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OC-0474 CARDIO-PULMONARY CONSEQUENCES OF THORACIC IRRADIATION IN RATS
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toxicity, presence of G2-G3 acute fecal incontinence, pelvic nodes and seminal vesicles irradiation, mean rectal dose, dose-volume histograms constraints (from V20Gy to V75Gy) and lrb/linc was investigated by uni- and multivariate (MVA) logistic analyses. 347/515 pts had at least 3 toxicity questionnaires in the first 36 mos after the end of RT. Correlation between the mean score of fecal incontinence in the first 36 mos and linc at 6 yrs was also investigated. Results: 32/515 G1, 2/515 G2 and 3/515 G3 lrb were registered. 50/515 G1, 3/515 G2 and 3/515 G3 linc were reported. Lrb (grade≥1) was only correlated to V75Gy (continuous variable): p=0.02, OR=1.07. The prevalence of grade≥1 lrb at 6 yrs was significantly correlated with incidence of G2-G3 lrb in the first 3 yrs after RT treatment: 42.3% in pts with G2-G3 bleeding in the first 3 yrs vs 5.6% in G0-G1 pts (p<0.0001, chi-squared). Linc (grade≥1) was correlated to multiple variables. In MVA, V40Gy (continuous variable, p=0.09, OR=1.015), presence of abdominal surgery before RT (p=0.004, OR=4.7), presence of haemorrhoids (p=0.008, OR=2.6) and presence of G2-G3 acute incontinence (p=0.007, OR=4.4) resulted to be correlated to linc. Linc at 6 yrs was also correlated to the mean incontinence scores in the first 36 mos (p<0.0001): pts without linc at 6 yrs had a mean score of 0.1 during the first 36 mos, while pts with G1 and with G2-G3 linc at 6 yrs had a mean score of 0.5 and 0.78 during the first 36 mos, respectively. The prevalence of linc≥1 at 6 yrs was significantly correlated with the mean incontinence scores in the first 3 yrs after RT treatment: 37.3% in pts with mean score ≥0.5 vs 10% in pts with mean score < 0.5 (p<0.0001, chi-squared). Conclusions: A fraction of pts is still experiencing rectal toxicity symptoms 6 yrs after RT: 7.2% lrb and 10.9% linc. Prevalence of toxicity at 6 yrs is significantly correlated to incidence in the first 3 yrs after RT treatment, this is an indication of a chronicization of symptoms, with late fecal incontinence playing the major role. Mean score for incontinence during the first 36 mos after RT can be used as a surrogate endpoint for late (>6yrs) fecal incontinence. OC-0474 CARDIO-PULMONARY CONSEQUENCES OF THORACIC IRRADIATION IN RATS R.P. Coppes1, G. Ghodabi2, S. van der Veen1, H. Faber2, B. Bartelds3, R.A. de Boer4, M.G. Dickingson4, S. Brandenburg5, J.A. Langendijk2, P. van Luijk2 1 University Medical Center Groningen, Department of Cell Biology, Groningen, The Netherlands 2 University Medical Center Groningen, Department of Radiation Oncology, Groningen, The Netherlands 3 University Medical Center Groningen, Center for Congenital Heart Disease, Groningen, The Netherlands 4 University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands 5 University of Groningen, Kernfysisch Versneller Instituut, Groningen, The Netherlands Purpose/Objective: The risk of early radiation pneumonitis limits the radiation dose and efficacy of radiotherapy of thoracic tumors. Besides lung dose, co-irradiation of the heart was shown as a risk factor of radiation pneumonitis in rats (1) and patients (2). Here we investigated whether the enhanced damage caused by combined heart and lung irradiation can be understood from their individual effects on cardio-pulmonary physiology. Materials and Methods: Rats’ heart and/or lung were irradiated to 20 Gy using high-precision proton beams. Subsequently 8 weeks postirradiation cardio-pulmonary performance was assessed by left/rightsided cardiac catheterization. Heart and lung tissue were evaluated using histopathology. Results: Irradiation of the heart (+ inevitable 25% of the lung) induced an increased left ventricle (LV) end-diastolic pressure and relaxation time from 3.8 ± 0.6 to 11.3 ± 1.8 mmHg and 8.7 ± 0.2 to 11.6 ± 0.4 msec, respectively indicating early LV diastolic dysfunction. Moreover, LV perivascular fibrosis (19% of vascular surface area) and pulmonary perivascular and interstitial edema in non-irradiated lungs were observed. Interestingly, lung irradiation alone also increased the relaxation time of LV to 12± 1 mmHg, n=5 and decreased LV stroke volume (40%) besides the known (3) irradiated-volume dependent increase in pulmonary artery pressure. Moreover, combined irradiation of lung and heart even further reduced LV volume
ESTRO 31
parameters and cardiac output. In addition to LV diastolic dysfunction and increased pulmonary artery pressure from 18 ± 1 to 30 ± 3 mmHg, combined lung/heart irradiation also induced pronounced right ventricle diastolic dysfunction indicated by increased right ventricle end diastolic pressure (from 0 ± 2 to 22 ± 1 mmHg). Conclusions: Heart and lung irradiation independently impair cardiac diastolic performance parameters albeit through different mechanisms. In our rat model heart irradiation may induce early subclinical patho-physiological changes that, if combined with lung irradiation may manifest as an enhanced risk and severity of radiation pneumonitis contrasting the classical view of the heart as a late responding organ. 1. Cancer Res. 65:6509-11, 2005; 2. Acta Oncol. 50:51-60, 2011; 3. Thorax 26 dec 2011 epub aop. OC-0475 THE USE OF IMRT REDUCES LATE NEPHROTOXICITY AFTER CHEMORADIOTHERAPY FOR GASTRIC CANCER A.K. Trip1, J. Nijkamp1, A. Cats2, H. Boot2, M. Verheij1, E.P.M. Jansen1 1 NKI-AVL, Radiotherapy, Amsterdam, The Netherlands 2 NKI-AVL, Gastroenterology, Amsterdam, The Netherlands Purpose/Objective: Postoperative chemoradiotherapy (CRT) is an evidence based treatment option in the management of operable gastric cancer. The most important late toxicity of this regimen is progressive functional renal impairment, which is associated with an increased incidence of hypertension. Nephrotoxicity is radiation dosevolume dependent and becomes clinically apparent approximately 6 months after treatment. We retrospectively evaluated the effect of different treatment planning techniques on late nephrotoxicity after post-operative CRT for gastric cancer. Materials and Methods: Since 2000, gastric cancer patients are treated with postoperative CRT in our institute. A total of 87 patients had completed CRT consisting of 45 Gy in 25 fractions of 1.8 Gy, combined with concurrent chemotherapy: 5FU/leucovorin (n=4), capecitabine (n=37), and capecitabine combined with cisplatin (n=46). All had undergone Tc99m-thiatide renography before the start of CRT and at regular intervals during follow-up. Treatment planning was by AP-PA (n=31), 3D-conformal (n=24) and IMRT (n=32). We combined the AP-PA and 3D-conformal group (non-IMRT) for comparison to the IMRT group. A dosimetric comparison of the non-IMRT and IMRT group was made of mean dose (Dmean) and relative volume receiving 20 Gy (V20) for both kidneys. We investigated the contribution of the left and right kidney to renal function from Tc99m-thiatide renography. These results were grouped in follow-up time intervals defined after the end of CRT. The two-tailed students T-test was used to compare treatment planning groups. Results: The mean V20 of the right kidney was 15.9% in the non-IMRT and 7.6% in the IMRT group and differed significantly (p<0.001) (see table). The mean V20 of the left kidney was 71.3% and 64.9% in the non-IMRT and IMRT group respectively, which was not significantly different. For the renographic analysis, comparison of the median time within each follow-up time interval did not show differences between the non-IMRT and IMRT group. In both groups, we observed a progressive decrease in left to right kidney function ratio relative to baseline (see figure). In the non-IMRT group this decrease was present earlier and to a larger extend compared to the IMRT group with values of 0.51 and 0.74 in the non-IMRT and IMRT group respectively (p=0.005) at 2 to 3 years of follow-up.
toxicity, presence of G2-G3 acute fecal incontinence, pelvic nodes and seminal vesicles irradiation, mean rectal dose, dose-volume histograms constraints (from V20Gy to V75Gy) and lrb/linc was investigated by uni- and multivariate (MVA) logistic analyses. 347/515 pts had at least 3 toxicity questionnaires in the first 36 mos after the end of RT. Correlation between the mean score of fecal incontinence in the first 36 mos and linc at 6 yrs was also investigated. Results: 32/515 G1, 2/515 G2 and 3/515 G3 lrb were registered. 50/515 G1, 3/515 G2 and 3/515 G3 linc were reported. Lrb (grade≥1) was only correlated to V75Gy (continuous variable): p=0.02, OR=1.07. The prevalence of grade≥1 lrb at 6 yrs was significantly correlated with incidence of G2-G3 lrb in the first 3 yrs after RT treatment: 42.3% in pts with G2-G3 bleeding in the first 3 yrs vs 5.6% in G0-G1 pts (p<0.0001, chi-squared). Linc (grade≥1) was correlated to multiple variables. In MVA, V40Gy (continuous variable, p=0.09, OR=1.015), presence of abdominal surgery before RT (p=0.004, OR=4.7), presence of haemorrhoids (p=0.008, OR=2.6) and presence of G2-G3 acute incontinence (p=0.007, OR=4.4) resulted to be correlated to linc. Linc at 6 yrs was also correlated to the mean incontinence scores in the first 36 mos (p<0.0001): pts without linc at 6 yrs had a mean score of 0.1 during the first 36 mos, while pts with G1 and with G2-G3 linc at 6 yrs had a mean score of 0.5 and 0.78 during the first 36 mos, respectively. The prevalence of linc≥1 at 6 yrs was significantly correlated with the mean incontinence scores in the first 3 yrs after RT treatment: 37.3% in pts with mean score ≥0.5 vs 10% in pts with mean score < 0.5 (p<0.0001, chi-squared). Conclusions: A fraction of pts is still experiencing rectal toxicity symptoms 6 yrs after RT: 7.2% lrb and 10.9% linc. Prevalence of toxicity at 6 yrs is significantly correlated to incidence in the first 3 yrs after RT treatment, this is an indication of a chronicization of symptoms, with late fecal incontinence playing the major role. Mean score for incontinence during the first 36 mos after RT can be used as a surrogate endpoint for late (>6yrs) fecal incontinence. OC-0474 CARDIO-PULMONARY CONSEQUENCES OF THORACIC IRRADIATION IN RATS R.P. Coppes1, G. Ghodabi2, S. van der Veen1, H. Faber2, B. Bartelds3, R.A. de Boer4, M.G. Dickingson4, S. Brandenburg5, J.A. Langendijk2, P. van Luijk2 1 University Medical Center Groningen, Department of Cell Biology, Groningen, The Netherlands 2 University Medical Center Groningen, Department of Radiation Oncology, Groningen, The Netherlands 3 University Medical Center Groningen, Center for Congenital Heart Disease, Groningen, The Netherlands 4 University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands 5 University of Groningen, Kernfysisch Versneller Instituut, Groningen, The Netherlands Purpose/Objective: The risk of early radiation pneumonitis limits the radiation dose and efficacy of radiotherapy of thoracic tumors. Besides lung dose, co-irradiation of the heart was shown as a risk factor of radiation pneumonitis in rats (1) and patients (2). Here we investigated whether the enhanced damage caused by combined heart and lung irradiation can be understood from their individual effects on cardio-pulmonary physiology. Materials and Methods: Rats’ heart and/or lung were irradiated to 20 Gy using high-precision proton beams. Subsequently 8 weeks postirradiation cardio-pulmonary performance was assessed by left/rightsided cardiac catheterization. Heart and lung tissue were evaluated using histopathology. Results: Irradiation of the heart (+ inevitable 25% of the lung) induced an increased left ventricle (LV) end-diastolic pressure and relaxation time from 3.8 ± 0.6 to 11.3 ± 1.8 mmHg and 8.7 ± 0.2 to 11.6 ± 0.4 msec, respectively indicating early LV diastolic dysfunction. Moreover, LV perivascular fibrosis (19% of vascular surface area) and pulmonary perivascular and interstitial edema in non-irradiated lungs were observed. Interestingly, lung irradiation alone also increased the relaxation time of LV to 12± 1 mmHg, n=5 and decreased LV stroke volume (40%) besides the known (3) irradiated-volume dependent increase in pulmonary artery pressure. Moreover, combined irradiation of lung and heart even further reduced LV volume
ESTRO 31
parameters and cardiac output. In addition to LV diastolic dysfunction and increased pulmonary artery pressure from 18 ± 1 to 30 ± 3 mmHg, combined lung/heart irradiation also induced pronounced right ventricle diastolic dysfunction indicated by increased right ventricle end diastolic pressure (from 0 ± 2 to 22 ± 1 mmHg). Conclusions: Heart and lung irradiation independently impair cardiac diastolic performance parameters albeit through different mechanisms. In our rat model heart irradiation may induce early subclinical patho-physiological changes that, if combined with lung irradiation may manifest as an enhanced risk and severity of radiation pneumonitis contrasting the classical view of the heart as a late responding organ. 1. Cancer Res. 65:6509-11, 2005; 2. Acta Oncol. 50:51-60, 2011; 3. Thorax 26 dec 2011 epub aop. OC-0475 THE USE OF IMRT REDUCES LATE NEPHROTOXICITY AFTER CHEMORADIOTHERAPY FOR GASTRIC CANCER A.K. Trip1, J. Nijkamp1, A. Cats2, H. Boot2, M. Verheij1, E.P.M. Jansen1 1 NKI-AVL, Radiotherapy, Amsterdam, The Netherlands 2 NKI-AVL, Gastroenterology, Amsterdam, The Netherlands Purpose/Objective: Postoperative chemoradiotherapy (CRT) is an evidence based treatment option in the management of operable gastric cancer. The most important late toxicity of this regimen is progressive functional renal impairment, which is associated with an increased incidence of hypertension. Nephrotoxicity is radiation dosevolume dependent and becomes clinically apparent approximately 6 months after treatment. We retrospectively evaluated the effect of different treatment planning techniques on late nephrotoxicity after post-operative CRT for gastric cancer. Materials and Methods: Since 2000, gastric cancer patients are treated with postoperative CRT in our institute. A total of 87 patients had completed CRT consisting of 45 Gy in 25 fractions of 1.8 Gy, combined with concurrent chemotherapy: 5FU/leucovorin (n=4), capecitabine (n=37), and capecitabine combined with cisplatin (n=46). All had undergone Tc99m-thiatide renography before the start of CRT and at regular intervals during follow-up. Treatment planning was by AP-PA (n=31), 3D-conformal (n=24) and IMRT (n=32). We combined the AP-PA and 3D-conformal group (non-IMRT) for comparison to the IMRT group. A dosimetric comparison of the non-IMRT and IMRT group was made of mean dose (Dmean) and relative volume receiving 20 Gy (V20) for both kidneys. We investigated the contribution of the left and right kidney to renal function from Tc99m-thiatide renography. These results were grouped in follow-up time intervals defined after the end of CRT. The two-tailed students T-test was used to compare treatment planning groups. Results: The mean V20 of the right kidney was 15.9% in the non-IMRT and 7.6% in the IMRT group and differed significantly (p<0.001) (see table). The mean V20 of the left kidney was 71.3% and 64.9% in the non-IMRT and IMRT group respectively, which was not significantly different. For the renographic analysis, comparison of the median time within each follow-up time interval did not show differences between the non-IMRT and IMRT group. In both groups, we observed a progressive decrease in left to right kidney function ratio relative to baseline (see figure). In the non-IMRT group this decrease was present earlier and to a larger extend compared to the IMRT group with values of 0.51 and 0.74 in the non-IMRT and IMRT group respectively (p=0.005) at 2 to 3 years of follow-up.