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Renal complications secondary to radiation treatment of upper abdominal malignancies
Copyright
0
0360-3016/86 1986 Pqamon
$3.00 + .OO Journals Ltd.
??Original Contribution
RENAL
COMPLICATIONS UPPER
CHRISTOPHER
G. WILLETT,
SECONDARY ABDOMINAL M.D.,
TO RADIATION MALIGNANCIES
JOEL E. TEPPER,
AND WILLIAM
M.D.,
TREATMENT
ERICA L. ORLOW,
OF
B.A.
U. SHIPLEY, M.D.
Department of Radi.ation Medicine, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School A retrospective review of all patients undergoing radiotherapy for carcinoma of the colon, pancreas, stomach, small bowel and bile ducts, lymphomas of the stomach, and other GI sites and retroperitoneal sarcomas was completed to assess the effects of secondary irradiation on the kidney. Eighty-six adult patients were identified who were treated with curative intent, received greater than 50% unilateral kidney irradiation to doses of at least 2600 cGy and survived for 1 year or more. Following treatment, the clinical course, blood pressure, addition of anti-hypertensive medications, serum creatinine and creatinine clearance were determined. Creatinine clearance was calculated by the formula: creatiinine clearance equals I(140 - age) X (weight in kilograms)] + (72 X serum creatinine) which has a close correlation to creatinine clearances measured by 24 hr. urine measurements. The percent change in creatinine clearance from pre-treatment values was analyzed. Of the thirteen patients with pre-radiotherapy hypertension, four required an increase in the number of medications for control and nine required no change in medication. Two patients developed hypertension in follow-up, one controlled with medication and the other malignant hypertension. Acute or chronic renal failure was not observed in any patient. The serum creatinine for all 86 patients prior to radiation therapy was below 2 mg/lOO ml; in follow-up it rose to between 2.2-2.9 mg/lOO ml. in five patients. The mean creatinine clearance for all 86 patients prior to radiotherapy was 77 ml/minute and for 16 patients with at least 5 years of follow-up it was 62 ml/minute. The mean percent decrease in creatinine clearance appeared to correspond to the percentage of kidney irradiated: for 38 patients with only 50% of the kidney irradiated the mean percent decrease was lo%, whereas for 31 patients having 90 to 100% of the kidney treated the decrease was 24%. Althouglh physiologic changes were seen in patients receiving 50% or more unilateral kidney irradiation, the development of significant clinical sequelae was limited to one patient. Kidney, Complications
radiotherapy, Creatinine clearance.
INTRODUCI
ION
noted morphological changes that occur in the irradiated kidney based on radionuclide studies. However, it appears that irradiation of l/2 or less of one kidney is well-tolerated without serious long term complications. There is little information on the effects of 50-100% unilateral kidney irradiation. It is the objective of this report to describe the clinical course of a series of patients who, during radiation treatments of their primary malignancy, received irradiation to 50% or more of one kidney.
With
the increased use of radiotherapy in the management of upper abdominal malignancies-neoplasms arising from the colon, stomach., pancreas, biliary tree, retroperitoneum, and small bowel-and the resultant prolonged survival and cures in these patients, consideration of potential complications of this treatment is required. The tolerance of spinal cord: small bowel, large bowel, and other GI viscera to fractionated radiotherapy has been defined. Early investigators have described the response and tolerance of both kidneys to fractionated radiotherapy.6 In recent literature., there has been increased attention to the biochemical, radiologic, and clinical sequelae of unilateral kidney irra.diation.‘,4,5 These studies have
METHODS
AND
MATERIALS
A retrospective review of the records of all patients diagnosed with carcinoma of the colon, pancreas, stomach, bile duct, and small bowel, lymphomas of the stomach
Acknowledgements-The authors wish to thank Joan Horgan for her secretarial assistance. Accepted for publication 24 March 1986.
Supported in part by an American Cancer Society Clinical Fellowship. Presented at the America:n Society for Therapeutic Radiology and Oncology, Miami, Florida, October 1, 1985. Reprint requests to: J. E. Tepper, Department of Radiation Medicine, Cox Building, Blossom Street, Boston, MA 02 114. 1601
1602
1. J. Radiation Oncology 0 Biology 0 Physics
and GI system, and retroperitoneal sarcoma treated with radiation therapy in the Department of Radiation Medicine of the Massachusetts General Hospital from January 1, 197 1 to December 3 1, 1983 was completed. From this review, 86 patients were identified who were treated with curative intent, received at least 2600 cGy in conventional fractionation to more than 50% of one kidney and survived greater than 1 year after radiation therapy. All patients were treated with megavoltage equipment-“Co, 2 MeV Van de Graff or Varian Clinac 18 or 35 linear accelerator in 150 to 180 cGy fractions with either parallel opposed fields or multifield technique. Simulation films were reviewed to estimate the percentage of kidney within the irradiated field. There were 52 males and 34 females with a median age at diagnosis of 59 years and range of 30 to 86 years. All patients were followed for a minimum of 1 year after radiotherapy with a median follow-up of 3 years and range of 1 to 9 years. Histological diagnoses of these patients were as follows: colonic carcinoma-22 patients, gastric carcinoma- 19 patients, pancreatic carcinoma- 16 patients, gastric lymphoma- 14 patients, retroperitoneal sarcoma-7 patients, GI lymphoma-4 patients, biliary carcinoma-3 patients and small bowel carcinoma- 1 patient. Table 1 subdivides the patients according to the percentage of kidney irradiated and dose delivered. Patients’ blood pressure, number and type of antihypertension medications if hypertensive, weight, serum creatinine, creatinine clearance, and renal complications were determined. The creatinine clearance was calculated by a formula described by Cockcroft and Gault which considers the patient’s age, sex, weight, and serum creatinine: creatinine clearance equals [( 140 - age) X (weight in kilograms)] + (72 X serum creatinine) for men and 0.85 X [(140 - age) X (weight in kilograms)] t (72 X serum creatinine) for females? In the original study by Cockcroft, values for creatinine clearance were calculated by this formula and the results compared with the means of two 24 hr creatinine clearances measured in 236 patients.2 The formula gave a correlation coefficient between the predicted and mean measured creatinine clearance of 0.83 and on average the difference between predicted and mean measured values was no greater than that between paired clearances. The percent change in creatinine clearTable 1. Subdivision of 86 patients according and percent kidney irradiated
to dose
% kidney irradiated Dose (cGy)
Total patients
50%
6085%
90- 100%
2500-2999 3000-3999 4000-4999 5000-5999 >6000
2 3 47 32 2
1 0 23 14 0
0 1 8 7 1
1 2 16 11 1
Total
86
38
17
31
September 1986, Volume 12, Number 9 Table 2. Mean serum creatinine of patients receiving 50% or greater kidney irradiation following radiotherapy
Follow-up
year
Number observed
Pre-RT 1 2 3 4 5 >5 Numbers
Mean serum creatinine (mg/lOO ml)
1.o (kO.3) 1.o (kO.4)
86 19 34 22 8 11 16 in parentheses
indicate
1.2 1.3 1.o 1.5 1.2 standard
(kO.5) (k0.7) (kO.2) (20.6) (kO.3)
deviation.
ante from the pre-radiotherapy level to each year of follow-up was determined. It should be noted that many patients had data available on multiple follow-ups.
RESULTS Of 86 patients, 13 patients were hypertensive and on antihypertensive medications prior to radiotherapy. In follow-up, four of these 13 patients required the addition of one medication for control of their hypertension and nine patients required no change in medication. Two patients developed hypertension after radiotherapy-one controlled with one medication and the other malignant hypertension. This latter patient was treated for an unresectable pancreatic carcinoma with a combination of external beam radiotherapy and intraoperative radiotherapy receiving 5040 cGy in 28 fractions to the renal artery and adjacent 50% kidney parenchyma followed by an intraoperative electron boost of 1750 cGy including the renal artery only, sparing the kidney parenchyma. Three years after treatment, this patient expired secondary to intestinal infarction with autopsy demonstrating myointimal proliferation and fibrosis of the superior mesenteric artery and renal vessels. The irradiated kidney weighed 100 grams compared to 140 grams of the contralateral kidney and microscopically the renal parenchyma showed extensive tubular atrophy and glomerular necrosis and sclerosis. The etiology of this patient’s malignant hypertension was probably secondary to renal vascular damage rather than kidney parenchymal abnormalities. Acute or chronic renal failure was not observed in any patient during follow-up. The mean serum creatinine of the 86 patients prior to radiotherapy was 1.O mg per 100 ml. with a range of 0.4 to 1.9 mg/ 100 ml. In follow-up, five patients experienced a rise in serum creatinine to levels between 2.2 to 2.9 mg/ 100 ml. Table 2 illustrates the mean serum creatinine and standard deviations as a function of time following radiotherapy. The mean creatinine clearance prior to radiotherapy was 77 ml/min. For 16 patients with at least 5 years of follow-up, the pre-treatment mean creatinine clearance was 76 ml/min and in follow-up it was 62 ml/min. Table 3 shows the mean creatinine clearance and standard de-
1603
Renal complications in radiation of abdominal malignancies 0 C. G. WILLET etd.
Table 3. Mean creatinine clearance for all patients and according to percent kidney irradiated and time after radiotherapy
50% kidney irradiated
All patients Creatinine clearance. (ml/min)
No. of observations
Year Pre-Radiotherapy 1 2 3 4 5 >5
86 19 34 2:! 8 1 !I 16
77 70 58 73 73 53 62
(?31) (*28) (+30) (&44) (f32) (?29) (?29)
Creatinine clearance (ml/min)
No. of observations 38 8 18 12 1 3 6
78 77 63 72
(rt39) (k31) (+36) (+51) 71 (k47) 71 (&39)
90-100% kidney irradiated
60-85% kidney irradiated No. of observations 17 6 4 5 1 2 3
Creatinine clearance (ml/min)
No. of observations
84 77 69 67
(+20) (?25) (&25) (f45) 48 (+30) 65 (+2)
31 5 12 5 6 6 7
Creatinine clearance (ml/min) 73 50 46 79 64 46 53
(+26) (+18) (+-15) (k28) (+33) (+17) (+25)
Numbers in parentheses indicate standard deviation.
Table 4. Percent decrease in mean creatinine clearance according to percent kidney irradiated
of patients
% kidney irradiated
Number of observations
% decrease in creatinine clearance
38 17 31 86
50% 60-85% 90-100% Total
48 21 41 110
10 (&31) 19 (k30) 24 (+29) 17 (?31)
Number
though there are a small number of patients in some subgroups, there does not appear to be a progressive decrease in creatinine clearance with time after treatment. Table 6 shows that for patients having 90 to 100% of the kidney irradiated, there is no clear correlation of dose to percent decrease in creatinine clearance. DISCUSSION
Numbers in parentheses indicate standard deviation.
viations for all 86 patients and subdivided according to the approximate percentage of kidney irradiated and time after treatment. These data can also be analyzed as the mean percent decrease in creatinine clearance after radiotherapy as described in the Methods !Section. As seen in Table 4, the mean percent decrease in creatinine clearance corresponded to the percentage of kidney irradiated-for 38 patients with only 50% of the kidney irradiated, the mean percent decrease was lo%, whereas for 31 patients having 90 to 100% of the kidney treated, the decrease was 24%. The percent decrease in treat inine clearance and standard deviations, according to the percentage of kidney irradiated and time after radiotherapy, is outlined in Table 5. Al-
The mean percent decrease in creatinine clearance after kidney irradiation for 86 patients was 17% and appeared to depend on the percentage of kidney irradiated ranging from 10% for 50% of the kidney irradiated to 24% for patients having 90 to 100% of the kidney treated. Donor kidney transplant patients after nephrectomy have been noted to have a 20 to 30% decrease in creatinine clearance, similar to patients having high dose irradiation to all of one kidney.3 There did not appear to be a progressive decline in creatinine clearance with time after 1 year of treatment indicating that the radiation effects on the kidney are manifested within 1 year of treatment and remain constant after this. A dose response relationship was also not observed in patients having 90-100% of the kidney irradiated, suggesting that the full effect occurs at relatively low doses and is consistent with the data of Luxton and Kunkler.‘j Note, that the standard deviations were large
Table 5. Percent decrease in mean creatinine clearance according to percent kidney irradiated and time after radiotherapy
50% kidney irradiated
Year 1 2 3 4 5 >5
No. of observations 8 18 12 1 3 6
% decrease in creatinine clearance
60-852 No. of observations
kidney irradiated % decrease in creatinine clearance
11 (+26) 9 (+32) 21 (+28)
6 4 5
14 (?9) 12 (+18) 22 (&54)
3 (f44) 7 (+36)
1 2 3
53 (+18) 24 (+17)
Numbers in parentheses indicate standard deviation.
90- 100% kidney irradiated No. of observations 5 12 5 6 6 7
% decrease in creatinine clearance 26 (+33) 21 (k45) 23 (+ 10) 14 (+16) 35 @13) 29 (+18)
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1. J. Radiation Oncology 0 Biology 0 Physics
Table 6. Percent decrease in mean creatinine clearance for patients having 90- 100% kidney irradiation according to dose delivered Number of Dose (Gray) 26-42 43-49 so-52 53-61
Total
observations
Percent decrease in creatinine
clearance
11 12 11 7
23 20 26 31
41
24 (+29)
(-t48) (f17) (?24) (+I 1)
Numbers in parentheses indicate standard deviation. in most of the analyses reflecting the heterogenity of this patient population. The mean serum creatinine remained essentially within normal limits in all years of follow-up and only five patients experienced a rise to between 2.2 and 2.9 mg/lOO ml. Although changes in serum creatinine and creatinine clearance suggested physiologic changes occurring in patients receiving irradiation of 50% or more of one kidney, the appearance of serious clinical sequelae was limited to only one patient who developed malignant hypertension probably secondary to renal vascular damage. One other patient developed hypertension controlled with one medication and four of thirteen patients hypertensive at the start of treatment have required one additional medication in follow-up. It is difficult to know whether to attribute this to secondary radiation effects or to the natural history of essential hypertension in an adult population. None of the sixteen patients with follow-up of at least 5 years after treatment have developed overt clinical signs or symptoms of renal nephropathy. The median follow-up in this series was only 3 years and other reports have noted latency periods of many years to the development of malignant hypertension following kidney irradiation.6 Investigators from the Royal Melbourne Hospital have reported on 67 patients who received an estimated 1500 to 2000 rad in 3 weeks to the
September 1986, Volume 12, Number 9
left upper quadrant and presumably to the entire left kidney during treatment to the stomach to reduce gastric hypersecretion.’ Neither the extent of right kidney irradiation nor the type of radiotherapy equipment or technique is specified. With a minimum follow-up of 15 years, it was observed that five patients developed chronic renal failure 8 to 14 years after radiation, four patients had malignant hypertension 8 months to 8 years after radiotherapy, ten patients had stable hypertension and twelve patients were clinically asymptomatic but with abnormal renal biochemical studies. Other investigators have not noted serious complications from unilateral kidney irradiation. Kim et aL4 reported on eighteen patients receiving 50 to 100% left kidney irradiation during treatment for Non-Hodgkin’s Lymphoma and noted nine patients with abnormal radioisotope imaging studies following treatment. Five patients were found to have a moderate elevation of systolic and/ or diastolic blood pressure and 3 required medication; however, no patient developed malignant hypertension or renal nephropathy with a follow-up of 2 1 months to 8 years. Similarly, LeBourgeois et al.’ noted no significant changes in blood pressure or biochemical tests for up to 5 years after treatment, after splenic irradiation in 74 lymphoma patients having 30-80% of the left kidney treated. Birkhead et al. ’reported on 23 Hodgkin’s disease patients receiving one-third kidney irradiation during para-aortic and intact spleen treatment with follow-up of 34-75 months. Although 6 of 16 patients had decreased activity in the upper pole of the left kidney on renal scan after treatment, only 1 patient developed medically controlled hypertension with no other complications seen. The available data from this series suggests that irradiation to 50% or more of one kidney to doses of at least 2600 cGy in conventional fractionation is associated with a limited risk of renal nephropathy. If justified during treatment of upper abdominal malignancies and if the contralateral kidney is functioning normally, this should not be considered a dose or volume limiting normal tissue.
REFERENCES Birkhead, B.M., Dobbs, C.E., Beard, M.F., Tyson, J.W., Fuller, E.A.: Assessment of renal function following irradiation of the intact spleen for Hodgkin’s disease. Radiology 130: 473-475, 1979. Cockcroft, D.W., Gault, M.H.: Prediction of creatinine clearance from serum creatinine. Nephron. 16: 3 l-4 1, 1976. Edgren, J., Laasonen, L., Kock, B., Brotherus, J.W., Pasternack, A., Kuhlback, B.: Kidney function and compensatory growth of the kidney in living kidney donors. &and. J. Ural. Nephrol. 10:134-136, 1976. Kim, T.H., Somerville, P.J., Freeman, C.R.: Unilateral ra-
diation nephropathy-The long-term significance. Radiat. Oncol. Biol. Phys. 10:2053-2059, 1984.
Int. J.
LeBourgeois, J.P., Meignan, M., Parmentier, C., Tubiana, M.: Renal consequences of irradiation of the spleen in lymphoma patients. Br. J. Radiol. 52: 56-60, 1979. Luxton, R.W., Kunkler, P.B.: Radiation nephritis. Acta Radiol. Ther. Phys. Biol. 2: 169-178, 1964. Thompson, P.L., Mackay, I.R., Robson, G.S.M., Wall, A.J.: Late radiation nephritis after gastric X-irradiation for peptic ulcer. Q. J. Med. 40: 145-157, 1971.
0
0360-3016/86 1986 Pqamon
$3.00 + .OO Journals Ltd.
??Original Contribution
RENAL
COMPLICATIONS UPPER
CHRISTOPHER
G. WILLETT,
SECONDARY ABDOMINAL M.D.,
TO RADIATION MALIGNANCIES
JOEL E. TEPPER,
AND WILLIAM
M.D.,
TREATMENT
ERICA L. ORLOW,
OF
B.A.
U. SHIPLEY, M.D.
Department of Radi.ation Medicine, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School A retrospective review of all patients undergoing radiotherapy for carcinoma of the colon, pancreas, stomach, small bowel and bile ducts, lymphomas of the stomach, and other GI sites and retroperitoneal sarcomas was completed to assess the effects of secondary irradiation on the kidney. Eighty-six adult patients were identified who were treated with curative intent, received greater than 50% unilateral kidney irradiation to doses of at least 2600 cGy and survived for 1 year or more. Following treatment, the clinical course, blood pressure, addition of anti-hypertensive medications, serum creatinine and creatinine clearance were determined. Creatinine clearance was calculated by the formula: creatiinine clearance equals I(140 - age) X (weight in kilograms)] + (72 X serum creatinine) which has a close correlation to creatinine clearances measured by 24 hr. urine measurements. The percent change in creatinine clearance from pre-treatment values was analyzed. Of the thirteen patients with pre-radiotherapy hypertension, four required an increase in the number of medications for control and nine required no change in medication. Two patients developed hypertension in follow-up, one controlled with medication and the other malignant hypertension. Acute or chronic renal failure was not observed in any patient. The serum creatinine for all 86 patients prior to radiation therapy was below 2 mg/lOO ml; in follow-up it rose to between 2.2-2.9 mg/lOO ml. in five patients. The mean creatinine clearance for all 86 patients prior to radiotherapy was 77 ml/minute and for 16 patients with at least 5 years of follow-up it was 62 ml/minute. The mean percent decrease in creatinine clearance appeared to correspond to the percentage of kidney irradiated: for 38 patients with only 50% of the kidney irradiated the mean percent decrease was lo%, whereas for 31 patients having 90 to 100% of the kidney treated the decrease was 24%. Althouglh physiologic changes were seen in patients receiving 50% or more unilateral kidney irradiation, the development of significant clinical sequelae was limited to one patient. Kidney, Complications
radiotherapy, Creatinine clearance.
INTRODUCI
ION
noted morphological changes that occur in the irradiated kidney based on radionuclide studies. However, it appears that irradiation of l/2 or less of one kidney is well-tolerated without serious long term complications. There is little information on the effects of 50-100% unilateral kidney irradiation. It is the objective of this report to describe the clinical course of a series of patients who, during radiation treatments of their primary malignancy, received irradiation to 50% or more of one kidney.
With
the increased use of radiotherapy in the management of upper abdominal malignancies-neoplasms arising from the colon, stomach., pancreas, biliary tree, retroperitoneum, and small bowel-and the resultant prolonged survival and cures in these patients, consideration of potential complications of this treatment is required. The tolerance of spinal cord: small bowel, large bowel, and other GI viscera to fractionated radiotherapy has been defined. Early investigators have described the response and tolerance of both kidneys to fractionated radiotherapy.6 In recent literature., there has been increased attention to the biochemical, radiologic, and clinical sequelae of unilateral kidney irra.diation.‘,4,5 These studies have
METHODS
AND
MATERIALS
A retrospective review of the records of all patients diagnosed with carcinoma of the colon, pancreas, stomach, bile duct, and small bowel, lymphomas of the stomach
Acknowledgements-The authors wish to thank Joan Horgan for her secretarial assistance. Accepted for publication 24 March 1986.
Supported in part by an American Cancer Society Clinical Fellowship. Presented at the America:n Society for Therapeutic Radiology and Oncology, Miami, Florida, October 1, 1985. Reprint requests to: J. E. Tepper, Department of Radiation Medicine, Cox Building, Blossom Street, Boston, MA 02 114. 1601
1602
1. J. Radiation Oncology 0 Biology 0 Physics
and GI system, and retroperitoneal sarcoma treated with radiation therapy in the Department of Radiation Medicine of the Massachusetts General Hospital from January 1, 197 1 to December 3 1, 1983 was completed. From this review, 86 patients were identified who were treated with curative intent, received at least 2600 cGy in conventional fractionation to more than 50% of one kidney and survived greater than 1 year after radiation therapy. All patients were treated with megavoltage equipment-“Co, 2 MeV Van de Graff or Varian Clinac 18 or 35 linear accelerator in 150 to 180 cGy fractions with either parallel opposed fields or multifield technique. Simulation films were reviewed to estimate the percentage of kidney within the irradiated field. There were 52 males and 34 females with a median age at diagnosis of 59 years and range of 30 to 86 years. All patients were followed for a minimum of 1 year after radiotherapy with a median follow-up of 3 years and range of 1 to 9 years. Histological diagnoses of these patients were as follows: colonic carcinoma-22 patients, gastric carcinoma- 19 patients, pancreatic carcinoma- 16 patients, gastric lymphoma- 14 patients, retroperitoneal sarcoma-7 patients, GI lymphoma-4 patients, biliary carcinoma-3 patients and small bowel carcinoma- 1 patient. Table 1 subdivides the patients according to the percentage of kidney irradiated and dose delivered. Patients’ blood pressure, number and type of antihypertension medications if hypertensive, weight, serum creatinine, creatinine clearance, and renal complications were determined. The creatinine clearance was calculated by a formula described by Cockcroft and Gault which considers the patient’s age, sex, weight, and serum creatinine: creatinine clearance equals [( 140 - age) X (weight in kilograms)] + (72 X serum creatinine) for men and 0.85 X [(140 - age) X (weight in kilograms)] t (72 X serum creatinine) for females? In the original study by Cockcroft, values for creatinine clearance were calculated by this formula and the results compared with the means of two 24 hr creatinine clearances measured in 236 patients.2 The formula gave a correlation coefficient between the predicted and mean measured creatinine clearance of 0.83 and on average the difference between predicted and mean measured values was no greater than that between paired clearances. The percent change in creatinine clearTable 1. Subdivision of 86 patients according and percent kidney irradiated
to dose
% kidney irradiated Dose (cGy)
Total patients
50%
6085%
90- 100%
2500-2999 3000-3999 4000-4999 5000-5999 >6000
2 3 47 32 2
1 0 23 14 0
0 1 8 7 1
1 2 16 11 1
Total
86
38
17
31
September 1986, Volume 12, Number 9 Table 2. Mean serum creatinine of patients receiving 50% or greater kidney irradiation following radiotherapy
Follow-up
year
Number observed
Pre-RT 1 2 3 4 5 >5 Numbers
Mean serum creatinine (mg/lOO ml)
1.o (kO.3) 1.o (kO.4)
86 19 34 22 8 11 16 in parentheses
indicate
1.2 1.3 1.o 1.5 1.2 standard
(kO.5) (k0.7) (kO.2) (20.6) (kO.3)
deviation.
ante from the pre-radiotherapy level to each year of follow-up was determined. It should be noted that many patients had data available on multiple follow-ups.
RESULTS Of 86 patients, 13 patients were hypertensive and on antihypertensive medications prior to radiotherapy. In follow-up, four of these 13 patients required the addition of one medication for control of their hypertension and nine patients required no change in medication. Two patients developed hypertension after radiotherapy-one controlled with one medication and the other malignant hypertension. This latter patient was treated for an unresectable pancreatic carcinoma with a combination of external beam radiotherapy and intraoperative radiotherapy receiving 5040 cGy in 28 fractions to the renal artery and adjacent 50% kidney parenchyma followed by an intraoperative electron boost of 1750 cGy including the renal artery only, sparing the kidney parenchyma. Three years after treatment, this patient expired secondary to intestinal infarction with autopsy demonstrating myointimal proliferation and fibrosis of the superior mesenteric artery and renal vessels. The irradiated kidney weighed 100 grams compared to 140 grams of the contralateral kidney and microscopically the renal parenchyma showed extensive tubular atrophy and glomerular necrosis and sclerosis. The etiology of this patient’s malignant hypertension was probably secondary to renal vascular damage rather than kidney parenchymal abnormalities. Acute or chronic renal failure was not observed in any patient during follow-up. The mean serum creatinine of the 86 patients prior to radiotherapy was 1.O mg per 100 ml. with a range of 0.4 to 1.9 mg/ 100 ml. In follow-up, five patients experienced a rise in serum creatinine to levels between 2.2 to 2.9 mg/ 100 ml. Table 2 illustrates the mean serum creatinine and standard deviations as a function of time following radiotherapy. The mean creatinine clearance prior to radiotherapy was 77 ml/min. For 16 patients with at least 5 years of follow-up, the pre-treatment mean creatinine clearance was 76 ml/min and in follow-up it was 62 ml/min. Table 3 shows the mean creatinine clearance and standard de-
1603
Renal complications in radiation of abdominal malignancies 0 C. G. WILLET etd.
Table 3. Mean creatinine clearance for all patients and according to percent kidney irradiated and time after radiotherapy
50% kidney irradiated
All patients Creatinine clearance. (ml/min)
No. of observations
Year Pre-Radiotherapy 1 2 3 4 5 >5
86 19 34 2:! 8 1 !I 16
77 70 58 73 73 53 62
(?31) (*28) (+30) (&44) (f32) (?29) (?29)
Creatinine clearance (ml/min)
No. of observations 38 8 18 12 1 3 6
78 77 63 72
(rt39) (k31) (+36) (+51) 71 (k47) 71 (&39)
90-100% kidney irradiated
60-85% kidney irradiated No. of observations 17 6 4 5 1 2 3
Creatinine clearance (ml/min)
No. of observations
84 77 69 67
(+20) (?25) (&25) (f45) 48 (+30) 65 (+2)
31 5 12 5 6 6 7
Creatinine clearance (ml/min) 73 50 46 79 64 46 53
(+26) (+18) (+-15) (k28) (+33) (+17) (+25)
Numbers in parentheses indicate standard deviation.
Table 4. Percent decrease in mean creatinine clearance according to percent kidney irradiated
of patients
% kidney irradiated
Number of observations
% decrease in creatinine clearance
38 17 31 86
50% 60-85% 90-100% Total
48 21 41 110
10 (&31) 19 (k30) 24 (+29) 17 (?31)
Number
though there are a small number of patients in some subgroups, there does not appear to be a progressive decrease in creatinine clearance with time after treatment. Table 6 shows that for patients having 90 to 100% of the kidney irradiated, there is no clear correlation of dose to percent decrease in creatinine clearance. DISCUSSION
Numbers in parentheses indicate standard deviation.
viations for all 86 patients and subdivided according to the approximate percentage of kidney irradiated and time after treatment. These data can also be analyzed as the mean percent decrease in creatinine clearance after radiotherapy as described in the Methods !Section. As seen in Table 4, the mean percent decrease in creatinine clearance corresponded to the percentage of kidney irradiated-for 38 patients with only 50% of the kidney irradiated, the mean percent decrease was lo%, whereas for 31 patients having 90 to 100% of the kidney treated, the decrease was 24%. The percent decrease in treat inine clearance and standard deviations, according to the percentage of kidney irradiated and time after radiotherapy, is outlined in Table 5. Al-
The mean percent decrease in creatinine clearance after kidney irradiation for 86 patients was 17% and appeared to depend on the percentage of kidney irradiated ranging from 10% for 50% of the kidney irradiated to 24% for patients having 90 to 100% of the kidney treated. Donor kidney transplant patients after nephrectomy have been noted to have a 20 to 30% decrease in creatinine clearance, similar to patients having high dose irradiation to all of one kidney.3 There did not appear to be a progressive decline in creatinine clearance with time after 1 year of treatment indicating that the radiation effects on the kidney are manifested within 1 year of treatment and remain constant after this. A dose response relationship was also not observed in patients having 90-100% of the kidney irradiated, suggesting that the full effect occurs at relatively low doses and is consistent with the data of Luxton and Kunkler.‘j Note, that the standard deviations were large
Table 5. Percent decrease in mean creatinine clearance according to percent kidney irradiated and time after radiotherapy
50% kidney irradiated
Year 1 2 3 4 5 >5
No. of observations 8 18 12 1 3 6
% decrease in creatinine clearance
60-852 No. of observations
kidney irradiated % decrease in creatinine clearance
11 (+26) 9 (+32) 21 (+28)
6 4 5
14 (?9) 12 (+18) 22 (&54)
3 (f44) 7 (+36)
1 2 3
53 (+18) 24 (+17)
Numbers in parentheses indicate standard deviation.
90- 100% kidney irradiated No. of observations 5 12 5 6 6 7
% decrease in creatinine clearance 26 (+33) 21 (k45) 23 (+ 10) 14 (+16) 35 @13) 29 (+18)
1604
1. J. Radiation Oncology 0 Biology 0 Physics
Table 6. Percent decrease in mean creatinine clearance for patients having 90- 100% kidney irradiation according to dose delivered Number of Dose (Gray) 26-42 43-49 so-52 53-61
Total
observations
Percent decrease in creatinine
clearance
11 12 11 7
23 20 26 31
41
24 (+29)
(-t48) (f17) (?24) (+I 1)
Numbers in parentheses indicate standard deviation. in most of the analyses reflecting the heterogenity of this patient population. The mean serum creatinine remained essentially within normal limits in all years of follow-up and only five patients experienced a rise to between 2.2 and 2.9 mg/lOO ml. Although changes in serum creatinine and creatinine clearance suggested physiologic changes occurring in patients receiving irradiation of 50% or more of one kidney, the appearance of serious clinical sequelae was limited to only one patient who developed malignant hypertension probably secondary to renal vascular damage. One other patient developed hypertension controlled with one medication and four of thirteen patients hypertensive at the start of treatment have required one additional medication in follow-up. It is difficult to know whether to attribute this to secondary radiation effects or to the natural history of essential hypertension in an adult population. None of the sixteen patients with follow-up of at least 5 years after treatment have developed overt clinical signs or symptoms of renal nephropathy. The median follow-up in this series was only 3 years and other reports have noted latency periods of many years to the development of malignant hypertension following kidney irradiation.6 Investigators from the Royal Melbourne Hospital have reported on 67 patients who received an estimated 1500 to 2000 rad in 3 weeks to the
September 1986, Volume 12, Number 9
left upper quadrant and presumably to the entire left kidney during treatment to the stomach to reduce gastric hypersecretion.’ Neither the extent of right kidney irradiation nor the type of radiotherapy equipment or technique is specified. With a minimum follow-up of 15 years, it was observed that five patients developed chronic renal failure 8 to 14 years after radiation, four patients had malignant hypertension 8 months to 8 years after radiotherapy, ten patients had stable hypertension and twelve patients were clinically asymptomatic but with abnormal renal biochemical studies. Other investigators have not noted serious complications from unilateral kidney irradiation. Kim et aL4 reported on eighteen patients receiving 50 to 100% left kidney irradiation during treatment for Non-Hodgkin’s Lymphoma and noted nine patients with abnormal radioisotope imaging studies following treatment. Five patients were found to have a moderate elevation of systolic and/ or diastolic blood pressure and 3 required medication; however, no patient developed malignant hypertension or renal nephropathy with a follow-up of 2 1 months to 8 years. Similarly, LeBourgeois et al.’ noted no significant changes in blood pressure or biochemical tests for up to 5 years after treatment, after splenic irradiation in 74 lymphoma patients having 30-80% of the left kidney treated. Birkhead et al. ’reported on 23 Hodgkin’s disease patients receiving one-third kidney irradiation during para-aortic and intact spleen treatment with follow-up of 34-75 months. Although 6 of 16 patients had decreased activity in the upper pole of the left kidney on renal scan after treatment, only 1 patient developed medically controlled hypertension with no other complications seen. The available data from this series suggests that irradiation to 50% or more of one kidney to doses of at least 2600 cGy in conventional fractionation is associated with a limited risk of renal nephropathy. If justified during treatment of upper abdominal malignancies and if the contralateral kidney is functioning normally, this should not be considered a dose or volume limiting normal tissue.
REFERENCES Birkhead, B.M., Dobbs, C.E., Beard, M.F., Tyson, J.W., Fuller, E.A.: Assessment of renal function following irradiation of the intact spleen for Hodgkin’s disease. Radiology 130: 473-475, 1979. Cockcroft, D.W., Gault, M.H.: Prediction of creatinine clearance from serum creatinine. Nephron. 16: 3 l-4 1, 1976. Edgren, J., Laasonen, L., Kock, B., Brotherus, J.W., Pasternack, A., Kuhlback, B.: Kidney function and compensatory growth of the kidney in living kidney donors. &and. J. Ural. Nephrol. 10:134-136, 1976. Kim, T.H., Somerville, P.J., Freeman, C.R.: Unilateral ra-
diation nephropathy-The long-term significance. Radiat. Oncol. Biol. Phys. 10:2053-2059, 1984.
Int. J.
LeBourgeois, J.P., Meignan, M., Parmentier, C., Tubiana, M.: Renal consequences of irradiation of the spleen in lymphoma patients. Br. J. Radiol. 52: 56-60, 1979. Luxton, R.W., Kunkler, P.B.: Radiation nephritis. Acta Radiol. Ther. Phys. Biol. 2: 169-178, 1964. Thompson, P.L., Mackay, I.R., Robson, G.S.M., Wall, A.J.: Late radiation nephritis after gastric X-irradiation for peptic ulcer. Q. J. Med. 40: 145-157, 1971.