- Email: [email protected]
600 Poster Evaluation of toxicities and effects of concurrent cisplatin (CDDP) and radiation therapy for unresectable carcinoma of the pancreas
Posters
Wednesday/Thursday, 18-19 September 2002 S185
Germany
St. Luke's Hospital, Radiation Oncology department, Dubfin, Ireland
2Abdominal surgery, Georg-August-Universit&t, Goettingen, Germany 3pathology, Georg-August-Universit~t, Goettingen, Germany
Purpose: Since publication of the Intergroup 116 trial (McDonald et at, 2001), adjuvant 5-Fluorouracil (5-FU)-based chemo-radiotherapy has been standard treatment in our institution for resectable adenocarcinoma of the stomach or gastro-oesophageal junction. The potential toxicity of this regime has caused considerable concern, and this retrospective review attempts to assess its feasibility within our institutional experience. Methods: From 2000 to 2001, 19 patients (pts) received adjuvant 5-FUbased chemo-radiotherapy for resectable gastric carcinoma. The median age of patients was 64 years. The sex ratio was 3.74:1 , favouring men. All pts had a gastric carcinoma (t pts Grade 1, 2 pts grade 2, 16 pts grade 3). 8 pts had a total or sub-total gastrectomy, 11 pts had a partial gastrectomy. 18 pts had a R0 resection and 1 pt had a R1 resection. Surgical stage were as follow: 1 AJCC stage IB, 1 stage II, 12 stage IliA, 1 stage IIIB, and 4 stage IV. Radiation treatment was delivered to the upper abdomen according to the protocol guidelines, i.e. to encompass the turnout bed with a 2 cm margin, perigastric, coeliac, local para-aortic, splenic, hepatoduodenal, or hepatic-portal, and pancreaticoduodenal lymph nodes, with a planned dose of 45 Gy/25 fractions over 5 weeks, delivered antero-posteriorty and postero-anteriorly. Chemotherapy consisted of a total of 4 cycles of combined 5-FU/Leucovorin regimen, 1 given concomitantly to radiation, as per protocol INT 116. However, chemotherapy could be administered either bolus (11 pts) or infusional (8pts) at physician discretion. Results: Only 2 RTOG Grade > 3 (grade-3 arrhythmia, grade-3 nausea) were reported, in 2 pts receiving bolus 5FU, both of which necessitated treatment cessation. Conclusion: Adjuvant Chemo-radiotherapy in resectable gastric carcinoma seems to be feasible in daily pract!ce in our institution. 5FU administration schedule could have an impact on toterability of the treatment.
Purpose: To evaluate the clinical outcome and prognostic factors in esophageal carcinoma treated with neoadjuvant radiochemotherapy, Methods: Retrospective analysis of 48 patients with locally advanced carcinomas of the middle and distal esophagus, treated 1995-2001 at the university hospital Goettingen. End points were overall- and disease specific survival and the influence of histological and clinical factors on survival. 24 patients with squamous cell carcinoma received 3 cycles of cisplatinum, etoposide, and 5-FU, followed by radiochemotherapy with 40 Gy. To reduce total treatment time we introduced a simultaneous radiochemotherapy with cisplatinum, 5-FU and 40 Gy for other 24 patients. 4 weeks after completion of therapy the patients were sent to operation, Results: Median follow-up was 1,9 years. One year overall survival (OS) was 82%, two years OS 60%, 3-y ©S 45%, 5-y OS 30%. 3 patients died perioperatively (pulmonary complications). 35% showed distant metastasis. 21% experienced local failure, mostly within the first two years after operation. Prognostic influence showed the pathological regression grade: With complete remission (13%) 3-y OS was 80%, with lower grade remission only 20%. Interestingly, endoluminal tumor showed better remission than cancer cells in deep layers of the esophageal wall. No prognostic influence showed histology, T-stage, hemoglobin levels, toxicity or time to operation. Conclusions: The current practiced simultaneous radiochemotherapy is well tolerated. In comparison to literature the rate of local failure is reduced by neoadjuvant therapy. The overall survival is comparable to the literature. Only prognostic factor was the histological regression, 597 Poster
Evaluation of the treatment modality offered by high energy (50MeV) electron and photons for pancreatic cancer Y,/to, Y. Kagami, M. Sumi, A. Imai, H. Ikeda National Cancer Center Hospital, Radiation Oncology, Tokyo, Japan Purpose: By adding a small fraction of photons with matching dose gradient (wedge) ,high energy electron (50MeV) was reported to be able to make a good dose distribution for deep-seated tumors. The aim of this study is to develop the treatment technique using the high energy electron and photons for pancreatic cancer and to evaluate the dose distributions of this treatment modality by comparing with those of conventional photon thera-
PY
Materials and Methods: Data sets of 16 patients with locally advanced pancreatic cancer treated with conventional photon therapy were used for this analysis. Data sets were consisted of; (1) Computed tomography (CT) scans: exhalation phase CT scans, 10 mm thickness with 10 mm interval of each slice, were obtained, and (2) the site of tumor lesion; pancreas head and/or body. Clinical target volume (CTV) was defined as primary tumor, nodal involvement and draining and para-aortic lymph nodes. The total dose was 50.4 Gy in 28 fractions of 1.8 Gy a day. The surrounding normal tissues such as liver, small intestine, and kidneys were delineated. Treatment technique using high energy electron and photons was planned with a three-field technique; anterior electron beam (50 MeV) and lateral photons beam (25MV) with wedge. Conventional treatmenttechniqueusing photons was planned with a four-field box technique. Dose-volume histogram (DVH) and normal tissue complication probability (NTCP) of the surrounding norreal tissues were calculated and compared in high energy electron plan and photon plan. Results: The mean dose of the c r v was not different between the two plans. The mean dose and NTCP of the small intestine in high energy electron plan was significant lower than those in conventional photon plan (475±322 cGy vs. 634±409 cGy; P<0.001,0.21% vs. 0.27%; P=0.001). The mean dose of the liver in high energy electron plan was significant lower than those in photon plan (910±334 cGy vs. 1167±396 cGy; P<0.001). 20% dose-volume of the bilateral kidneys in high energy electron plan was also lower than those in photon plan (25.1±8.5% vs. 28.8+9.0%; P<0.001) NTCP of the liver and bilateral kidneys was not different between the two plans. Conclusion: We could develop a treatment technique using the high energy electron (50MeV) and photons for pancreatic cancer. It is suggested that this new treatment modality can be a useful plan and may allow a higher dose to the tumor with reducing the dose to the surrounding normal tissues. 598
Poster
Toxicity of adjuvant ¢hemo-radiotherapy for resectable gastric carcinoma: possible impact of 5-flourouracil administration schedule
B. O'Nei//. P. Thirion, D. Ho//ywood, M. Moriarty, J. Armstrong
599
Poster
Intraoperative radiation therapy for extrahepatic biliary tract cancer C. Y. Kim, D.S. Yang, W.S. Youn, M.S. Choi Korea Universiti Hospital, Radiation Oncology, Seoul, South Korea Purpose: Extrahepatic biliary tract cancer is relatively uncommon and poor prognosis. This study is to investigate the effectiveness of the intraoperative radiation therapy (IORT) in locally advanced extrahepatic biliary tract cancers. Methods and Materials: Between December 1993 and December 2000, nineteen patients with extrahepatic biliary tract cancer were treated with IORT. There were eleven men and eight women in mean age 57 years (40 - 75 years). All tumors were locally advanced cancer ( more than T3 or T4, N-positive). Location of tumor was common bile duct (9/19), gallbladder (7/19), and amppula of vater (3/19). Surgery was followed by IORT using total doses of 10-30 Gy specified to 60-100% isodose with electron beam (6 to 20 MeV). Postoperative external irradiation was delivered in 12 patients with total doses of 21.6 - 50.4 Gy by 10 MV x-ray. Results : The overall median survival time was 14.7 months. Acute complication from IORT were uncommon and major post-IORT complications (grade 3 or 4) were not seen in this study. The major cause of failure was Iocoregional recurrence (7/19, 36.8%). In univariate analysis, post-IORT external irradiation (p=0.0268) and extent of surgical tumor removal (p=0.0102) were significant prognostic factors. Conclusions: Extrahepatic biliary tract cancer is poor prognosis and difficult to remove surgically. IORT with surgical tumor removal as possible and post-IORT external irradiation was effective for survival without major cornplications in locally advanced extrahepatic biliary tract cancer. 600
Poster
Evaluation of toxicities and effects of concurrent cisplatin (CDDP) and radiation therapy for unresectable carcinoma of the pancreas H. Kawakami. T. Uno, T. Aruga, K. /sobe, N. Machida, N. Ueno, T. Kawata, H. /to Chiba University Graduate Schoo/of Medicine, Radio/ogy, Chiba City 2608670, Japan Purpose: The objectives of this study were to evaluate toxicities and effects of concurrent cbemoradiotherapy for advanced pancreas carcinoma. Materials and Methods: Form 1995, twenty-four patients with unresectable adenocarcinomaof the pancreas were enrolled into the present study. There were 18 men and 6 women with the median age of 59 years. Eleven patients without liver metastasis received daily CDDP (5 mg/m =) by intravenous infusion concurrently with radiotherapy. For 13 patients with liver metastasis, combination of daily CDDP (3 mg/m =) / 5-fluorouracil (300
S 186 Wednesday/Thursday, 18-19 September 2002
mg/m 2) were delivered via hepatic artery. All patients were treated with 10 MV photons. Opposed anterior and posterior field, 3 field or 4 filed technique were used. The planning treatment volume included primary tumor and surrounding clinically enlarged lymph nodes. Fractional daily dose of 1.8 to 2 Gy at an isocenter, up to a total dose of 40-50.4 Gy (median 50 Gy) were delivered. In order to evaluate treatment efficacies, changes in tumor size, value of CA19-9, performance status, pain grade, required dosage of analgesics were monitored. Acute toxicities were evaluated according to the criteria of NCT-CTC. Results: Of the 18 patients who had abdominal pain before the treatment, 10 patients (56%) achieved pain relief. At the end of the treatment, obvious tumor response could not be observed in any of the patients. However, local tumor showed gradual shrinkage in about one third of all patients, and partial response was obtained in 3 patients. There were 2 patients who lived more than 2 years after the treatment. Of 11 patients without liver metastasis, the value of CA19-9 decreased in 8 patients (72%). Except for 3 patients with disease progression, all patients could complete the treatment. Four patients experienced grade 3 nausea, which was the most frequently observed complaint in this regimen. At the time of data analysis, the median follow-up was 5.2 months for all. No patients experienced grade 4 acute toxcities. Median survival time was 8.1 months and 3.6 months, for patients with and without liver metastasis, respectively. Conclusion: Results indicated that this regimen was well tolerable and efficient for symptomatic advanced pancreas carcinoma, 601
noma (EXHC) is controversial in adjuvant setting and even more as curative treatment for unresectable cases. We undertook this retrospective analysis to evaluate our initial results with two different CRT regimens given after an R1 resection or for unresectable EXHC. Material & methods: As of March 2001, 14 patients (pts) had been treated with ORT at CAL, after palliative biliary drainage or a R1 resection, PS < 2, < 80 yr, good renal, cardiac and biological parameters. Only I 0 patients were analysed, having at least 12 months of follow-up. Treatment protocol: regimen A = 40Gy/20fr/6wk D1- D12 (20Gy), "split", D29- 40 (20Gy) with 5FU 750 mg/m2/24h x 5 days, DI- 5 and D29- 33; regimen B = 50Gy/25fr/ 5 wk with same 5FU schedule, + Cisplatin 100 mg/m 2 D2 and D30. RT technique: 25 MV photons, 3 or 4 fields ("box"), CTV = GTV + 3 cm margins in all directions, 3D dosimetry. Results: all patients evaluable, 9 males, 1 female, age 53- 77 yr (mean 68). Five patients in each regimen arm, equally represented (1 unresectable and 4 R1 surgery). Minimal follow-up 12 mo, mean 25 mo, maximal 102+ mo. No major protocol deviation. Actuarial survival rate 73, 30 and 12 % at 1,3 and 5 yr respectively (median 23 mo). Median survival 10.7 mo arm A vs. 23 mo for arm B. Toxicity: no G4 EORTC acute toxiciy, 20 % G3 (Gt & hematologic) for arm B vs no G3 toxicity for arm A. Median TTP (local + distant): 8.7 mo arm A vs. not reached for arm B. .,t Conclusion: Based on this preliminary results, we Changed our treatment policy for unresectable or incompletely resected EXHC in favour of CRT type B regimen.
Poster
Radiochemotherapy in the management of locally advanced carcinoma of the cervical esophagus M. Signor 1, S. Fongione 1, A. lop2 1Radiotherapy, Radiation Oncology, Udine, Italy 2Medical Oncology, Latisana, Italy Purpose: To analyze the experience of our institution in the management of locally advanced carcinoma of the cervical esophagus with chemoradiation therapy (CTRT). Data relating to toxic effects, local control of disease and overall survival were collected and evaluated prospectively. Methods and Materials: Induction and concurrent chemotherapy regimen consisted of two courses of 120 hours infusion of 5-FU 600 mg./m ~, from days 1 to 5 and from days 22 to 26, and cisplatin 20 mg./m 2, in the same days, followed by high-dose external beam radiotherapy plus endoluminal brachytherapy up to 54-70 Gy and concurrent chemotherapy with cisplatin and 5-FU during the first and fifth week. Since april 1994, a series of 19 patients (pts.), with biopsy-proved carcinoma of the cervical esophagus received CTRT and were evaluated, Results: Global median follow up was 22.89 months. For alive pts median follow up was 30.8 months The pts. were 4 female and 15 male, mean age of 64,2 (range 49-77), mean Kamofsky Index of 80 (range 60-90), 18 in clinical stage III and one in IIA, mean lesional length was 5.64 cm. (range 3-9).The mean radiation dose administered was 59.84 Gy (range 54-70), specified at the minimal isodose of 95%, in conventional fractionation. We used high dose rate endoluminal brachytherapy, as a boost, in 5 pts. All the pts. completed the treatment; we had no toxic deaths while acute and late toxicity of this schedule was moderate. Two long survivers developed stricture requiring dilatation. We observed 10 (52.63%) complete endoscopic remissions, 8 (42.1%) partial remissions and 1 stable disease. Overall survival was 36.8% at 2 years and 31.57% at 3 years. The probabilities of Iocoragional tumour recurrences and distant metastases, as sites of first relapse, were 31.57% and 10.5% at 2 years, Conclusions: The radJochemotherapy treatment offers a definitive chance of long term survival for pts with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk, after treatment. Intensifications of the regimen seems possible, using X rays dose escalations protocols with 3D treatment planning, because no dose limiting late toxicities were observed, 602
Posters
Poster
Concurrent chemo-radiation therapy for extrahepatic cholangiocarcinoma G. Kacso 1, K. Benezery 1, G. Rossi 3, E. Frangois 2, J. Gugenheim 3, R. Bensadoun 1 1Centre Antoine Lacassagne, Radiotherapy, Nice 02, France 2Centre Antoine Lacassagne, Medical Oncology, Nice 02, France 3Hopital Archet II, Surgery, Nice 02, France The role of chemo-radiation therapy (CRT) for extrahepatic cholangiocarci-
HYPOXIA/TUMOR MICROENVIRONMENT 603
Poster
Evaluation of RH1 as an innovative bioreductive agent and a potential radiosensitizer J. Kim 1, C. West 1, H. Valentine 1, T. Ward"?, I. Stratford3, A. Patterson 3, J. Hendry 1 1paterson Institute for Cancer Research, Experimental Radiation Oncology, Manchester, United Kingdom 2paterson Institute for Cancer Research, Drug Development, Manchester, United Kingdom 3Manchester University, School of Pharmacy and Pharmaceutical Sciences, Manchester, United Kingdom RH1 is a newly-developed quinone-containing alkylating agent which is metabolized by a 2-electron reduction pathway using the enzyme NQO1 (NAD(P}H: quinone oxidoreductase, also called DT-diaphorase(DTD}). This enzyme is overexpressed in some tumours, hence providing selectivity of RH1 action. The cytotoxicity of RH1 and its effect in combination with irradiation were investigated. The human breast cancer MDA231 line which has an homologous point mutation in the NQO1 gene and no detectable DTD activity was used, along with MDA231 D7 cells which was derived from the parental ceil line by transfection with the human NQO1 gene. Cytotoxicity of RH1 was assessed by exposing the cells to a range of drug concentration for 3 hrs. For combined treatment, radiation was given at the end of 3hrs with IC90% dose. For hypoxic experiments, 95%N2/5%CO2 gas mixture was used and was maintained during irradiation. Different radiation schedules were also tested in aerobic conditions, delaying irradiation for 12, 24 and 48 hrs after drug treatment. RH1 showed a high clonogenic cytotoxicity to D7 cells in nM concentrations of drug under oxic conditions and the cytotoxicity was maintained the same under hypoxic conditions. RH1 also showed some-eytotox'i¢ effect on the parent cells under aerobic conditions, but the cytotoxicity was enhanced by 3-fold under hypoxia. When radiation was given at later time points, the SF2 value for the combined treatment was significantly lower at the 12 and 24 hour time points (p=0.O05 for both) compared to their radiation-alone values. When radiation was given at 48 hours, the SF2 value for the combination was higher than for radiation alone, suggesting a protective effect. Dose modifying factors (DMF) at 2 Gy were 1.0, 1.7, 1.5 and 0.5 for 0, 12, 24, and 48 hrs. The DMF values at the later time points were significantly different from the 0 hr point (p=o.oo04, 0.003 and 0.007 for 12, 24, 48 hrs vs. 0 hr). The same trend was observed for the parental cell line but the differences were not significant. In conclusion, RH1 shows a major cytotoxic effect in DTD-rich cancer cells. The increasing radiosensitivity for longer intervals between drug and irradiation with the DTD-rich cell line compared to the DTD-null cell line indicates a greater drug/radiation interaction for the DTD-rich cells, which might be due to different damage induction and repair pathways.
Wednesday/Thursday, 18-19 September 2002 S185
Germany
St. Luke's Hospital, Radiation Oncology department, Dubfin, Ireland
2Abdominal surgery, Georg-August-Universit&t, Goettingen, Germany 3pathology, Georg-August-Universit~t, Goettingen, Germany
Purpose: Since publication of the Intergroup 116 trial (McDonald et at, 2001), adjuvant 5-Fluorouracil (5-FU)-based chemo-radiotherapy has been standard treatment in our institution for resectable adenocarcinoma of the stomach or gastro-oesophageal junction. The potential toxicity of this regime has caused considerable concern, and this retrospective review attempts to assess its feasibility within our institutional experience. Methods: From 2000 to 2001, 19 patients (pts) received adjuvant 5-FUbased chemo-radiotherapy for resectable gastric carcinoma. The median age of patients was 64 years. The sex ratio was 3.74:1 , favouring men. All pts had a gastric carcinoma (t pts Grade 1, 2 pts grade 2, 16 pts grade 3). 8 pts had a total or sub-total gastrectomy, 11 pts had a partial gastrectomy. 18 pts had a R0 resection and 1 pt had a R1 resection. Surgical stage were as follow: 1 AJCC stage IB, 1 stage II, 12 stage IliA, 1 stage IIIB, and 4 stage IV. Radiation treatment was delivered to the upper abdomen according to the protocol guidelines, i.e. to encompass the turnout bed with a 2 cm margin, perigastric, coeliac, local para-aortic, splenic, hepatoduodenal, or hepatic-portal, and pancreaticoduodenal lymph nodes, with a planned dose of 45 Gy/25 fractions over 5 weeks, delivered antero-posteriorty and postero-anteriorly. Chemotherapy consisted of a total of 4 cycles of combined 5-FU/Leucovorin regimen, 1 given concomitantly to radiation, as per protocol INT 116. However, chemotherapy could be administered either bolus (11 pts) or infusional (8pts) at physician discretion. Results: Only 2 RTOG Grade > 3 (grade-3 arrhythmia, grade-3 nausea) were reported, in 2 pts receiving bolus 5FU, both of which necessitated treatment cessation. Conclusion: Adjuvant Chemo-radiotherapy in resectable gastric carcinoma seems to be feasible in daily pract!ce in our institution. 5FU administration schedule could have an impact on toterability of the treatment.
Purpose: To evaluate the clinical outcome and prognostic factors in esophageal carcinoma treated with neoadjuvant radiochemotherapy, Methods: Retrospective analysis of 48 patients with locally advanced carcinomas of the middle and distal esophagus, treated 1995-2001 at the university hospital Goettingen. End points were overall- and disease specific survival and the influence of histological and clinical factors on survival. 24 patients with squamous cell carcinoma received 3 cycles of cisplatinum, etoposide, and 5-FU, followed by radiochemotherapy with 40 Gy. To reduce total treatment time we introduced a simultaneous radiochemotherapy with cisplatinum, 5-FU and 40 Gy for other 24 patients. 4 weeks after completion of therapy the patients were sent to operation, Results: Median follow-up was 1,9 years. One year overall survival (OS) was 82%, two years OS 60%, 3-y ©S 45%, 5-y OS 30%. 3 patients died perioperatively (pulmonary complications). 35% showed distant metastasis. 21% experienced local failure, mostly within the first two years after operation. Prognostic influence showed the pathological regression grade: With complete remission (13%) 3-y OS was 80%, with lower grade remission only 20%. Interestingly, endoluminal tumor showed better remission than cancer cells in deep layers of the esophageal wall. No prognostic influence showed histology, T-stage, hemoglobin levels, toxicity or time to operation. Conclusions: The current practiced simultaneous radiochemotherapy is well tolerated. In comparison to literature the rate of local failure is reduced by neoadjuvant therapy. The overall survival is comparable to the literature. Only prognostic factor was the histological regression, 597 Poster
Evaluation of the treatment modality offered by high energy (50MeV) electron and photons for pancreatic cancer Y,/to, Y. Kagami, M. Sumi, A. Imai, H. Ikeda National Cancer Center Hospital, Radiation Oncology, Tokyo, Japan Purpose: By adding a small fraction of photons with matching dose gradient (wedge) ,high energy electron (50MeV) was reported to be able to make a good dose distribution for deep-seated tumors. The aim of this study is to develop the treatment technique using the high energy electron and photons for pancreatic cancer and to evaluate the dose distributions of this treatment modality by comparing with those of conventional photon thera-
PY
Materials and Methods: Data sets of 16 patients with locally advanced pancreatic cancer treated with conventional photon therapy were used for this analysis. Data sets were consisted of; (1) Computed tomography (CT) scans: exhalation phase CT scans, 10 mm thickness with 10 mm interval of each slice, were obtained, and (2) the site of tumor lesion; pancreas head and/or body. Clinical target volume (CTV) was defined as primary tumor, nodal involvement and draining and para-aortic lymph nodes. The total dose was 50.4 Gy in 28 fractions of 1.8 Gy a day. The surrounding normal tissues such as liver, small intestine, and kidneys were delineated. Treatment technique using high energy electron and photons was planned with a three-field technique; anterior electron beam (50 MeV) and lateral photons beam (25MV) with wedge. Conventional treatmenttechniqueusing photons was planned with a four-field box technique. Dose-volume histogram (DVH) and normal tissue complication probability (NTCP) of the surrounding norreal tissues were calculated and compared in high energy electron plan and photon plan. Results: The mean dose of the c r v was not different between the two plans. The mean dose and NTCP of the small intestine in high energy electron plan was significant lower than those in conventional photon plan (475±322 cGy vs. 634±409 cGy; P<0.001,0.21% vs. 0.27%; P=0.001). The mean dose of the liver in high energy electron plan was significant lower than those in photon plan (910±334 cGy vs. 1167±396 cGy; P<0.001). 20% dose-volume of the bilateral kidneys in high energy electron plan was also lower than those in photon plan (25.1±8.5% vs. 28.8+9.0%; P<0.001) NTCP of the liver and bilateral kidneys was not different between the two plans. Conclusion: We could develop a treatment technique using the high energy electron (50MeV) and photons for pancreatic cancer. It is suggested that this new treatment modality can be a useful plan and may allow a higher dose to the tumor with reducing the dose to the surrounding normal tissues. 598
Poster
Toxicity of adjuvant ¢hemo-radiotherapy for resectable gastric carcinoma: possible impact of 5-flourouracil administration schedule
B. O'Nei//. P. Thirion, D. Ho//ywood, M. Moriarty, J. Armstrong
599
Poster
Intraoperative radiation therapy for extrahepatic biliary tract cancer C. Y. Kim, D.S. Yang, W.S. Youn, M.S. Choi Korea Universiti Hospital, Radiation Oncology, Seoul, South Korea Purpose: Extrahepatic biliary tract cancer is relatively uncommon and poor prognosis. This study is to investigate the effectiveness of the intraoperative radiation therapy (IORT) in locally advanced extrahepatic biliary tract cancers. Methods and Materials: Between December 1993 and December 2000, nineteen patients with extrahepatic biliary tract cancer were treated with IORT. There were eleven men and eight women in mean age 57 years (40 - 75 years). All tumors were locally advanced cancer ( more than T3 or T4, N-positive). Location of tumor was common bile duct (9/19), gallbladder (7/19), and amppula of vater (3/19). Surgery was followed by IORT using total doses of 10-30 Gy specified to 60-100% isodose with electron beam (6 to 20 MeV). Postoperative external irradiation was delivered in 12 patients with total doses of 21.6 - 50.4 Gy by 10 MV x-ray. Results : The overall median survival time was 14.7 months. Acute complication from IORT were uncommon and major post-IORT complications (grade 3 or 4) were not seen in this study. The major cause of failure was Iocoregional recurrence (7/19, 36.8%). In univariate analysis, post-IORT external irradiation (p=0.0268) and extent of surgical tumor removal (p=0.0102) were significant prognostic factors. Conclusions: Extrahepatic biliary tract cancer is poor prognosis and difficult to remove surgically. IORT with surgical tumor removal as possible and post-IORT external irradiation was effective for survival without major cornplications in locally advanced extrahepatic biliary tract cancer. 600
Poster
Evaluation of toxicities and effects of concurrent cisplatin (CDDP) and radiation therapy for unresectable carcinoma of the pancreas H. Kawakami. T. Uno, T. Aruga, K. /sobe, N. Machida, N. Ueno, T. Kawata, H. /to Chiba University Graduate Schoo/of Medicine, Radio/ogy, Chiba City 2608670, Japan Purpose: The objectives of this study were to evaluate toxicities and effects of concurrent cbemoradiotherapy for advanced pancreas carcinoma. Materials and Methods: Form 1995, twenty-four patients with unresectable adenocarcinomaof the pancreas were enrolled into the present study. There were 18 men and 6 women with the median age of 59 years. Eleven patients without liver metastasis received daily CDDP (5 mg/m =) by intravenous infusion concurrently with radiotherapy. For 13 patients with liver metastasis, combination of daily CDDP (3 mg/m =) / 5-fluorouracil (300
S 186 Wednesday/Thursday, 18-19 September 2002
mg/m 2) were delivered via hepatic artery. All patients were treated with 10 MV photons. Opposed anterior and posterior field, 3 field or 4 filed technique were used. The planning treatment volume included primary tumor and surrounding clinically enlarged lymph nodes. Fractional daily dose of 1.8 to 2 Gy at an isocenter, up to a total dose of 40-50.4 Gy (median 50 Gy) were delivered. In order to evaluate treatment efficacies, changes in tumor size, value of CA19-9, performance status, pain grade, required dosage of analgesics were monitored. Acute toxicities were evaluated according to the criteria of NCT-CTC. Results: Of the 18 patients who had abdominal pain before the treatment, 10 patients (56%) achieved pain relief. At the end of the treatment, obvious tumor response could not be observed in any of the patients. However, local tumor showed gradual shrinkage in about one third of all patients, and partial response was obtained in 3 patients. There were 2 patients who lived more than 2 years after the treatment. Of 11 patients without liver metastasis, the value of CA19-9 decreased in 8 patients (72%). Except for 3 patients with disease progression, all patients could complete the treatment. Four patients experienced grade 3 nausea, which was the most frequently observed complaint in this regimen. At the time of data analysis, the median follow-up was 5.2 months for all. No patients experienced grade 4 acute toxcities. Median survival time was 8.1 months and 3.6 months, for patients with and without liver metastasis, respectively. Conclusion: Results indicated that this regimen was well tolerable and efficient for symptomatic advanced pancreas carcinoma, 601
noma (EXHC) is controversial in adjuvant setting and even more as curative treatment for unresectable cases. We undertook this retrospective analysis to evaluate our initial results with two different CRT regimens given after an R1 resection or for unresectable EXHC. Material & methods: As of March 2001, 14 patients (pts) had been treated with ORT at CAL, after palliative biliary drainage or a R1 resection, PS < 2, < 80 yr, good renal, cardiac and biological parameters. Only I 0 patients were analysed, having at least 12 months of follow-up. Treatment protocol: regimen A = 40Gy/20fr/6wk D1- D12 (20Gy), "split", D29- 40 (20Gy) with 5FU 750 mg/m2/24h x 5 days, DI- 5 and D29- 33; regimen B = 50Gy/25fr/ 5 wk with same 5FU schedule, + Cisplatin 100 mg/m 2 D2 and D30. RT technique: 25 MV photons, 3 or 4 fields ("box"), CTV = GTV + 3 cm margins in all directions, 3D dosimetry. Results: all patients evaluable, 9 males, 1 female, age 53- 77 yr (mean 68). Five patients in each regimen arm, equally represented (1 unresectable and 4 R1 surgery). Minimal follow-up 12 mo, mean 25 mo, maximal 102+ mo. No major protocol deviation. Actuarial survival rate 73, 30 and 12 % at 1,3 and 5 yr respectively (median 23 mo). Median survival 10.7 mo arm A vs. 23 mo for arm B. Toxicity: no G4 EORTC acute toxiciy, 20 % G3 (Gt & hematologic) for arm B vs no G3 toxicity for arm A. Median TTP (local + distant): 8.7 mo arm A vs. not reached for arm B. .,t Conclusion: Based on this preliminary results, we Changed our treatment policy for unresectable or incompletely resected EXHC in favour of CRT type B regimen.
Poster
Radiochemotherapy in the management of locally advanced carcinoma of the cervical esophagus M. Signor 1, S. Fongione 1, A. lop2 1Radiotherapy, Radiation Oncology, Udine, Italy 2Medical Oncology, Latisana, Italy Purpose: To analyze the experience of our institution in the management of locally advanced carcinoma of the cervical esophagus with chemoradiation therapy (CTRT). Data relating to toxic effects, local control of disease and overall survival were collected and evaluated prospectively. Methods and Materials: Induction and concurrent chemotherapy regimen consisted of two courses of 120 hours infusion of 5-FU 600 mg./m ~, from days 1 to 5 and from days 22 to 26, and cisplatin 20 mg./m 2, in the same days, followed by high-dose external beam radiotherapy plus endoluminal brachytherapy up to 54-70 Gy and concurrent chemotherapy with cisplatin and 5-FU during the first and fifth week. Since april 1994, a series of 19 patients (pts.), with biopsy-proved carcinoma of the cervical esophagus received CTRT and were evaluated, Results: Global median follow up was 22.89 months. For alive pts median follow up was 30.8 months The pts. were 4 female and 15 male, mean age of 64,2 (range 49-77), mean Kamofsky Index of 80 (range 60-90), 18 in clinical stage III and one in IIA, mean lesional length was 5.64 cm. (range 3-9).The mean radiation dose administered was 59.84 Gy (range 54-70), specified at the minimal isodose of 95%, in conventional fractionation. We used high dose rate endoluminal brachytherapy, as a boost, in 5 pts. All the pts. completed the treatment; we had no toxic deaths while acute and late toxicity of this schedule was moderate. Two long survivers developed stricture requiring dilatation. We observed 10 (52.63%) complete endoscopic remissions, 8 (42.1%) partial remissions and 1 stable disease. Overall survival was 36.8% at 2 years and 31.57% at 3 years. The probabilities of Iocoragional tumour recurrences and distant metastases, as sites of first relapse, were 31.57% and 10.5% at 2 years, Conclusions: The radJochemotherapy treatment offers a definitive chance of long term survival for pts with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk, after treatment. Intensifications of the regimen seems possible, using X rays dose escalations protocols with 3D treatment planning, because no dose limiting late toxicities were observed, 602
Posters
Poster
Concurrent chemo-radiation therapy for extrahepatic cholangiocarcinoma G. Kacso 1, K. Benezery 1, G. Rossi 3, E. Frangois 2, J. Gugenheim 3, R. Bensadoun 1 1Centre Antoine Lacassagne, Radiotherapy, Nice 02, France 2Centre Antoine Lacassagne, Medical Oncology, Nice 02, France 3Hopital Archet II, Surgery, Nice 02, France The role of chemo-radiation therapy (CRT) for extrahepatic cholangiocarci-
HYPOXIA/TUMOR MICROENVIRONMENT 603
Poster
Evaluation of RH1 as an innovative bioreductive agent and a potential radiosensitizer J. Kim 1, C. West 1, H. Valentine 1, T. Ward"?, I. Stratford3, A. Patterson 3, J. Hendry 1 1paterson Institute for Cancer Research, Experimental Radiation Oncology, Manchester, United Kingdom 2paterson Institute for Cancer Research, Drug Development, Manchester, United Kingdom 3Manchester University, School of Pharmacy and Pharmaceutical Sciences, Manchester, United Kingdom RH1 is a newly-developed quinone-containing alkylating agent which is metabolized by a 2-electron reduction pathway using the enzyme NQO1 (NAD(P}H: quinone oxidoreductase, also called DT-diaphorase(DTD}). This enzyme is overexpressed in some tumours, hence providing selectivity of RH1 action. The cytotoxicity of RH1 and its effect in combination with irradiation were investigated. The human breast cancer MDA231 line which has an homologous point mutation in the NQO1 gene and no detectable DTD activity was used, along with MDA231 D7 cells which was derived from the parental ceil line by transfection with the human NQO1 gene. Cytotoxicity of RH1 was assessed by exposing the cells to a range of drug concentration for 3 hrs. For combined treatment, radiation was given at the end of 3hrs with IC90% dose. For hypoxic experiments, 95%N2/5%CO2 gas mixture was used and was maintained during irradiation. Different radiation schedules were also tested in aerobic conditions, delaying irradiation for 12, 24 and 48 hrs after drug treatment. RH1 showed a high clonogenic cytotoxicity to D7 cells in nM concentrations of drug under oxic conditions and the cytotoxicity was maintained the same under hypoxic conditions. RH1 also showed some-eytotox'i¢ effect on the parent cells under aerobic conditions, but the cytotoxicity was enhanced by 3-fold under hypoxia. When radiation was given at later time points, the SF2 value for the combined treatment was significantly lower at the 12 and 24 hour time points (p=0.O05 for both) compared to their radiation-alone values. When radiation was given at 48 hours, the SF2 value for the combination was higher than for radiation alone, suggesting a protective effect. Dose modifying factors (DMF) at 2 Gy were 1.0, 1.7, 1.5 and 0.5 for 0, 12, 24, and 48 hrs. The DMF values at the later time points were significantly different from the 0 hr point (p=o.oo04, 0.003 and 0.007 for 12, 24, 48 hrs vs. 0 hr). The same trend was observed for the parental cell line but the differences were not significant. In conclusion, RH1 shows a major cytotoxic effect in DTD-rich cancer cells. The increasing radiosensitivity for longer intervals between drug and irradiation with the DTD-rich cell line compared to the DTD-null cell line indicates a greater drug/radiation interaction for the DTD-rich cells, which might be due to different damage induction and repair pathways.