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606Photodynamic therapy (PDT) in combined non small cell lung cancer (NSCLC) treatment
S155 606
607
PHOTODYNAbllC IN C O M B I N E D N O N S M A L L C E L L (N SCLC) T R E A T M E N T
THERAPY iPDT) LUNG CANCER
S.Cicdnas*. A.Jackevi,~ius, E.Aleknavi~.ius. l..Bloznelyt& B.Alekuavi6ien,~ Lithuanian C a n c e r Center. Vilnius, Lithuania
M o r e than 20 years P D T has it's experimental and clinical background. Since 1989 in Lithuania photoserLsitisers were used for t r e a t m e n t of various malignancies. Material taut m e d z o d s : F r o m L994-1995 14 patients (pts) with N S C L C underwent P D T and external beam radiation ( E B R ) t r e a t m e n t in Lithuanian C a n c e r C e n t e r . Pts were with : T 2 N O M 0 - 6; T3NOM0 - 5; T a N 2 M 0 - 1. M o r e 2 pts were treated with local reccurrences after surgical operations. W e used h a e m a t o p o r p h y r i n 5 m g ] k g and 630 nm metal v a p o u r laser beam. A f t e r 2 - 3 laser aplication.s pt.s were treated with external b e a m radiation 60 Gy to primary t u m o u r and regional metastatic sites. Results: In group T2NOMO we have full t u m o u r response a f t e r P D T t r e a t m e n t in 6 pts, T a N t M 0 - in 2 pLs and in 2 pts with recurrences. In g r o u p T a N I M 0 partial t u m o u r response we achvieved in 3 pts and in group T 3 N 2 M 0 - in 1 pts. All these pts were treated with EBR. Conch~sions :
1. P D T as radical t r e a t m e n t is effective in T2NI)M(I and "1"3_N0- i M 0 cases. 2. E B R to metast:~tic sites prolong disease fi'ee period. 3 P1)T should be used in t u m o u r reinpse cases, when other t r e a t m e n t methods are ineffective.
G.S. Brunl, 1". Pasta, "C. Gulda, Ip. Ruffolo, elF.Scognnmlgllo, olD.dl Glacomo, "G. Scoppa,
B MedicalOncologyRadiotherapyOepartmentA,SurgeryDeparlmento. I.N.T. "Foundation Pascole" Naples (Italy).
In order to test a new active chemoradiotherapy regimen for advanced NSCLC we have conducted a phase II tdal of three agents with recognized activity in NSCLC. From January 95 to December 95 were treated 15 patients (13 male and 2 female), affected by unmsectabla NSCLC (stage IliA, IIIB) with a combination of IFX, CDDP, VNR and hyparfractionated radiation therapy. IFX was delivered on day 1g at 3 gr/sm dose, with Mesna protection; CDDP on day 29 at 80 mgr/sm dose; VNR on days 1Qand 8~ at 25 mgr/sm dose. The treatment plan consisted of two cicles followed by hyperfractionated radiation therapy with CBDCA radiosensitizing at 15 mgdsm daily dose. Radiation therapy was given with two tractions of 180 cgy a day for 17 days. So total dose at referance point (icru 50) was 6120 cgy. Patients (pts) characteristics were median age 61 (range 35-70) 10 pts stage IlIB, 5 stage IliA, 9 squamous cell carcinomas in stage IIIB, 3 in stage IliA, 2 adenocarcinomas in stage IliA. Performance Status grade 1 in all patients. 13 of the 1510ts were evaluable for response: 1 patient refused treatment, 1 lost the follow up. All patients were evaluable for toxicity. Complete response were observed in 2 patients, and partial response in 5, in 4 patients there was disease progression and in 2 no change. Median survival not reached. Analysis of toxicity showed that treatment protocol was not very well tolerated. Overall 27 cycles chemotherapy have been administered up to now from G-CSF. Grade 4 neutropania in 4 patients, grade 3 in 5 and in 8 pts grade 2. None pts have thrombocytopania and anemia. Nausea and vomiting in all patients. No renal and hepatic toxicity was registered. Mucositis and aesophagitis grade 4 in 4 pts, grade 3 in 1 pt, grade 2 in 9 pts. In conclusion the combined treatment arms show an increase of mainly acute toxicity, partly due to enhancement, partly due to general effects. So we think we have to modify the schedule of treatment to obtain less toxicity as possible and a bettor quality of life in treated patients.
609
608 RE-IRRADIATION OF ('ONCOMITANT DAILY "SENSITIZER".
A PHASEII TRIALOF IFOSFAMIOE(IFX).CISPLANTIN(CDDP),VINORELBINE(VNR). +HYPERFRACTIONATEDRADIATIONTHERAPYWITHCARBOPLANTINRADIOSENSITIZlNG FOR STAGEIliA. BIB.NON SMALLCELLLUNGCANCER(NSCLC):A PILOTSTUDY.
IN-FIELD
LOW-DOSE
RECURRENCES WITH C I S P L A T I N (CDDP) AS
Irradiation
o f m u r i n e lip m u c o s a in c o m b i n a t i o n with Gemcitabine
"
P. L a m b i n and W. Landuyt F Lonardl, G Pavanato, M Coeh, G Bouctarelh', V D Ferrart', A Jtnllo' Uinta d= Radioterapm Oncolog~ca. Umt~i di Oncologia Medtca', ULSS21, Legnago (VR), Italy Background. Although some biolog2eal mechanisms remain unclear, CDDP and other platm compounds are widely used m radlatton therapy (RT) as "sensltlzers" Recent reports have gwen stronger support to the retJonale ot the combination and have focused the tnlportance of the I/me factor platm compounds enhance cltotoxicity when given close m time to rediatmn This poteunatmn should be constderad when re-irradiation of m-field fadures is needed, J e when high doses of RT are no longer dehverable Purpose. To evaluate feasththty attd tolerance of re-trrethatton of m-field recurrences Material and methods. From 1990 to 1995, 29 patients (pts) with previously chemo-RT-treated advanced solid neoplasms ( 13 head 8: neck, 5 breast cancer, 4 lung. 3 large bowel, 4 others) were gwen re-RT of symptomatic in-field recurrences In all but two pts CDDP was administered dally at 5rag/m-' bolus without hydration ,~ to I hour before R T One pt had 24 hour infusion CDDP at the same daily dose wa a portable pump One pt with altered renal function was gweu carboplatm at 15mg/m:/day Residual RT dose was detemlmed after NSD-TDF careful evaluation and administered with standard schedule (180-200 cGy per daily frectton) Medina dose of RT was 2340 cGy (range 1440-3600). the CDDP total dose varied depending on the number of RT fractmns (median 65 rug, range 40100) Resulls. Response was evaluable in 25/29 pts according to W H O criteria, 9 pts had PR (36%), 13 had SD (52%) and 3 had PD (12%) Medina duration of response (PR+SD) was 4 months (1-22) All PR pts and 6 SD pts had good remission of symptoms (mamly pare and dysphagia) No renal impairment or local RT sequelae emerged Hematologic toxicity was hmited to grade Ill leucopenia during infusional CDDP Conclusion. Out findings are consistent wah similar published data and support the feasibility and low toxicity of re-RT plus concomitant cisplatin The sigmficant response rate and duration we have observed led us to consider this as a rt)ulttW therapeutic approach ut pts who present symptomatic H-field recurrence after prior RT • chemotherapy
Department of Experimental Radiotherapy. University Hospital Gasdiuisberg, Leuven. Belgium. Introduction: Gemcitabine is a novel nucleoside analogue that has shown clinical activity in a variety of solid tumours and which is usually very well tolerated. Gemcitahine was demonstrated to be a potent radiosensitizer in vitro even at non cytotoxic concentrations. Biochemical studies indicated that a reduction in the dATP pool was the most likely mechanism of radiosensitization by Gemcitabine. The association of gemcitabine to standard radical radiotherapy to the chest was evaluated in a phase VII study in patients with inoperable NSCLC. Only 8 patients were enrolled due to the unexpected severe toxici W profile, To our knowledge this combination has never been tested experimentally in vivo on normal tissues. Aim: To study the possible interaction in vivo of Gemcitabine and irradiation on mouse lip mucosa as a model for human mucosal response. Material and method: The possible modification by the drug of radiationinduced damage to the lip mucosa of female NMRI mice and the systemic toxicity was assessed. Gemcitabine was administered by a single i.p. injection at doses which do not cause any lethal toxicity (300 and 400 mg/kg). Results and Discussion: Addition of gemcitahin¢ 400 mg/kg concomitantly to 16 Gy radiation increased the moist desquamation from 15 % to 63 %. This effect was maximal when gemcitabine was administered simultaneous to the radiation. The effect was minimal or absent if gemcitabine was administered 2.6, 24 or 48 hours prior to radiation. This combination also increased dramatically the systemic toxicity (in terms of weight loss and lethality) which was maximum when Gemcitabinc was administered in close timing with irradiation. There was no increased systemic toxicity when gemcitabine was administered 24 hours prior to radiation. This finding can have important clinical .implications. It is suggested that this in~:reasod systemic toxicity is caused by the combined effects of irradiation and Gemcitabine on the alimentary tract, although we could not demonstrate the mechanism of it. Hittclman et a/. (MDA. Houston) has recently shown that the peak enhancement of radiation-induced growth delay was observed when gemcitahine was given 48 hours prior to radiation. They also shown that the active metabolite of Gemcitabthe (dFdCTP) stay longer in normal tissues than in the tumoral model they used. Therefore a window of therapeutic opportunity could exist where Gemcitahine can be given more than 6 hours before radiation.
607
PHOTODYNAbllC IN C O M B I N E D N O N S M A L L C E L L (N SCLC) T R E A T M E N T
THERAPY iPDT) LUNG CANCER
S.Cicdnas*. A.Jackevi,~ius, E.Aleknavi~.ius. l..Bloznelyt& B.Alekuavi6ien,~ Lithuanian C a n c e r Center. Vilnius, Lithuania
M o r e than 20 years P D T has it's experimental and clinical background. Since 1989 in Lithuania photoserLsitisers were used for t r e a t m e n t of various malignancies. Material taut m e d z o d s : F r o m L994-1995 14 patients (pts) with N S C L C underwent P D T and external beam radiation ( E B R ) t r e a t m e n t in Lithuanian C a n c e r C e n t e r . Pts were with : T 2 N O M 0 - 6; T3NOM0 - 5; T a N 2 M 0 - 1. M o r e 2 pts were treated with local reccurrences after surgical operations. W e used h a e m a t o p o r p h y r i n 5 m g ] k g and 630 nm metal v a p o u r laser beam. A f t e r 2 - 3 laser aplication.s pt.s were treated with external b e a m radiation 60 Gy to primary t u m o u r and regional metastatic sites. Results: In group T2NOMO we have full t u m o u r response a f t e r P D T t r e a t m e n t in 6 pts, T a N t M 0 - in 2 pLs and in 2 pts with recurrences. In g r o u p T a N I M 0 partial t u m o u r response we achvieved in 3 pts and in group T 3 N 2 M 0 - in 1 pts. All these pts were treated with EBR. Conch~sions :
1. P D T as radical t r e a t m e n t is effective in T2NI)M(I and "1"3_N0- i M 0 cases. 2. E B R to metast:~tic sites prolong disease fi'ee period. 3 P1)T should be used in t u m o u r reinpse cases, when other t r e a t m e n t methods are ineffective.
G.S. Brunl, 1". Pasta, "C. Gulda, Ip. Ruffolo, elF.Scognnmlgllo, olD.dl Glacomo, "G. Scoppa,
B MedicalOncologyRadiotherapyOepartmentA,SurgeryDeparlmento. I.N.T. "Foundation Pascole" Naples (Italy).
In order to test a new active chemoradiotherapy regimen for advanced NSCLC we have conducted a phase II tdal of three agents with recognized activity in NSCLC. From January 95 to December 95 were treated 15 patients (13 male and 2 female), affected by unmsectabla NSCLC (stage IliA, IIIB) with a combination of IFX, CDDP, VNR and hyparfractionated radiation therapy. IFX was delivered on day 1g at 3 gr/sm dose, with Mesna protection; CDDP on day 29 at 80 mgr/sm dose; VNR on days 1Qand 8~ at 25 mgr/sm dose. The treatment plan consisted of two cicles followed by hyperfractionated radiation therapy with CBDCA radiosensitizing at 15 mgdsm daily dose. Radiation therapy was given with two tractions of 180 cgy a day for 17 days. So total dose at referance point (icru 50) was 6120 cgy. Patients (pts) characteristics were median age 61 (range 35-70) 10 pts stage IlIB, 5 stage IliA, 9 squamous cell carcinomas in stage IIIB, 3 in stage IliA, 2 adenocarcinomas in stage IliA. Performance Status grade 1 in all patients. 13 of the 1510ts were evaluable for response: 1 patient refused treatment, 1 lost the follow up. All patients were evaluable for toxicity. Complete response were observed in 2 patients, and partial response in 5, in 4 patients there was disease progression and in 2 no change. Median survival not reached. Analysis of toxicity showed that treatment protocol was not very well tolerated. Overall 27 cycles chemotherapy have been administered up to now from G-CSF. Grade 4 neutropania in 4 patients, grade 3 in 5 and in 8 pts grade 2. None pts have thrombocytopania and anemia. Nausea and vomiting in all patients. No renal and hepatic toxicity was registered. Mucositis and aesophagitis grade 4 in 4 pts, grade 3 in 1 pt, grade 2 in 9 pts. In conclusion the combined treatment arms show an increase of mainly acute toxicity, partly due to enhancement, partly due to general effects. So we think we have to modify the schedule of treatment to obtain less toxicity as possible and a bettor quality of life in treated patients.
609
608 RE-IRRADIATION OF ('ONCOMITANT DAILY "SENSITIZER".
A PHASEII TRIALOF IFOSFAMIOE(IFX).CISPLANTIN(CDDP),VINORELBINE(VNR). +HYPERFRACTIONATEDRADIATIONTHERAPYWITHCARBOPLANTINRADIOSENSITIZlNG FOR STAGEIliA. BIB.NON SMALLCELLLUNGCANCER(NSCLC):A PILOTSTUDY.
IN-FIELD
LOW-DOSE
RECURRENCES WITH C I S P L A T I N (CDDP) AS
Irradiation
o f m u r i n e lip m u c o s a in c o m b i n a t i o n with Gemcitabine
"
P. L a m b i n and W. Landuyt F Lonardl, G Pavanato, M Coeh, G Bouctarelh', V D Ferrart', A Jtnllo' Uinta d= Radioterapm Oncolog~ca. Umt~i di Oncologia Medtca', ULSS21, Legnago (VR), Italy Background. Although some biolog2eal mechanisms remain unclear, CDDP and other platm compounds are widely used m radlatton therapy (RT) as "sensltlzers" Recent reports have gwen stronger support to the retJonale ot the combination and have focused the tnlportance of the I/me factor platm compounds enhance cltotoxicity when given close m time to rediatmn This poteunatmn should be constderad when re-irradiation of m-field fadures is needed, J e when high doses of RT are no longer dehverable Purpose. To evaluate feasththty attd tolerance of re-trrethatton of m-field recurrences Material and methods. From 1990 to 1995, 29 patients (pts) with previously chemo-RT-treated advanced solid neoplasms ( 13 head 8: neck, 5 breast cancer, 4 lung. 3 large bowel, 4 others) were gwen re-RT of symptomatic in-field recurrences In all but two pts CDDP was administered dally at 5rag/m-' bolus without hydration ,~ to I hour before R T One pt had 24 hour infusion CDDP at the same daily dose wa a portable pump One pt with altered renal function was gweu carboplatm at 15mg/m:/day Residual RT dose was detemlmed after NSD-TDF careful evaluation and administered with standard schedule (180-200 cGy per daily frectton) Medina dose of RT was 2340 cGy (range 1440-3600). the CDDP total dose varied depending on the number of RT fractmns (median 65 rug, range 40100) Resulls. Response was evaluable in 25/29 pts according to W H O criteria, 9 pts had PR (36%), 13 had SD (52%) and 3 had PD (12%) Medina duration of response (PR+SD) was 4 months (1-22) All PR pts and 6 SD pts had good remission of symptoms (mamly pare and dysphagia) No renal impairment or local RT sequelae emerged Hematologic toxicity was hmited to grade Ill leucopenia during infusional CDDP Conclusion. Out findings are consistent wah similar published data and support the feasibility and low toxicity of re-RT plus concomitant cisplatin The sigmficant response rate and duration we have observed led us to consider this as a rt)ulttW therapeutic approach ut pts who present symptomatic H-field recurrence after prior RT • chemotherapy
Department of Experimental Radiotherapy. University Hospital Gasdiuisberg, Leuven. Belgium. Introduction: Gemcitabine is a novel nucleoside analogue that has shown clinical activity in a variety of solid tumours and which is usually very well tolerated. Gemcitahine was demonstrated to be a potent radiosensitizer in vitro even at non cytotoxic concentrations. Biochemical studies indicated that a reduction in the dATP pool was the most likely mechanism of radiosensitization by Gemcitabine. The association of gemcitabine to standard radical radiotherapy to the chest was evaluated in a phase VII study in patients with inoperable NSCLC. Only 8 patients were enrolled due to the unexpected severe toxici W profile, To our knowledge this combination has never been tested experimentally in vivo on normal tissues. Aim: To study the possible interaction in vivo of Gemcitabine and irradiation on mouse lip mucosa as a model for human mucosal response. Material and method: The possible modification by the drug of radiationinduced damage to the lip mucosa of female NMRI mice and the systemic toxicity was assessed. Gemcitabine was administered by a single i.p. injection at doses which do not cause any lethal toxicity (300 and 400 mg/kg). Results and Discussion: Addition of gemcitahin¢ 400 mg/kg concomitantly to 16 Gy radiation increased the moist desquamation from 15 % to 63 %. This effect was maximal when gemcitabine was administered simultaneous to the radiation. The effect was minimal or absent if gemcitabine was administered 2.6, 24 or 48 hours prior to radiation. This combination also increased dramatically the systemic toxicity (in terms of weight loss and lethality) which was maximum when Gemcitabinc was administered in close timing with irradiation. There was no increased systemic toxicity when gemcitabine was administered 24 hours prior to radiation. This finding can have important clinical .implications. It is suggested that this in~:reasod systemic toxicity is caused by the combined effects of irradiation and Gemcitabine on the alimentary tract, although we could not demonstrate the mechanism of it. Hittclman et a/. (MDA. Houston) has recently shown that the peak enhancement of radiation-induced growth delay was observed when gemcitahine was given 48 hours prior to radiation. They also shown that the active metabolite of Gemcitabthe (dFdCTP) stay longer in normal tissues than in the tumoral model they used. Therefore a window of therapeutic opportunity could exist where Gemcitahine can be given more than 6 hours before radiation.