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Non-invasive tumour perfusion measurement by dynamic CT: preliminary results
ELSEVIER
Radiotherapy and Oncology 44 (1997) 159- 162
Short communication
Non-invasive tumour perfusion measurement by dynamic CT: preliminary results Robert Hermansa,*, Philippe Lambinb, Walter Van den Bogaertb, Karin Haustermansb, Ann Van der Gotena, Albert L. Baerta aDepanment of Radiology, University Hospitals, Herestraat 49, B-3000 Leuven, Belgium bDepartment of Radiation Oncology, University Hospitals, Herestraat 49, B-3000 Leuven, Belgium
Received 8 October 1996;revised version received 3 December 1996; accepted31 December 1996
Abstract In 18 patients the perfusion of a malignant head and neck tumour was estimated using contrast enhanced dynamic computed tomography. The mean estimated perfusion was 75.5 ml/100 g/min, varying between 27.9 and 131.9. Eleven patients were treated with radiation therapy; the obtained perfusion rates were significantly different between tumours with a favourable and those with an unfavourable early outcome. 0 1997 Elsevier Science Ireland Ltd. Keywords:
Tumour; Head and neck; Dynamic computed tomography (CT); Contrast enhanced; Perfusion
1. Introduction In some human tumours treatment may fail due to the presence of hypoxia [5]. Such hypoxic tumours need to be identified and selected for the special measures which exist for dealing with hypoxic cells, but can not be used in all patients. The oxygen-sensitive micro-electrode needle method provides ‘gold standard’ data concerning intratumoural PO* distribution, but is too invasive and inconvenient for general clinical use. There is a need for a reliable non-invasive method to assess tumour oxygenation. Dynamic computed tomography could be useful in this regard. Phantom investigations have shown that the analysis of the time-density curve during the first pass of the contrast medium yields reliable perfusion measurement results [3]. Perfusion measurement of solid tumours could be interesting as perfusion is known to correlate with tissue oxygenation [7]. The underlying hypothesis in the quantification of perfusion using dynamic computed tomography is that during the initial pass of the tracer through an organ there exists a time,
* Correspondingauthor
before the tracer reaches the venous drainage, when all the tracer is within the region of interest and can be considered to be totally extracted. A major condition to be satisfied is that the time needed for making the perfusion measurement is short enough such that no tracer has left the volume during the period of data acquisition; if so, then only the arterial input has to be taken into account to calculate tissue perfusion [4]. A short and sharp arterial bolus of contrast as ‘input function’ is needed, so that the measurements can be done before venous outflow occurs. The original algorithm as described by Mullani and Gould [4] for use in PET scanning was mathematically simplified by Blomley et al. [1,2] and applied to dynamic computed tomography, using a iodinebased contrast medium. Perfusion = Peak gradient of tissue time - density curve Peak arterial density This relationship is homologous to one used in nuclear medicine [6], which has been validated using microspheres. The model contains no requirements in its derivation for diffusion or extraction of the tracer. Perfusion rates of liver, spleen and kidney parenchyma have been calculated with dynamic CT, giving similar results as those obtained with inert gas washout.
0167-8140/97/$17.00 0 1997Elsevier Science Ireland Ltd. All rights reserved PII SO167-8140(97)01913-0
R. Hermans et al. /Radiotherapy
160
and Oncology 44 (1997) 159-162
Table 1 Patients included in this study Age/sex
Tumor location
Stage
Tumor volume (ml)
Perfusion (ml/100 g/mitt)
Therapy
Outcome (months)
61/F 80/M 53/M 4% 61 /M 56/M 56/M 4llM 43/M 81 iP 75/M 49/M 40/M 62lM 60/M 48/M 58/M 58iM
Hypwhvnx Oropharynx Oropharynx Oropharynx Supraglottis Supraglottis Wpophwnx Oropharynx Oropharynx Nasopharynx Wpopharynx Hypopharynx Wpopharynx Tongue Oropharynx Supraglottis Glottis Oropharynx
T3 Nl T3 NO T3 Nl T3 NO T2Nl T2 N2 T4 N3 T4 N3 T4 N2 T3 N3 T4 Nl T4 Nl T3 NO T3 NO T2 NO T4 NO T4 N2 T3 Nl
24.9 26.9 28.4 1.1 0.8 8.1 165.7 29.8 118.5 127 72.1 22.1 46.2 7.1 3.3 23.1 21.7 13.1
131.9 112 95.4 91.7 17.3 65.1 49 82.9 74.6 44.7 35.9 69.8 65 113.7 60.9 69.4 94.7 27.9
RT* RT RT RT RT RT RT RT RT RT RT Surgery + RT Surgery + RT Sww Surgery Surgery Surgery Surgery
NED (10) NED (6) NED (13) NED (14) NED (14) NED (12) ALD (5) DLD (7) DLD (4) DLD (3) DLD (3) NED( 13) NED (13) NED (12) NED (12) AMD (12) DMD (3) DWD (2)
RT, radiotherapy; RT*, RT in other institution; NED, no evidence of disease; ALD, alive with local disease; AMD, alive with metastatic disease; DLD, dead with local disease; DMD, dead with metastatic disease. Duration in parentheses is that of follow-up after completion of therapy.
2. Material
and methods
Eighteen patients were included, 15 men and three women, all having a squamous cell carcinoma in the head and neck region (Table 1). None of them was previously irradiated. The CT-examinations were performed using a Somatom Plus S scanner (Siemens, Erlangen, Germany). The table position showing the largest axial tumour diameter was chosen to obtain the enhanced dynamic scan series. A 40-ml intravenous bolus of a low-osmolar nonionic contrast agent (Optiray8 300, Guerbet, Paris, France or OmnipaqueB 300, Nycomed, Oslo, Norway) was rapidly injected over 5 s (8 ml/s), while a dynamic acquisition (l-s scan time) of image data was obtained during 40 sec. In the first six patients a interscan delay of 2 s was used; in the remaining patients, the scans were obtained continuously without interscan delay. All patients tolerated without problems this rapid injection of contrast medium. After this dynamic acquisition, the examination was continued using the routine protocol for neck CT, injecting an additional loo-120 ml of contrast medium at a slow rate. None of the primary tumours appeared necrotic on these CT examinations. A time-density curve was constructed for the primary tumour and the carotid artery nearest to the tumour (Fig. 1). The region of interest (ROI) for the tumour was chosen as large as possible. The perfusion in the selected tumour ROI was calculated by dividing the slope of the tumour time-density curve by the maximal value in arterial density. To calculate the intratumoural coefficient of variation, the perfusion was calculated for three smaller ROIs placed within the area of the primary tumour.
Tumour volume (including adenopathies if present) was calculated out of the CT images using the summation-ofareas technique, and correlated with the perfusion measurements. Tumour perfusion and volume were also correlated with early outcome after radiotherapy.
3. Results The mean calculated perfusion was 75.7 ml/100 g/min (median 72.2: SD 27.7 ml/l00 g/min; range 27.9-131.9). The intertumoural coefficient of variation was 0.37, while the intratumoural coefficient of variation ranged from 0.070.33 (mean 0.22). Mean total tumour volume was 41.8 ml (range 0.77-165.7). No significant correlation was found by linear regression between the perfusion measurements and total tumour volume although larger tumours tended to show lower perfusion rates (Spearman’s p = -0.25, P = 0.29). Four out of six tumours with a calculated perfusion rate of <80 ml/100 g/min were not controlled by radiotherapy, while four out of five tumours with a rate >80 ml/ 100 g/min did show a favourable early response. The mean perfusion rate for the controlled, respectively uncontrolled tumours with radiation therapy was 95.6 and 57.4 ml/l00 g/ min (P = 0.03, Mann-Whitney U); the mean total tumour volume was respectively 16.1 and 102.6 ml (P = 0.006, Mann-Whitney U).
4. Discussion Our perfusion measurements seem to have a normal dis-
R. Hermans et al. /Radiotherapy
Fig. 1. Time-density curves obtained during the first pass of the contrast agent through two different tumours and homolateral carotid artery. The ROIs (tumour: arrowhead; carotid artery: arrow) are indicated on the reference image (‘Ref ima’); the values displayed in the time-density curves are obtained after substracting the density measured in an unenhanced image (‘Pre ima’). The slope of tumour time-density curve (double arrowhead) and the maximal arterial density (arrow) are indicated. (A) Patient 4. Oropharyngeal carcinoma. Calculated tumour perfusion was 91.7 ml/l00 g/min. (B) Patient 11. Hypopharyngeal carcinoma. Slope of tumour time-density curve is less steep as seen in A; the maximal arterial density is also lower. Calculated tumour perfusion was 35.9 ml/100 g/mitt.
tribution, but a rather low intertumoural variability was found: this may be a limiting factor in the use of the technique, although the preliminary results obtained in the radiotherapeutically treated patients qualitatively agree with the assumption that less well perfused tumours show a poorer response. The perfusion was calculated as the ratio of the slope of the tumour time density curve and the peak rise in the arterial density. The obtained perfusion rates are rather high compared to those found with other methods [7]. A possible explanation could be an systematic underestimation of the arterial peak density. On the CT scanner used, the
and Oncology 44 (1997) 159-162
161
arterial density is averaged over a 1 s acquisition time and the measured maximum arterial density may therefore not really represent the ‘peak’. The occurrence of image artefacts due to surrounding dense bone or movements due to respiration, swallowing or pulsations of nearby arteries can give rise to tissue density analysis problems is some head and neck tumours. A limitation of this technique is that only one level through the tumour can be examined; the obtained results may not be representative for the entire tumour. The calculated intratumoural coefficient of variation might therefore underestimate the true intratumoural variability of perfusion. This might be an important disadvantage, as only the average perfusion rate in a large ROI is estimated, while a few hypoxic clonogenic cells in a small low-perfusion area may determine the long-term outcome in spite of a high overall perfusion rate. The presented technique is not well suited to examination of the known temporal heterogeneity of tumour perfusion, as several hours are needed before the baseline tissue density is restored through renal clearance of the contrast medium; temporal fluctuations in tumour perfusion can therefore not be estimated. The presented technique estimates arterial tumour perfusion; extensive arteriovenous shunting occurring in some tumours [7] deprives the tissue of some of its supplies in spite of a high apparent arterial perfusion. Tumour volume was significantly correlated with early outcome. We found indications of a possible negative correlation between the obtained perfusion rates and the tumour volume, especially in the radiotherapeutically treated tumours. As tumour volume can be more easily measured on CT-images, this parameter may prove more feasible as predictive factor for tumour hypoxia than perfusion. In conclusion, a low perfusion rate measured in a primary head and neck tumour with dynamic CT during the first pass of a contrast agent may predict the presence of hypoxia. Such enhancement analysis could be considered for study as a prognostic factor, especially as it can be performed during a routine staging CT-examination. Further studies are needed to evaluate the reproducibility of these perfusion measurements, and their use as predictive factor. We are currently also examining the value of dynamic gadolinium-enhanced MRI as a tool for estimating the perfusion of malignant head and neck tumours. References [ 1] Blomley, M.J.K., Coulden, R., Buflkin, C., Lipton, M.J. and Dawson, P. Contrast bolus dynamic computed tomography for the measurement of solid organ perfusion. Invest. Radiol. 28: S72-S77, 1993. [2] Blomley, M.J.K., Coulden, R., Dawson, P., Kormano, M., Buflkin, C. and Lipton, M.J. Liver perfusion studied with ultrafast CT. J. Comput. Assist. Tomogr. 19: 424-433, 1995. [3] Jaschke, W., Gould, R.G., Assimakopoulos, P.A. and Lipton, M.J. Flow measurements with a high-speed computed tomography scanner. Med. Phys. 14: 238-243, 1984. [4] Mullani, N.A. and Gould, K.L. First-pass measurements of regional blood Bow with external detectors. J. Nucl. Med. 24: 577-581, 1983.
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R. Hemans et al. /Radiotherapy
[5] Overgaard, J. Importance of tumor hypoxia in radiotherapy. A metaanalysis of controlled clinical trials [abstract]. Radiother. Oncol. 24: S64, 1992. [6] Peters, A.M., Gunasekera, R.D. and Henderson, B.L. Non-invasive measurements of blood flow and extraction fraction. Nucl. Med. Cornmun. 8: 823-837, 1987.
and Oncology 44 (1997) 159-162 [7] Vaupel, P., Kallinowski, F. and Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of humor tumors: a review. Cancer. Res. 49: 6449-6465, 1989.
Radiotherapy and Oncology 44 (1997) 159- 162
Short communication
Non-invasive tumour perfusion measurement by dynamic CT: preliminary results Robert Hermansa,*, Philippe Lambinb, Walter Van den Bogaertb, Karin Haustermansb, Ann Van der Gotena, Albert L. Baerta aDepanment of Radiology, University Hospitals, Herestraat 49, B-3000 Leuven, Belgium bDepartment of Radiation Oncology, University Hospitals, Herestraat 49, B-3000 Leuven, Belgium
Received 8 October 1996;revised version received 3 December 1996; accepted31 December 1996
Abstract In 18 patients the perfusion of a malignant head and neck tumour was estimated using contrast enhanced dynamic computed tomography. The mean estimated perfusion was 75.5 ml/100 g/min, varying between 27.9 and 131.9. Eleven patients were treated with radiation therapy; the obtained perfusion rates were significantly different between tumours with a favourable and those with an unfavourable early outcome. 0 1997 Elsevier Science Ireland Ltd. Keywords:
Tumour; Head and neck; Dynamic computed tomography (CT); Contrast enhanced; Perfusion
1. Introduction In some human tumours treatment may fail due to the presence of hypoxia [5]. Such hypoxic tumours need to be identified and selected for the special measures which exist for dealing with hypoxic cells, but can not be used in all patients. The oxygen-sensitive micro-electrode needle method provides ‘gold standard’ data concerning intratumoural PO* distribution, but is too invasive and inconvenient for general clinical use. There is a need for a reliable non-invasive method to assess tumour oxygenation. Dynamic computed tomography could be useful in this regard. Phantom investigations have shown that the analysis of the time-density curve during the first pass of the contrast medium yields reliable perfusion measurement results [3]. Perfusion measurement of solid tumours could be interesting as perfusion is known to correlate with tissue oxygenation [7]. The underlying hypothesis in the quantification of perfusion using dynamic computed tomography is that during the initial pass of the tracer through an organ there exists a time,
* Correspondingauthor
before the tracer reaches the venous drainage, when all the tracer is within the region of interest and can be considered to be totally extracted. A major condition to be satisfied is that the time needed for making the perfusion measurement is short enough such that no tracer has left the volume during the period of data acquisition; if so, then only the arterial input has to be taken into account to calculate tissue perfusion [4]. A short and sharp arterial bolus of contrast as ‘input function’ is needed, so that the measurements can be done before venous outflow occurs. The original algorithm as described by Mullani and Gould [4] for use in PET scanning was mathematically simplified by Blomley et al. [1,2] and applied to dynamic computed tomography, using a iodinebased contrast medium. Perfusion = Peak gradient of tissue time - density curve Peak arterial density This relationship is homologous to one used in nuclear medicine [6], which has been validated using microspheres. The model contains no requirements in its derivation for diffusion or extraction of the tracer. Perfusion rates of liver, spleen and kidney parenchyma have been calculated with dynamic CT, giving similar results as those obtained with inert gas washout.
0167-8140/97/$17.00 0 1997Elsevier Science Ireland Ltd. All rights reserved PII SO167-8140(97)01913-0
R. Hermans et al. /Radiotherapy
160
and Oncology 44 (1997) 159-162
Table 1 Patients included in this study Age/sex
Tumor location
Stage
Tumor volume (ml)
Perfusion (ml/100 g/mitt)
Therapy
Outcome (months)
61/F 80/M 53/M 4% 61 /M 56/M 56/M 4llM 43/M 81 iP 75/M 49/M 40/M 62lM 60/M 48/M 58/M 58iM
Hypwhvnx Oropharynx Oropharynx Oropharynx Supraglottis Supraglottis Wpophwnx Oropharynx Oropharynx Nasopharynx Wpopharynx Hypopharynx Wpopharynx Tongue Oropharynx Supraglottis Glottis Oropharynx
T3 Nl T3 NO T3 Nl T3 NO T2Nl T2 N2 T4 N3 T4 N3 T4 N2 T3 N3 T4 Nl T4 Nl T3 NO T3 NO T2 NO T4 NO T4 N2 T3 Nl
24.9 26.9 28.4 1.1 0.8 8.1 165.7 29.8 118.5 127 72.1 22.1 46.2 7.1 3.3 23.1 21.7 13.1
131.9 112 95.4 91.7 17.3 65.1 49 82.9 74.6 44.7 35.9 69.8 65 113.7 60.9 69.4 94.7 27.9
RT* RT RT RT RT RT RT RT RT RT RT Surgery + RT Surgery + RT Sww Surgery Surgery Surgery Surgery
NED (10) NED (6) NED (13) NED (14) NED (14) NED (12) ALD (5) DLD (7) DLD (4) DLD (3) DLD (3) NED( 13) NED (13) NED (12) NED (12) AMD (12) DMD (3) DWD (2)
RT, radiotherapy; RT*, RT in other institution; NED, no evidence of disease; ALD, alive with local disease; AMD, alive with metastatic disease; DLD, dead with local disease; DMD, dead with metastatic disease. Duration in parentheses is that of follow-up after completion of therapy.
2. Material
and methods
Eighteen patients were included, 15 men and three women, all having a squamous cell carcinoma in the head and neck region (Table 1). None of them was previously irradiated. The CT-examinations were performed using a Somatom Plus S scanner (Siemens, Erlangen, Germany). The table position showing the largest axial tumour diameter was chosen to obtain the enhanced dynamic scan series. A 40-ml intravenous bolus of a low-osmolar nonionic contrast agent (Optiray8 300, Guerbet, Paris, France or OmnipaqueB 300, Nycomed, Oslo, Norway) was rapidly injected over 5 s (8 ml/s), while a dynamic acquisition (l-s scan time) of image data was obtained during 40 sec. In the first six patients a interscan delay of 2 s was used; in the remaining patients, the scans were obtained continuously without interscan delay. All patients tolerated without problems this rapid injection of contrast medium. After this dynamic acquisition, the examination was continued using the routine protocol for neck CT, injecting an additional loo-120 ml of contrast medium at a slow rate. None of the primary tumours appeared necrotic on these CT examinations. A time-density curve was constructed for the primary tumour and the carotid artery nearest to the tumour (Fig. 1). The region of interest (ROI) for the tumour was chosen as large as possible. The perfusion in the selected tumour ROI was calculated by dividing the slope of the tumour time-density curve by the maximal value in arterial density. To calculate the intratumoural coefficient of variation, the perfusion was calculated for three smaller ROIs placed within the area of the primary tumour.
Tumour volume (including adenopathies if present) was calculated out of the CT images using the summation-ofareas technique, and correlated with the perfusion measurements. Tumour perfusion and volume were also correlated with early outcome after radiotherapy.
3. Results The mean calculated perfusion was 75.7 ml/100 g/min (median 72.2: SD 27.7 ml/l00 g/min; range 27.9-131.9). The intertumoural coefficient of variation was 0.37, while the intratumoural coefficient of variation ranged from 0.070.33 (mean 0.22). Mean total tumour volume was 41.8 ml (range 0.77-165.7). No significant correlation was found by linear regression between the perfusion measurements and total tumour volume although larger tumours tended to show lower perfusion rates (Spearman’s p = -0.25, P = 0.29). Four out of six tumours with a calculated perfusion rate of <80 ml/100 g/min were not controlled by radiotherapy, while four out of five tumours with a rate >80 ml/ 100 g/min did show a favourable early response. The mean perfusion rate for the controlled, respectively uncontrolled tumours with radiation therapy was 95.6 and 57.4 ml/l00 g/ min (P = 0.03, Mann-Whitney U); the mean total tumour volume was respectively 16.1 and 102.6 ml (P = 0.006, Mann-Whitney U).
4. Discussion Our perfusion measurements seem to have a normal dis-
R. Hermans et al. /Radiotherapy
Fig. 1. Time-density curves obtained during the first pass of the contrast agent through two different tumours and homolateral carotid artery. The ROIs (tumour: arrowhead; carotid artery: arrow) are indicated on the reference image (‘Ref ima’); the values displayed in the time-density curves are obtained after substracting the density measured in an unenhanced image (‘Pre ima’). The slope of tumour time-density curve (double arrowhead) and the maximal arterial density (arrow) are indicated. (A) Patient 4. Oropharyngeal carcinoma. Calculated tumour perfusion was 91.7 ml/l00 g/min. (B) Patient 11. Hypopharyngeal carcinoma. Slope of tumour time-density curve is less steep as seen in A; the maximal arterial density is also lower. Calculated tumour perfusion was 35.9 ml/100 g/mitt.
tribution, but a rather low intertumoural variability was found: this may be a limiting factor in the use of the technique, although the preliminary results obtained in the radiotherapeutically treated patients qualitatively agree with the assumption that less well perfused tumours show a poorer response. The perfusion was calculated as the ratio of the slope of the tumour time density curve and the peak rise in the arterial density. The obtained perfusion rates are rather high compared to those found with other methods [7]. A possible explanation could be an systematic underestimation of the arterial peak density. On the CT scanner used, the
and Oncology 44 (1997) 159-162
161
arterial density is averaged over a 1 s acquisition time and the measured maximum arterial density may therefore not really represent the ‘peak’. The occurrence of image artefacts due to surrounding dense bone or movements due to respiration, swallowing or pulsations of nearby arteries can give rise to tissue density analysis problems is some head and neck tumours. A limitation of this technique is that only one level through the tumour can be examined; the obtained results may not be representative for the entire tumour. The calculated intratumoural coefficient of variation might therefore underestimate the true intratumoural variability of perfusion. This might be an important disadvantage, as only the average perfusion rate in a large ROI is estimated, while a few hypoxic clonogenic cells in a small low-perfusion area may determine the long-term outcome in spite of a high overall perfusion rate. The presented technique is not well suited to examination of the known temporal heterogeneity of tumour perfusion, as several hours are needed before the baseline tissue density is restored through renal clearance of the contrast medium; temporal fluctuations in tumour perfusion can therefore not be estimated. The presented technique estimates arterial tumour perfusion; extensive arteriovenous shunting occurring in some tumours [7] deprives the tissue of some of its supplies in spite of a high apparent arterial perfusion. Tumour volume was significantly correlated with early outcome. We found indications of a possible negative correlation between the obtained perfusion rates and the tumour volume, especially in the radiotherapeutically treated tumours. As tumour volume can be more easily measured on CT-images, this parameter may prove more feasible as predictive factor for tumour hypoxia than perfusion. In conclusion, a low perfusion rate measured in a primary head and neck tumour with dynamic CT during the first pass of a contrast agent may predict the presence of hypoxia. Such enhancement analysis could be considered for study as a prognostic factor, especially as it can be performed during a routine staging CT-examination. Further studies are needed to evaluate the reproducibility of these perfusion measurements, and their use as predictive factor. We are currently also examining the value of dynamic gadolinium-enhanced MRI as a tool for estimating the perfusion of malignant head and neck tumours. References [ 1] Blomley, M.J.K., Coulden, R., Buflkin, C., Lipton, M.J. and Dawson, P. Contrast bolus dynamic computed tomography for the measurement of solid organ perfusion. Invest. Radiol. 28: S72-S77, 1993. [2] Blomley, M.J.K., Coulden, R., Dawson, P., Kormano, M., Buflkin, C. and Lipton, M.J. Liver perfusion studied with ultrafast CT. J. Comput. Assist. Tomogr. 19: 424-433, 1995. [3] Jaschke, W., Gould, R.G., Assimakopoulos, P.A. and Lipton, M.J. Flow measurements with a high-speed computed tomography scanner. Med. Phys. 14: 238-243, 1984. [4] Mullani, N.A. and Gould, K.L. First-pass measurements of regional blood Bow with external detectors. J. Nucl. Med. 24: 577-581, 1983.
162
R. Hemans et al. /Radiotherapy
[5] Overgaard, J. Importance of tumor hypoxia in radiotherapy. A metaanalysis of controlled clinical trials [abstract]. Radiother. Oncol. 24: S64, 1992. [6] Peters, A.M., Gunasekera, R.D. and Henderson, B.L. Non-invasive measurements of blood flow and extraction fraction. Nucl. Med. Cornmun. 8: 823-837, 1987.
and Oncology 44 (1997) 159-162 [7] Vaupel, P., Kallinowski, F. and Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of humor tumors: a review. Cancer. Res. 49: 6449-6465, 1989.