and early RT were associated with significantly longer PFS. On multivariate analysis, only the timing of RT was found to be associated significantly with better PFS (p ⬍ 0.007). In respect to DSS, there was no significant difference in the 5- and 10-year actuarial survival rate according to the timing of RT (60.5% and 26.5% vs. 66.6% and 23.7%; p ⫽ 0.75). Patient age (⬎ 30 years vs. ⱕ30 years; RR: 2.04) and extent of surgery (total vs. subtotal; RR: 0.58) were significant prognostic variables in respect to DSS. Subdividing patients based on the extent of surgery, early RT in the subtotal group significantly improved 5-year PFS (60.0% vs. 12.4%; p ⫽ 0.004) and DSS (66.7% vs. 49.8%; p ⫽ 0.04). However, postoperative RT had no influence on PFS (p ⫽ 0.68) and DSS (p ⫽ 0.40) in the totally resected group. Conclusions: Early postoperative RT in subtotally resected, WHO Grade II astrocytomas significantly improves both progression-free and disease-specific survival. Early RT has no benefit in the totally resected group, therefore RT should be withheld in these patients until progression.
163
Preoperative Concurrent Chemoradiation in Locally Advanced Rectal Cancer with 50 Gy and Oxaliplatin (OXA), Fluorouracil (FU), I-Folinic Acid (l-LV). The Lyon R0-04 Phase II Trial
J. Gerard1, O. Chapet2, P. Romestaing2, F. Mornex2, R. Coquard3, N. Barbet4, D. Atlan5, G. Freyer2 1 Centre Antoine-Lacassagne, Nice, France, 2Lyon Sud Hospital Pierre Benite, Lyon, France, 3Clinique St Jean, Lyon, France, 4Clinique Denis, Macon, France, 5Hopital G Pompidou, Paris, France Purpose/Objective: The standard treatment of T3-4 NxM0 rectal cancer in France is preoperative radiotherapy and surgery. It has been demonstrated (Freyer JCO 2001; 19: 2433) that concurrent radiotherapy (45 Gy) and chemotherapy with OXA, FU, I-LV (FolfoR 1) was a feasible regimen with a recommended dose of OXA of 130 mg/m2 on day 1 and 29. The purpose of this study was to assess the tolerance and the efficacy of FolfoR 2 regimen in preoperative setting. Materials/Methods: Between May 2000 and October 2001, 40 patients with rectal adenocarcinoma were included in this prospective phase II trial (median age 60 (38-76) years, 26 males, 14 females). Staging was performed in all patients with endorectal ultrasound (T3⫽ 36, T4⫽ 5, N0⫽ 23, N1⫽ 18 –All M0). Posterior pelvic irradiation was given with a 3-4 fields technique, ⫻ 18 MV, total dose: 50 Gy in five weeks (45 Gy/25 fractions/5 weeks ⫹ concomitant boost 5GY/5F (1 Gy per fraction on day 5, 12, 19, 26, 33). Chemotherapy regimen was two cycles of OXA, FU, l-LV (day 1-5 and 29-33), FU 350 mg/m2/D, protracted venous infusion 5 days with l-LV 100 mg/m2/day, OXA 130 mg/m2 on D1, D29. Surgery was planned for all patients after a rest period of 4 weeks. Results: They are available for 40 patients, all evaluable for immediate toxicities. Treatment was stopped after the first cycle in 1 patient with probable low-DPD, due to severe cystitis/rectitis, alopecia, grade 4 neutropenia, grade 3 mucositis and hand-foot syndrome. Symptoms recovered within 10 days. All other patients completed treatment and no major event occurred except: transitory grade 3 diarrhea and asthenia (1 pt) and neutropenia (1 pt). Neurotoxicity was mild: cold-induced dysesthesiae grade 1 in 25 pts, grade 2 in 1 pt. All patients had substantial tumor shrinkage before surgery. Anterior resection was performed in 25 pts, APR in 10. There was no postoperative death. Four fistulae/pelvic abcedations requiring salvage surgery ⫾colostomy were observed (11%). The pathologic reports showed 15 (43%) major responses (sterilization or rare residual cells), of which 5 (14%) were complete. Conclusions: These results demonstrate that this FolfoR 2 regiment is well tolerated and does not increase surgical complication. It gives a high rate of clinical and pathological response. It could be proposed as a new experimental arm when the results of the FFCD 92-03, EORTC 22912 trials will be available.
164
A Phase I-II Study of Pre-Operative Radiotherapy and Escalating Doses of Oral UFT for Rectal Cancer
R.M. Pfeffer1, Y. Kundel1, M. Zehavi1, M. Koller2, Z. Symon1 1 Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel, 2Department of Surgery, Sheba Medical Center, Tel Hashomer, Israel Purpose/Objective: Pre-operative radiotherapy (XRT) increases local control and survival of patients with rectal cancer. Continuous infusion (CI) 5FU added to radiotherapy results in down-staging of a large percentage of tumors, but requires continued venous access. UFT (a combination of tegafur, an orally absorbed derivative of 5FU, together with uracil) has pharmaco-kinetics and anti-tumor effect similar to CI 5FU with a similar toxicity spectrum but with the advantage of oral administration. The primary objective of this phase I-II study is to determine the maximum tolerated dose of oral UFT (uracil & tegafur in 4:1 ratio) and low dose leucovorin with preoperative pelvic irradiation (XRT) for rectal cancer and to assess the toxicity of this combination. The secondary objective is to assess response as determined by clinico-pathological downstaging and trans-rectal ultrasound before and after chemo-radiation. The maximum tolerated dose (MTD) is defined as the dose resulting in a break of XRT, for a total of 7 days or more, due to grade III toxicity. The target dose level is 300 mg/m2 which is the recommended dose of UFT without XRT. After determining the MTD a total of 20 patients will be treated at this dose in order to assess tumor response in a larger population. Materials/Methods: The treatment protocol includes a fixed, standard dose of pelvic XRT, 45 Gy in 1.8 Gy daily fractions over 5 weeks (RL/LL/PA fields) with an escalating dose of oral UFT in 3 divided doses/day and a fixed dose of 30 mg/day oral leucovorin. UFT and leucovorin are given for 28 consecutive days concomitant with the first 4 weeks of radiotherapy. Surgery is planned 4-6 weeks after completion of XRT. The surgical procedure is determined by the surgeon at the time of surgery. After
97
98
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
surgery patients receive 4 cycles of oral UFT at a dose of 300 mg/m2 UFT per day with leukovorin 30 mg/day for 4 weeks followed by one week break. Results: Sixteen patients aged 42-79 years have been enrolled. Tumors were situated 3-11 cm from the anal verge. Four patients completed pre-operative treatment at the starting dose of 200 mg/m2/day UFT with no grade III toxicity. One out of 8 patients treated at a dose of 240 mg/m2/day UFT developed grade IV diarrhoea requiring intravenous fluid replacement. Another patient required a 3 day treatment break for GI symptoms. Four patients received a dose of 270 mg/m2/day UFT. One of them was hospitalized with grade IV diarrhoea and leukopenic fever and died during hospitalization. Since there was a fatal toxicity at this level it was decided to consider 240 mg/m2 as the MTD. Thirteen of 15 evaluable patients had tumor downstaging as seen by TRUS and at surgery. Two patients, with tumors 3 and 5 cm from the anal verge and who had significant down-staging of their tumors, refused abdomino-perineal resection, one is without evidence of disease after receiving brachytherapy. Ten patients have undergone anterior resection with no surgical complications except for one patient who underwent a cholecystectomy at the time of tumor resection developed a post-operative infection. Three patients with low (⬍5cm from anal verge) tumors underwent colo-anal anastamosis without complications. Conclusions: The maximum tolerated dose of UFT together with Leucovorin and pre-operative radiotherapy for rectal cancer is 240 mg/m2. This combination is well tolerated with the major toxicity being diarrhea. Significant down-staging was noted and enabled anal sphincter preserving surgery even in patients with very low tumors. An unpredicted complication is the refusal of patients, who had tumor down-staging, to undergo abdomino-perineal resection. We are continuing accrual of patients for the phase II study at a dose of 240 mg/m2 UFT.
165
Radioimmunotherapy of Colon Cancer with an Improved Humanized Monoclonal Antibody Design
R.F. Meredith1, A. Forero1, M. Khazaeli1, M. Carpenter1, J. Schlom2, A. LoBuglio1 1 University of Alabama Comprehensive Cancer Center, Birmingham, AL, 2National Cancer Institute, Bethesda, MD Purpose/Objective: To conduct a clinical trial using a novel improved antibody for targeting of radionuclide therapy. Immune response against murine antibodies has limited their application for radioimmunotherapy and has resulted in mechanisms to reduce immunogenicity. However, humanization (Hu) has prolonged plasma circulation in patients, with increased normal tissue retention leading to high background radioactivity and prolonged exposure of the bone marrow to radiolabeled antibody. To overcome these problems a CDR grafted Hu monoclonal antibody(Mab) with a CH2 domain deletion (⌬CH2) was developed utilizing murine MAb CC49. CC49 is directed against a pan carcinoma antigen TAG-72 that is expressed on the majority of colorectal, gastric, breast, ovarian, prostate, pancreatic, and lung carcinomas. The plasma clearance studies in athymic and SCID mice after i.v. or i.p. administrations demonstrated that HuCC49⌬CH2 clears more rapidly from the plasma than HuCC49. (Cancer Biotherapy & Radiopharmaceuticals 12(5):305-316, 1997). Materials/Methods: A Phase I clinical trial of 131I-HuCC49⌬CH2 was conducted in patients with metastatic colon cancer. Biodistribution/pharmacokinetics and dosimetry were obtained after 10 mCi of 131I-HuCC49⌬CH2 in the first cohort of patients prior to dose escalation therapy in subsequent cohorts. Results: Our phase I clinical trial has confirmed the expected quicker plasma clearance and decreased immunogenicity compared to the parent murine CC49. The mean and standard deviation for pharmacokinetic parameter estimates resulting from a one-compartment bolus model were generated using the NLIN procedure in SAS威 for four patients in the first cohort who received 10mCi of 131I-HuCC49⌬CH2 as a biodistribution study. The pharmacokinetic analysis of 131I-HuCC49⌬CH2 and 131 I-mCC49 in humans are compared in the table below. The 131I-HuCC49⌬CH2 plasma mean T1/2 and MRT were significantly shorter and the mean clearance rate significantly greater than m-CC49. (p⬍0.001). The whole body and marrow radiation dose estimates were 0.50⫹0.06 cGy/mCi, 1.00⫹0.14 cGy/mCi with a tumor estimate of 7.4⫹1.9 cGy/mCi. The 131 I-HuCC49⌬CH2 biodistribution was similar to m-CC49. HuCC49⌬CH2 is also expected have improved radioisotope delivery because of its smaller size. All patients studied for biodistribution have shown areas of increased uptake consistent with known metastases. The location of 3 tumors allowed quantitative dosimetry. The mean tumor to marrow radiation dose ratios are ⬎ 3 fold higher for 131I-HuCC49⌬CH2 compared to 131I-mCC49(JNM 35:1017-1022, 1994). The dosimetry estimates indicate that patients will tolerate much higher doses of radiolabeled antibody (higher MTD) with resultant improved tumor radiation doses. Dose escalated therapy with 131I- HuCC49⌬CH2 has been well tolerated with hematologic toxicity being the most frequent side effect. The dose level of 75mCi/m2 mCC49 resulted in ⬎ Grade 3 hematologic toxicity in ⬎ 60% of patients compared to 25% of patients receiving 131I-HuCC49⌬CH2. None of the patients has yet developed human antibody response to HuCC49⌬CH2 whereas murine CC49 has been highly immunogenic with ⬎ 90% of patients developing an immune response, some within one week of initial exposure. Conclusions: Improved antibody design has resulted in a humanized, smaller antibody product with potential for increased radiation dose delivery to TAG-72-expressing adenocarcinomas.
HuCC49⌬CH2(n⫽4) m-CC49 (n⫽13)
166
T 1/2(hrs)
MRT (hrs)
C1 (ml/hr.kg)
AUC
20 ⫾ 3 50 ⫾ 11
29 ⫾ 4 73 ⫾ 16
1.5 ⫾ 0.1 0.9 ⫾ 0.2
10.3 ⫾ 2.2 ...
Prognostic Significance of Epidermal Growth Factor Receptor (EGFR) in Patients with Rectal Cancer Treated with Preoperative Radiotherapy: A GICOR Study
J.L. Giralt1, E. Aranzazu1, d. Manuel2, C. Laura3, J. Elorza-Ricart4, D. Velez5, G. Valero6, S. Benavente1, M. Armengol7, I. de Torres8 1 Department of Radiation Oncology, H Vall d, Barcelona, Spain, 2Department of Radiation Oncology, H Virgen Arrixaca, Murcia, Spain, 3Department of Radiation Oncology, H de la Princesa, Madrid, Spain, 4Department of Preventive Medicine, H Vall d, Barcelona, Spain, 5Department of Pathology, H de la Princesa, Madrid, Spain, 6Department of Surgery, H Virgen Arrixaca, Murcia, Spain, 7Department of Surgery, H Vall d, Barcelona, Spain, 8Department of Pathology, H Vall d, Barcelona, Spain
(median dose: 54 Gy; range: 50 to 60 Gy) was given to 36 out of 97 patients (37%). The two group of patients (early vs. delayed RT) were well balanced in respect to extent of surgery and other main clinical prognostic factors. PFS and DSS were estimated for all eligible patients using the Kaplan-Meier method, and tested for equality with log-rank test. Uni- and multivariate analyses of treatment related and clinical prognostic factors were performed using the Cox proportional hazards model. Results: At a median follow-up of 79 months (range: 28 to 154 months) the 5- and 10-year PFS was 52.2 % and 30.7% with early RT and 39.5% and 12.4% with delayed RT (p ⬍ 0.04; RR: 0.60). Univariate analysis demonstrated that only extent of surgery, and early RT were associated with significantly longer PFS. On multivariate analysis, only the timing of RT was found to be associated significantly with better PFS (p ⬍ 0.007). In respect to DSS, there was no significant difference in the 5- and 10-year actuarial survival rate according to the timing of RT (60.5% and 26.5% vs. 66.6% and 23.7%; p ⫽ 0.75). Patient age (⬎ 30 years vs. ⱕ30 years; RR: 2.04) and extent of surgery (total vs. subtotal; RR: 0.58) were significant prognostic variables in respect to DSS. Subdividing patients based on the extent of surgery, early RT in the subtotal group significantly improved 5-year PFS (60.0% vs. 12.4%; p ⫽ 0.004) and DSS (66.7% vs. 49.8%; p ⫽ 0.04). However, postoperative RT had no influence on PFS (p ⫽ 0.68) and DSS (p ⫽ 0.40) in the totally resected group. Conclusions: Early postoperative RT in subtotally resected, WHO Grade II astrocytomas significantly improves both progression-free and disease-specific survival. Early RT has no benefit in the totally resected group, therefore RT should be withheld in these patients until progression.
163
Preoperative Concurrent Chemoradiation in Locally Advanced Rectal Cancer with 50 Gy and Oxaliplatin (OXA), Fluorouracil (FU), I-Folinic Acid (l-LV). The Lyon R0-04 Phase II Trial
J. Gerard1, O. Chapet2, P. Romestaing2, F. Mornex2, R. Coquard3, N. Barbet4, D. Atlan5, G. Freyer2 1 Centre Antoine-Lacassagne, Nice, France, 2Lyon Sud Hospital Pierre Benite, Lyon, France, 3Clinique St Jean, Lyon, France, 4Clinique Denis, Macon, France, 5Hopital G Pompidou, Paris, France Purpose/Objective: The standard treatment of T3-4 NxM0 rectal cancer in France is preoperative radiotherapy and surgery. It has been demonstrated (Freyer JCO 2001; 19: 2433) that concurrent radiotherapy (45 Gy) and chemotherapy with OXA, FU, I-LV (FolfoR 1) was a feasible regimen with a recommended dose of OXA of 130 mg/m2 on day 1 and 29. The purpose of this study was to assess the tolerance and the efficacy of FolfoR 2 regimen in preoperative setting. Materials/Methods: Between May 2000 and October 2001, 40 patients with rectal adenocarcinoma were included in this prospective phase II trial (median age 60 (38-76) years, 26 males, 14 females). Staging was performed in all patients with endorectal ultrasound (T3⫽ 36, T4⫽ 5, N0⫽ 23, N1⫽ 18 –All M0). Posterior pelvic irradiation was given with a 3-4 fields technique, ⫻ 18 MV, total dose: 50 Gy in five weeks (45 Gy/25 fractions/5 weeks ⫹ concomitant boost 5GY/5F (1 Gy per fraction on day 5, 12, 19, 26, 33). Chemotherapy regimen was two cycles of OXA, FU, l-LV (day 1-5 and 29-33), FU 350 mg/m2/D, protracted venous infusion 5 days with l-LV 100 mg/m2/day, OXA 130 mg/m2 on D1, D29. Surgery was planned for all patients after a rest period of 4 weeks. Results: They are available for 40 patients, all evaluable for immediate toxicities. Treatment was stopped after the first cycle in 1 patient with probable low-DPD, due to severe cystitis/rectitis, alopecia, grade 4 neutropenia, grade 3 mucositis and hand-foot syndrome. Symptoms recovered within 10 days. All other patients completed treatment and no major event occurred except: transitory grade 3 diarrhea and asthenia (1 pt) and neutropenia (1 pt). Neurotoxicity was mild: cold-induced dysesthesiae grade 1 in 25 pts, grade 2 in 1 pt. All patients had substantial tumor shrinkage before surgery. Anterior resection was performed in 25 pts, APR in 10. There was no postoperative death. Four fistulae/pelvic abcedations requiring salvage surgery ⫾colostomy were observed (11%). The pathologic reports showed 15 (43%) major responses (sterilization or rare residual cells), of which 5 (14%) were complete. Conclusions: These results demonstrate that this FolfoR 2 regiment is well tolerated and does not increase surgical complication. It gives a high rate of clinical and pathological response. It could be proposed as a new experimental arm when the results of the FFCD 92-03, EORTC 22912 trials will be available.
164
A Phase I-II Study of Pre-Operative Radiotherapy and Escalating Doses of Oral UFT for Rectal Cancer
R.M. Pfeffer1, Y. Kundel1, M. Zehavi1, M. Koller2, Z. Symon1 1 Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel, 2Department of Surgery, Sheba Medical Center, Tel Hashomer, Israel Purpose/Objective: Pre-operative radiotherapy (XRT) increases local control and survival of patients with rectal cancer. Continuous infusion (CI) 5FU added to radiotherapy results in down-staging of a large percentage of tumors, but requires continued venous access. UFT (a combination of tegafur, an orally absorbed derivative of 5FU, together with uracil) has pharmaco-kinetics and anti-tumor effect similar to CI 5FU with a similar toxicity spectrum but with the advantage of oral administration. The primary objective of this phase I-II study is to determine the maximum tolerated dose of oral UFT (uracil & tegafur in 4:1 ratio) and low dose leucovorin with preoperative pelvic irradiation (XRT) for rectal cancer and to assess the toxicity of this combination. The secondary objective is to assess response as determined by clinico-pathological downstaging and trans-rectal ultrasound before and after chemo-radiation. The maximum tolerated dose (MTD) is defined as the dose resulting in a break of XRT, for a total of 7 days or more, due to grade III toxicity. The target dose level is 300 mg/m2 which is the recommended dose of UFT without XRT. After determining the MTD a total of 20 patients will be treated at this dose in order to assess tumor response in a larger population. Materials/Methods: The treatment protocol includes a fixed, standard dose of pelvic XRT, 45 Gy in 1.8 Gy daily fractions over 5 weeks (RL/LL/PA fields) with an escalating dose of oral UFT in 3 divided doses/day and a fixed dose of 30 mg/day oral leucovorin. UFT and leucovorin are given for 28 consecutive days concomitant with the first 4 weeks of radiotherapy. Surgery is planned 4-6 weeks after completion of XRT. The surgical procedure is determined by the surgeon at the time of surgery. After
97
98
I. J. Radiation Oncology
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
surgery patients receive 4 cycles of oral UFT at a dose of 300 mg/m2 UFT per day with leukovorin 30 mg/day for 4 weeks followed by one week break. Results: Sixteen patients aged 42-79 years have been enrolled. Tumors were situated 3-11 cm from the anal verge. Four patients completed pre-operative treatment at the starting dose of 200 mg/m2/day UFT with no grade III toxicity. One out of 8 patients treated at a dose of 240 mg/m2/day UFT developed grade IV diarrhoea requiring intravenous fluid replacement. Another patient required a 3 day treatment break for GI symptoms. Four patients received a dose of 270 mg/m2/day UFT. One of them was hospitalized with grade IV diarrhoea and leukopenic fever and died during hospitalization. Since there was a fatal toxicity at this level it was decided to consider 240 mg/m2 as the MTD. Thirteen of 15 evaluable patients had tumor downstaging as seen by TRUS and at surgery. Two patients, with tumors 3 and 5 cm from the anal verge and who had significant down-staging of their tumors, refused abdomino-perineal resection, one is without evidence of disease after receiving brachytherapy. Ten patients have undergone anterior resection with no surgical complications except for one patient who underwent a cholecystectomy at the time of tumor resection developed a post-operative infection. Three patients with low (⬍5cm from anal verge) tumors underwent colo-anal anastamosis without complications. Conclusions: The maximum tolerated dose of UFT together with Leucovorin and pre-operative radiotherapy for rectal cancer is 240 mg/m2. This combination is well tolerated with the major toxicity being diarrhea. Significant down-staging was noted and enabled anal sphincter preserving surgery even in patients with very low tumors. An unpredicted complication is the refusal of patients, who had tumor down-staging, to undergo abdomino-perineal resection. We are continuing accrual of patients for the phase II study at a dose of 240 mg/m2 UFT.
165
Radioimmunotherapy of Colon Cancer with an Improved Humanized Monoclonal Antibody Design
R.F. Meredith1, A. Forero1, M. Khazaeli1, M. Carpenter1, J. Schlom2, A. LoBuglio1 1 University of Alabama Comprehensive Cancer Center, Birmingham, AL, 2National Cancer Institute, Bethesda, MD Purpose/Objective: To conduct a clinical trial using a novel improved antibody for targeting of radionuclide therapy. Immune response against murine antibodies has limited their application for radioimmunotherapy and has resulted in mechanisms to reduce immunogenicity. However, humanization (Hu) has prolonged plasma circulation in patients, with increased normal tissue retention leading to high background radioactivity and prolonged exposure of the bone marrow to radiolabeled antibody. To overcome these problems a CDR grafted Hu monoclonal antibody(Mab) with a CH2 domain deletion (⌬CH2) was developed utilizing murine MAb CC49. CC49 is directed against a pan carcinoma antigen TAG-72 that is expressed on the majority of colorectal, gastric, breast, ovarian, prostate, pancreatic, and lung carcinomas. The plasma clearance studies in athymic and SCID mice after i.v. or i.p. administrations demonstrated that HuCC49⌬CH2 clears more rapidly from the plasma than HuCC49. (Cancer Biotherapy & Radiopharmaceuticals 12(5):305-316, 1997). Materials/Methods: A Phase I clinical trial of 131I-HuCC49⌬CH2 was conducted in patients with metastatic colon cancer. Biodistribution/pharmacokinetics and dosimetry were obtained after 10 mCi of 131I-HuCC49⌬CH2 in the first cohort of patients prior to dose escalation therapy in subsequent cohorts. Results: Our phase I clinical trial has confirmed the expected quicker plasma clearance and decreased immunogenicity compared to the parent murine CC49. The mean and standard deviation for pharmacokinetic parameter estimates resulting from a one-compartment bolus model were generated using the NLIN procedure in SAS威 for four patients in the first cohort who received 10mCi of 131I-HuCC49⌬CH2 as a biodistribution study. The pharmacokinetic analysis of 131I-HuCC49⌬CH2 and 131 I-mCC49 in humans are compared in the table below. The 131I-HuCC49⌬CH2 plasma mean T1/2 and MRT were significantly shorter and the mean clearance rate significantly greater than m-CC49. (p⬍0.001). The whole body and marrow radiation dose estimates were 0.50⫹0.06 cGy/mCi, 1.00⫹0.14 cGy/mCi with a tumor estimate of 7.4⫹1.9 cGy/mCi. The 131 I-HuCC49⌬CH2 biodistribution was similar to m-CC49. HuCC49⌬CH2 is also expected have improved radioisotope delivery because of its smaller size. All patients studied for biodistribution have shown areas of increased uptake consistent with known metastases. The location of 3 tumors allowed quantitative dosimetry. The mean tumor to marrow radiation dose ratios are ⬎ 3 fold higher for 131I-HuCC49⌬CH2 compared to 131I-mCC49(JNM 35:1017-1022, 1994). The dosimetry estimates indicate that patients will tolerate much higher doses of radiolabeled antibody (higher MTD) with resultant improved tumor radiation doses. Dose escalated therapy with 131I- HuCC49⌬CH2 has been well tolerated with hematologic toxicity being the most frequent side effect. The dose level of 75mCi/m2 mCC49 resulted in ⬎ Grade 3 hematologic toxicity in ⬎ 60% of patients compared to 25% of patients receiving 131I-HuCC49⌬CH2. None of the patients has yet developed human antibody response to HuCC49⌬CH2 whereas murine CC49 has been highly immunogenic with ⬎ 90% of patients developing an immune response, some within one week of initial exposure. Conclusions: Improved antibody design has resulted in a humanized, smaller antibody product with potential for increased radiation dose delivery to TAG-72-expressing adenocarcinomas.
HuCC49⌬CH2(n⫽4) m-CC49 (n⫽13)
166
T 1/2(hrs)
MRT (hrs)
C1 (ml/hr.kg)
AUC
20 ⫾ 3 50 ⫾ 11
29 ⫾ 4 73 ⫾ 16
1.5 ⫾ 0.1 0.9 ⫾ 0.2
10.3 ⫾ 2.2 ...
Prognostic Significance of Epidermal Growth Factor Receptor (EGFR) in Patients with Rectal Cancer Treated with Preoperative Radiotherapy: A GICOR Study
J.L. Giralt1, E. Aranzazu1, d. Manuel2, C. Laura3, J. Elorza-Ricart4, D. Velez5, G. Valero6, S. Benavente1, M. Armengol7, I. de Torres8 1 Department of Radiation Oncology, H Vall d, Barcelona, Spain, 2Department of Radiation Oncology, H Virgen Arrixaca, Murcia, Spain, 3Department of Radiation Oncology, H de la Princesa, Madrid, Spain, 4Department of Preventive Medicine, H Vall d, Barcelona, Spain, 5Department of Pathology, H de la Princesa, Madrid, Spain, 6Department of Surgery, H Virgen Arrixaca, Murcia, Spain, 7Department of Surgery, H Vall d, Barcelona, Spain, 8Department of Pathology, H Vall d, Barcelona, Spain