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Renal Toxicity of Adjuvant Chemoradiotherapy With Cisplatin in Gastric Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 5, pp. 1429–1435, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.05.021
CLINICAL INVESTIGATION
Stomach
RENAL TOXICITY OF ADJUVANT CHEMORADIOTHERAPY WITH CISPLATIN IN GASTRIC CANCER STEFAN WELZ, M.D.,* THOMAS HEHR, M.D.,*x CHRISTIAN KOLLMANNSBERGER, M.D.,y CARSTEN BOKEMEYER, M.D.,z CLAUS BELKA, M.D.,x AND WILFRIED BUDACH, M.D.* * Heinrich-Heine-University of Du¨sseldorf, Du¨sseldorf, Germany; y University of British Columbia, Vancouver, British Columbia, Canada; z University of Hamburg-Eppendorf, Hamburg, Germany; and x Eberhard-Karls-University of Tu¨bingen, Tu¨bingen, Germany Purpose: Adjuvant, 5-fluorouracil (5-FU)–based chemoradiotherapy for completely resected high-risk gastric adenocarcinoma has been shown to improve survival in a randomized Intergroup trial. However, the results still showed an unsatisfactory outcome. On the basis of previously reported results of a Phase II trial using a more aggressive, cisplatin-containing chemoradiotherapy schedule, we investigated the effects of this approach on long-term renal function. Patients and Methods: Between December 2000 and September 2003, 27 patients were treated at Tu¨bingen University in a Phase II multicenter trial investigating adjuvant chemoradiotherapy. The adjuvant chemoradiotherapy consisted of two cycles of adjuvant 5-FU, folinic acid, cisplatin (200 mg/m2), and paclitaxel before and after radiotherapy (45 Gy in 1.8-Gy fractions) with daily concomitant 5-FU (225 mg/m2/24 h). A dose constraint of #12 Gy for 37.5% of the functional volume of both kidneys was used. Renal function was assessed by the changes in creatinine and creatinine clearance during follow-up. Results: The prescribed 45 Gy was administered to 100% of the patients, and the cumulative cisplatin dose was 200 mg/m2 in 74% of all patients. In 89%, the constraints concerning the renal absorbed doses were met. The median follow-up for the creatinine and clearance values was 30 and 26 months, respectively. The creatinine values tended to worsen over time without reaching critical levels. We were unable to demonstrate a significant dose–response relationship for renal damage in the tested dose range. Conclusions: Using a dose constraint of #12 Gy for 37.5% of the functional volume of both kidneys appears to be safe at a median follow-up of 2 years for a cumulative cisplatin dose of 200 mg/m2 administered before and after simultaneous 5-FU and radiotherapy. Ó 2007 Elsevier Inc. Radiotherapy, Cisplatin, Gastric cancer, Toxicity, Renal.
results seem mostly to have resulted from improved local control, because the rate of distant metastases remained high. Therefore, more aggressive chemotherapy regimens before and after radiochemotherapy have been used in recent studies. A cooperative German Phase II study, using a different chemotherapy regimen but an identical chemoradiotherapy approach (45 Gy plus folinic acid and 24-h infusion of 5-FU), was performed by the Arbeitsgemeinschaft Internistische Onkologie/Arbeitsgruppe Radiologische Onkologie/Arbeitsgemeinschaft Chirurgische Onkologie (AIO/ARO/ACO). The results have already been published, with a projected 2-year progression-free survival rate of 61–64% and an acceptable toxicity profile (2). The study used 5-FU, folinic acid, paclitaxel, and cisplatin before and after the application of radiochemotherapy with concomitant 5-FU infusion.
INTRODUCTION The only possibility of curing gastric cancer is complete (R0) surgical resection, including D1 or D2 lymphadenectomy. However, even if complete resection can be achieved, most patients with locally advanced disease will eventually develop a relapse. The recurrent disease will be distant and locoregional, highlighting the need for adjuvant therapy addressing subclinical metastatic disease, as well as any remaining tumor cells at the primary tumor site. The Intergroup Study 0116 used an adjuvant chemoradiotherapy protocol with 45 Gy combined with folinic acid and a 24-h infusion of 5-fluorouracil (5-FU) (Mayo protocol) after R0 resection and was able to demonstrate significant improvement in the progression-free and overall survival rate after 3 years of 17% and 9%, respectively (1). However, these
Conflict of interest: none. Received April 13, 2007, and in revised form May 11, 2007. Accepted for publication May 11, 2007.
Reprint requests to: Stefan Welz, M.D., Department of Radiation Oncology, Eberhard-Karls-University of Tu¨bingen, Hoppe-Seyler Str. 3, Tu¨bingen D-72076 Germany. Tel: (00) 410-7071-2984854; Fax: (00) 410-7071-298-6052; E-mail: stefan.welz@med. uni-tuebingen.de 1429
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Because at least partial volume irradiation of the kidneys cannot be avoided with adjuvant radiotherapy (RT) in gastric carcinoma, concern exists that the additional use of nephrotoxic drugs such as cisplatin could lead to irreversible, symptomatic renal toxicity. However, few clinical data about the toxic potential of this combination are available. For RT alone, assumptions on the radiation doses tolerated by the kidneys mention a 5% risk at 5 years of 23 Gy to 100% of the kidney volume and 30 Gy to 66% of the kidney volume (3). Experimental studies have shown an additive toxicity of fractionated RT and cisplatin on mouse kidneys with an enhancement factor of 1.2–1.4 (4). To date, these are the only available data on the renal tolerance of this sequential chemoradiotherapy regimen. On the basis of these data, dose restrictions for the kidneys with adjuvant RT in the AIO/ARO/ACO study were prescribed. To comply with these restrictions, special beam arrangements were necessary. We evaluated the renal toxicity of this adjuvant treatment with a cisplatin-containing chemotherapy regimen and sequential RT in the patients treated within the AIO/ARO/ ACO study at the University Hospital Tu¨bingen.
PATIENTS AND METHODS Between December 2000 and September 2003, 27 patients with gastric cancer were treated within a Phase II multicenter protocol of the AIO/ARO/ACO (2) at Tu¨bingen University. All 27 patients underwent evaluation of post-treatment renal toxicity. The local ethics committee of Tu¨bingen University approved the study protocol, which was in accordance with the Helsinki Declaration of 1975.
Patients The eligibility criteria were complete (R0) or microscopically incomplete (R1) resection of histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction; Stage II-IV disease according to the International Union Against Cancer (1997); Eastern Cooperative Oncology Group performance status of 0–2; age 18–65 years; adequate hematologic, renal, and hepatic function (hemogram with normal limits, bilirubin concentration not exceeding twice the normal upper limit, creatinine clearance $60 mL/min); and written informed consent. The start of adjuvant treatment had to be within 6 weeks after surgery. The exclusion criteria were severe concurrent, insufficiently treated diseases such as heart, renal, or hepatic failure, acute infection, previous chemotherapy, and a second malignant disease, with the exception of basal cell carcinoma or carcinoma in situ of the cervix. All patients underwent computed tomography of the chest and abdomen, a complete physical examination, complete blood count, serum chemistry, creatinine clearance determination, electrocardiography, and an audiogram. Before RT, renal scintigraphy with technetium-99m-mercaptoacetyltriglycine was required to allow for modification of the beam arrangements if significant difference in function was found between the two kidneys and to allow for accordance with the dose constraints, described below.
Treatment The treatment schedule is detailed in Fig. 1.
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Chemotherapy. All patients had a permanent venous access implanted and, therefore, could be treated on an outpatient basis. Dose reductions were applied if toxicity (Common Toxicity Criteria) of Grade 2 or more occurred. One cycle of 5-fluorouracil, leucovorin (folinic acid), cisplatin, and paclitaxel consisted of a 2-h infusion of 500 mg/m2 folinic acid followed by a 24-h continuous infusion of 2,000 mg/m2 5-FU on Days 1, 8, 15, 22, 29, and 36. Paclitaxel was given as a 3-h infusion of 175 mg/m2 on Days 1 and 22. Cisplatin was administered at a dose of 50 mg/m2 within 1 h on Days 8 and 29. All patients received dexamethasone and ranitidine, as well as diphenhydramine, as premedication to paclitaxel. Adequate hydration was administered in combination with the cisplatin. Chemoradiotherapy. Radiotherapy was administered in 25 fractions with 1.8-Gy/d, resulting in an overall treatment time of 5 weeks and a total dose of 45 Gy. Patients received concomitant 5-FU as a continuous 24-h infusion on all RT days in a dosage of 225 mg/m2. An oral 5-HT3 antagonist was recommended during chemotherapy. Patients with residual gastric tissue received a proton pump inhibitor. Radiotherapy was administered with linear accelerators using 15-MV photons after three-dimensional planning according to International Commission on Radiation Units and Measurements Reports 50 and 62. The clinical target volume (CTV) included the regional (perigastric, celiac axis, prevertebral, para-aortic, hepatoduodenal, and pancreaticoduodenal, including the splenic and hepatic hilus) lymph nodes, the anastomosis region, and a minimal 4-cm safety margin in respect to the formerly involved mucosal site. If a proximal T3 tumor was treated, the CTV also encompassed the medial part of the diaphragm. In the case of involvement of the gastroesophageal junction, a 5-cm safety margin in this direction, as well as the inclusion of the paraesophageal lymph nodes in the CTV, was used. For distally localized tumors, the safety margin was 5 cm in the aboral direction. The planning target volume (PTV) included the CTV with an additional 12-mm margin in every direction. Both kidneys and the liver, heart, and spinal cord were considered organs at risk and had the following dose/volume restrictions: kidneys, #12 Gy to <37.5% of the functional volume for both kidneys using functional scintigraphy for calculation; liver, <30 Gy to <60% of the liver volume; heart, <40 Gy to <30% of the volume defined by the outline of both ventricles; and spinal cord, <47.5 Gy (single dose <1.9 Gy). The kidneys were contoured, excluding the renal pelvis. RT planning was done using one computed tomography scan with normal breathing and without correction for breathing-induced kidney movement. Whenever the dose constraints were met, an anteroposterior–posteroanterior technique was chosen. In the case of violation of these constraints, more complex beam arrangements were used. An example of a five-beam plan with a cranial and caudal half-beam-arrangement is shown in Fig. 2. If the prescribed dose to the PTV still caused a violation of these restrictions, the CTV was reduced in favor of the organs at risk.
Endpoints and follow-up The endpoints for the assessment of renal function were the changes in the urea, creatinine, and creatinine clearance values and clinical signs of nephrotoxicity such as anemia or arterial hypertension. The calculation of creatinine clearance was done according to the formula of Cockcroft and Gault (5): creatinine clearance ¼ ½ð140 ageÞ weight=72 serum creatinine, with age in years, weight in kilograms, and serum creatinine in milligrams per deciliter. The results were adjusted for body surface area and female gender (6)—adjustment for body surface area: creatinine
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Fig. 1. Study design. FLPP = 5-fluorouracil, leucovorin (folinic acid), cisplatin, paclitaxel; CHX = chemotherapy; RTCHX = chemoradiotherapy. clearance 1:73=body surface area ðin meters squaredÞ; and adjustment for female gender: creatinine clearance 0:85. During follow-up, the data for 14 patients only showed that the serum creatinine level was ‘‘normal,’’ meaning within the normal laboratory range. We, therefore, calculated clearance according to the above-mentioned formula using the upper laboratory range value (1.2 mg/dL) for creatinine when the exact value was unknown.
Follow-up examinations were done at 3-month intervals for 2 years followed by 6-month visits for another 3 years, and yearly thereafter.
Statistical analysis Statistical analysis was done using Statistical Analysis Systems software (Statistica) for uni- and multivariate analysis.
Fig. 2. Example of radiotherapy plan with (a) cranial (three beams) and (b) caudal (two beams) half beams. Corresponding dose–volume histogram for (c) left and (d) right kidney.
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Table 1. Patient characteristics
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A total of 27 evaluable patients were treated within these studies at Tu¨bingen University Hospital. The median age was 50 years (range, 25–66). All patients received the prescribed radiation dose, but 26% received less than the intended cisplatin dose. Additional information on patient characteristics is given in Table 1. To encompass the primary tumor region, as well as the adjacent lymphatic tissue, and to meet the dose constraints for the liver, spinal cord, and kidneys, it was necessary to apply more complex beam arrangements than anteroposterior– posteroanterior beams in about two-thirds of all patients.
However, even with these techniques (Fig. 2) and with moderate reductions of the PTV in favor of the organs at risk when necessary, in 11% of patients, the dose to the kidneys exceeded the recommended dose–volume histogram restrictions. Figure 2 displays an example of a beam arrangement and the resulting absorbed doses of both kidneys. Figure 3 shows the distribution of the absorbed dose per kidney volume for all patients. All creatinine values were normal (i.e., lower than the upper laboratory range of 1.2 mg/dL) before the start of adjuvant therapy. Patients with unilateral renal function impairment were excluded from the study. Figure 4 displays the creatinine values from the start of therapy to the longest available followup examination in absolute values, and Fig. 5 illustrates the change in creatinine (delta) with the months of follow-up. Whenever the creatinine value obtained from the study management center could only be classified as ‘‘normal,’’ we assumed the worst possible case (i.e., a value of 1.2 mg/dL). For the creatinine and creatinine clearance values, 37% and 41% of all patients were at risk of not reaching the 2 years of follow-up. Most patients experienced a slight increase in creatinine, but only one had a value that was greater than the upper laboratory range. Almost all patients had a decreased calculated creatinine clearance value at the longest available follow-up point. The worst outcome was a reduction of about 50%. The same tendency was true for the urea values (data not shown). We defined a high-risk group of patients (n = 10) who received a dose of >12 Gy to >50% (median, 59%; range, 54– 87%) of the functional renal volume. The median absorbed renal dose in this subgroup was 12.8 Gy. All but 1 patient (95%) received 100% of the intended cisplatin dose. The patients in this group are indicated separately in Figs. 4 and 5. The results for this subgroup with a follow-up period for the clearance and creatinine values of 24 and 26 months,
Fig. 3. Dose distribution of both kidneys indicating volume cluster of kidneys receiving dose of >12, >15, >18, or >22.5 Gy in which percentage of patients.
Fig. 4. Change in creatinine values before therapy and at longest available follow-up point. Many latter values were worst-case assumptions (see text). Bold lines and large icons indicate high-risk group.
Characteristic
Value
Gender (n) Male Female Age (y) Median Range Radiation dose (ICRU 50/62) (Gy) Stage (UICC 1997) (%) II III IV Gastric adenocarcinoma (%) Pathologic grade (%) G2 G3 Complete resection (%)
21 6 50 25–66 45 37 30 33 100 15 85 96
Abbreviations: ICRU 50/62 = International Commission on Radiation Units and Measurements Reports 50 and 62; UICC = International Union Against Cancer.
RESULTS
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Fig. 5. Difference between creatinine values before therapy and at longest available follow-up point (delta). Circles indicate high-risk group.
respectively, were not significantly different from those of the whole population. Univariate analysis considering the change in creatinine and creatinine clearance over time compared with the volume of the kidneys irradiated showed no significant dose– volume relationship in the tested dose range. No patient had signs of clinically relevant nephrotoxicity, including arterial hypertension or nephritis. DISCUSSION For patients with high-risk, completely resected gastric cancer, adjuvant chemoradiotherapy has been shown to significantly improve overall survival in a randomized trial (1). However, the high rate of distant metastases still needs to be addressed further. In this regard, new chemotherapy regimens have been introduced, which included the use of drugs such as the nephrotoxic cisplatin, which has been shown to be effective against this disease (2). Adjuvant RT in gastric cancer targets the area in which the stomach itself was located with the primary tumor site, as well as the locoregional lymphatic pathways along both former curvatures, the splenic hilus, liver hilus, and pancreaticoduodenal lymphatic area. The boundaries of the resulting, complex-shaped CTV are usually in direct contact with the surface of both kidneys, on the left side to a greater extent than on the right. Setup errors and breathing-induced organ motion require margins between the CTV and PTV of $1 cm in the axial and $1.5 cm in the craniocaudal direction. In most cases, a substantial overlap of the PTV and kidney
volumes is the result. Hence, it is inevitable, even if one uses optimized three-dimensional planning or intensitymodulated RT, to irradiate large parts of the kidneys with a considerable dose (Table 2). The effect of RT on renal function was reviewed by Emami et al. (3), who made assumptions concerning the doses tolerated by the kidneys according to retrospective patient data. Their conclusion was that the 5% risk at 5 years (for nephritis) is 23 Gy and the 50% risk at 5 years is 28 Gy for irradiation of the whole kidney. On the basis of these data, constraints on the absorbed doses by the kidneys were defined. Because the kidney is an organ with a parallel functional structure, the assessment of the effects of partial volume irradiation is difficult. Even less is known about the renal toxicity of the combined approach of sequential cisplatin chemotherapy and RT on renal toxicity. Data from an animal model study, which investigated the influence of cisplatin on mouse kidneys exposed to multifractionated irradiation (4), suggested additive toxicity with the two nephrotoxic treatments. The investigators calculated an enhancement factor of 1.2–1.4 for the addition of cisplatin to fractionated irradiation. They also found that renal tolerance was dependent on the sequence of RT and chemotherapy. The administration of cisplatin before RT yielded a greater tolerance dose for RT than when cisplatin was administered after RT. However, in the protocol used in the present study, cisplatin was a part of the chemotherapy regimens both before and after RT (Fig. 1). The patients described in our study were treated in the AIO/ARO/ACO protocol (2), detailed in the ‘‘Patients and
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Table 2. Radiotherapy/chemotherapy parameters Parameter
Value
Patients receiving 45-Gy RT (%) Median PTV (cm3) Median no. of beams used Patients receiving beam no. and configuration (%) Two AP–PA Angled AP–PA AP–lateral Three (AP–lateral opposing) Four or more Patients with median absorbed dose for both kidneys (%) >12 Gy >15 Gy >18 Gy >22.5 Gy Accordance with renal constraints* (%) 5-FU chemotherapy during RT (%) Cisplatin dose received (%) 100 $75 Median follow-upy (mo) Creatinine Creatinine clearance
100 1,326 (670–2,477) 3 (2–5)
37 4 7 19 33 44 (19–87) 39 (14–61) 32 (12–56) 25 (5–55) 89 100 74 100 30 (13–55) 26 (6–56)
Abbreviations: RT = radiotherapy; PTV = planning target volume; AP = anteroposterior; PA = posteroanterior; FU = fluorouracil. Data in parentheses are ranges. * Renal constraints: #12 Gy to <37.5% of functional volume. y Difference in median follow-up for creatinine and creatinine clearance occurred because clearance not always measured with creatinine.
Methods’’ section. The constraints on the radiation doses absorbed by the kidneys within these studies were derived from the data from Emami et al. (3) and Stewart et al. (4). However, because no data were available for the sequence of sequential cisplatin, RT, and cisplatin, we assumed a lower tolerance than did those studies. Each patient underwent functional renal scintigraphy before chemoradiotherapy. However, only a few patients underwent this examination after the end of therapy, so it could not be used for recalculation. We, therefore, used the creatinine values and calculated creatinine clearance to measure the renal function during follow-up. Creatinine values were readily available for all patients. However, in many cases, the records of the study management center displayed only ‘‘normal’’ creatinine levels, without giving the exact number. In these cases, we used the upper normal laboratory range (i.e., 1.2 mg/dL) to calculate the creatinine clearance. It is important to note that this resulted in a worst-case calculation of renal function. The data concerning renal function after irradiation mostly come from the investigation of patients who had undergone total body irradiation (TBI). Igaki et al. (7) investigated 109 patients treated with TBI of 12 Gy at a dose rate of 5 Gy/ min. TBI was part of a conditioning regimen containing predominantly busulfan and cyclophosphamide. Renal shielding limited the renal dose to 10 Gy in 39 patients. The investiga-
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tors found a renal dysfunction-free rate of 78.5% without shielding and 100% if the renal dose was restricted to 10 Gy. van Kleef et al. (8) found only mild morphologic renal damage after TBI with single doses or two fractions in rhesus monkeys after 6 to 8 years of follow-up. The dose needed for morphologic changes was equivalent to 12–13 Gy (assuming an a/b ratio of 6 to 8 Gy [9]) or 19 Gy (assuming an a/b ratio of 2.5 [10]) with conventionally fractionated RT. Lawton et al. (11) investigated renal dysfunction after TBI in 72 patients who had received 14 Gy in nine fractions (1.5 Gy/fraction). Renal shielding had limited the absorbed doses to 14, 11.9, and 9.8 Gy. After 2.5 years, 29.4%, 14.1%, and 0% of all patients had measurable renal dysfunction, indicating that the renal dose should be restricted to 10 Gy in this setting. Miralbell et al. (12) obtained similar results with TBI doses of 19, 12, and 13.5 Gy, which yielded a renal dysfunction-free rate of 95%, 74%, and 55%, respectively, after 18 months. These data clearly indicate a dose dependency for renal damage after RT and suggest a dose of 10 Gy to the whole functional renal volume to be entirely safe. Doses of 12–19 Gy (dependent on the assumed a/b ratio) result in minor renal toxicity. When an enhancement ratio of 1.2–1.4 (4) for the addition of cisplatin is taken into account, a safe dose for the irradiation of the whole functional volume of the kidneys should be in the range of 7–16 Gy. According to the data of Emami et al. (3) with a 5% risk at 5 years of 23 Gy, one would not expect these doses to cause renal damage. The answer could be that the TBI patients received additional nephrotoxic chemotherapy during conditioning and nephrotoxic cyclosporine as maintenance, as well as nephrotoxic antibiotics in the case of infection. In our study population, a maximal irradiated volume of 37.5% of the functional renal volume was allowed to be irradiated with #12 Gy. Because a dose–volume relationship is not known, the aim of this study was to investigate whether these constraints would really yield no significant renal toxicity. At a median renal absorbed dose of 9.9 Gy (range, 2.5– 24.1) and constraints of #12 Gy to 37.5% of the functional volume of both kidneys, no measurable deterioration in renal function was detected. In 11% of all patients, the dose constraints to the kidneys could not be kept. These patients received 12 Gy to 64%, 68%, and 87% of their functional renal volume. However, no renal damage was observed in this small subgroup of patients at a corresponding followup of 24, 16, and 21 months. The same was true for a highrisk subgroup of patients who received >12 Gy to >50% of the functional renal volume. Furthermore, our calculated results represent a worst-case scenario, with the true impairment of renal function as measured by creatinine/urea or creatinine clearance being smaller than shown in our results (Fig. 4). Therefore, it can be concluded that our restrictions in the setting with sequential 200 mg/m2 cisplatin and RT were entirely safe. We were unable to show any dose dependency for renal damage with an absorbed dose per functional volume in the tested dose range, indicating that we were still below the
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critical dose range even with the combination of sequential administration of a cumulative cisplatin dose of approximately 200 mg/m2. CONCLUSIONS The dose restriction of 12 Gy to 37.5% of the functional renal volume in addition to two cycles of full-dose sequential chemotherapy with cisplatin in adjuvant chemoradiotherapy for gastric cancer in this study yielded no relevant renal toxicity after 2 years of follow-up. Our results must be confirmed
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with longer follow-up. The morphologic equivalent of radiation nephropathy are glomerular lesions resulting from alteration of capillary tissue as late effects (10, 13), which were found to be dose dependent in animal studies. Because no recovery from induced damage can occur and even slow progression with time is assumed (10), a median follow-up of 2 years is too short to draw final conclusions. However, the absence of significant renal toxicity observed at 2 years is reassuring for the use of this aggressive multimodal therapeutic approach against gastric cancer.
REFERENCES 1. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730. 2. Kollmannsberger C, Budach W, Stahl M, et al. Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: Two cooperative phase II studies of the AIO/ARO/ACO. Ann Oncol 2005;16:1326–1333. 3. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21: 109–122. 4. Stewart FA, Oussoren Y, Bartelink H. The influence of cisplatin on the response of mouse kidneys to multifraction irradiation. Radiother Oncol 1989;15:93–102. 5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. 6. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863. 7. Igaki H, Karasawa K, Sakamaki H, et al. Renal dysfunction after total-body irradiation: Significance of selective renal shielding blocks. Strahlenther Onkol 2005;181:704–708.
8. van Kleef EM, Zurcher C, Oussoren YG, et al. Long-term effects of total-body irradiation on the kidney of rhesus monkeys. Int J Radiat Biol 2000;76:641–648. 9. Safwat A, Bentzen SM, Nielsen OS, et al. Time-course of the hazard of murine nephropathy induced by total-body irradiation. Int J Radiat Biol 2000;76:979–983. 10. Trott KR, Herrmann T, Do¨rr W. Strahlenwirkung auf Normalgewebe. Munich: Urban and Vogel; 2002. p. 53–55. 11. Lawton CA, Cohen EP, Murray KJ, et al. Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 1997;20:1069–1074. 12. Miralbell R, Sancho G, Bieri S, et al. Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: A prospective assessment. Int J Radiat Oncol Biol Phys 2004;58: 809–816. 13. Down JD, Berman AJ, Warhol M, et al. Late complications following total-body irradiation and bone marrow rescue in mice: Predominance of glomerular nephropathy and hemolytic anemia. Int J Radiat Biol 1990;57:551–565.
doi:10.1016/j.ijrobp.2007.05.021
CLINICAL INVESTIGATION
Stomach
RENAL TOXICITY OF ADJUVANT CHEMORADIOTHERAPY WITH CISPLATIN IN GASTRIC CANCER STEFAN WELZ, M.D.,* THOMAS HEHR, M.D.,*x CHRISTIAN KOLLMANNSBERGER, M.D.,y CARSTEN BOKEMEYER, M.D.,z CLAUS BELKA, M.D.,x AND WILFRIED BUDACH, M.D.* * Heinrich-Heine-University of Du¨sseldorf, Du¨sseldorf, Germany; y University of British Columbia, Vancouver, British Columbia, Canada; z University of Hamburg-Eppendorf, Hamburg, Germany; and x Eberhard-Karls-University of Tu¨bingen, Tu¨bingen, Germany Purpose: Adjuvant, 5-fluorouracil (5-FU)–based chemoradiotherapy for completely resected high-risk gastric adenocarcinoma has been shown to improve survival in a randomized Intergroup trial. However, the results still showed an unsatisfactory outcome. On the basis of previously reported results of a Phase II trial using a more aggressive, cisplatin-containing chemoradiotherapy schedule, we investigated the effects of this approach on long-term renal function. Patients and Methods: Between December 2000 and September 2003, 27 patients were treated at Tu¨bingen University in a Phase II multicenter trial investigating adjuvant chemoradiotherapy. The adjuvant chemoradiotherapy consisted of two cycles of adjuvant 5-FU, folinic acid, cisplatin (200 mg/m2), and paclitaxel before and after radiotherapy (45 Gy in 1.8-Gy fractions) with daily concomitant 5-FU (225 mg/m2/24 h). A dose constraint of #12 Gy for 37.5% of the functional volume of both kidneys was used. Renal function was assessed by the changes in creatinine and creatinine clearance during follow-up. Results: The prescribed 45 Gy was administered to 100% of the patients, and the cumulative cisplatin dose was 200 mg/m2 in 74% of all patients. In 89%, the constraints concerning the renal absorbed doses were met. The median follow-up for the creatinine and clearance values was 30 and 26 months, respectively. The creatinine values tended to worsen over time without reaching critical levels. We were unable to demonstrate a significant dose–response relationship for renal damage in the tested dose range. Conclusions: Using a dose constraint of #12 Gy for 37.5% of the functional volume of both kidneys appears to be safe at a median follow-up of 2 years for a cumulative cisplatin dose of 200 mg/m2 administered before and after simultaneous 5-FU and radiotherapy. Ó 2007 Elsevier Inc. Radiotherapy, Cisplatin, Gastric cancer, Toxicity, Renal.
results seem mostly to have resulted from improved local control, because the rate of distant metastases remained high. Therefore, more aggressive chemotherapy regimens before and after radiochemotherapy have been used in recent studies. A cooperative German Phase II study, using a different chemotherapy regimen but an identical chemoradiotherapy approach (45 Gy plus folinic acid and 24-h infusion of 5-FU), was performed by the Arbeitsgemeinschaft Internistische Onkologie/Arbeitsgruppe Radiologische Onkologie/Arbeitsgemeinschaft Chirurgische Onkologie (AIO/ARO/ACO). The results have already been published, with a projected 2-year progression-free survival rate of 61–64% and an acceptable toxicity profile (2). The study used 5-FU, folinic acid, paclitaxel, and cisplatin before and after the application of radiochemotherapy with concomitant 5-FU infusion.
INTRODUCTION The only possibility of curing gastric cancer is complete (R0) surgical resection, including D1 or D2 lymphadenectomy. However, even if complete resection can be achieved, most patients with locally advanced disease will eventually develop a relapse. The recurrent disease will be distant and locoregional, highlighting the need for adjuvant therapy addressing subclinical metastatic disease, as well as any remaining tumor cells at the primary tumor site. The Intergroup Study 0116 used an adjuvant chemoradiotherapy protocol with 45 Gy combined with folinic acid and a 24-h infusion of 5-fluorouracil (5-FU) (Mayo protocol) after R0 resection and was able to demonstrate significant improvement in the progression-free and overall survival rate after 3 years of 17% and 9%, respectively (1). However, these
Conflict of interest: none. Received April 13, 2007, and in revised form May 11, 2007. Accepted for publication May 11, 2007.
Reprint requests to: Stefan Welz, M.D., Department of Radiation Oncology, Eberhard-Karls-University of Tu¨bingen, Hoppe-Seyler Str. 3, Tu¨bingen D-72076 Germany. Tel: (00) 410-7071-2984854; Fax: (00) 410-7071-298-6052; E-mail: stefan.welz@med. uni-tuebingen.de 1429
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Because at least partial volume irradiation of the kidneys cannot be avoided with adjuvant radiotherapy (RT) in gastric carcinoma, concern exists that the additional use of nephrotoxic drugs such as cisplatin could lead to irreversible, symptomatic renal toxicity. However, few clinical data about the toxic potential of this combination are available. For RT alone, assumptions on the radiation doses tolerated by the kidneys mention a 5% risk at 5 years of 23 Gy to 100% of the kidney volume and 30 Gy to 66% of the kidney volume (3). Experimental studies have shown an additive toxicity of fractionated RT and cisplatin on mouse kidneys with an enhancement factor of 1.2–1.4 (4). To date, these are the only available data on the renal tolerance of this sequential chemoradiotherapy regimen. On the basis of these data, dose restrictions for the kidneys with adjuvant RT in the AIO/ARO/ACO study were prescribed. To comply with these restrictions, special beam arrangements were necessary. We evaluated the renal toxicity of this adjuvant treatment with a cisplatin-containing chemotherapy regimen and sequential RT in the patients treated within the AIO/ARO/ ACO study at the University Hospital Tu¨bingen.
PATIENTS AND METHODS Between December 2000 and September 2003, 27 patients with gastric cancer were treated within a Phase II multicenter protocol of the AIO/ARO/ACO (2) at Tu¨bingen University. All 27 patients underwent evaluation of post-treatment renal toxicity. The local ethics committee of Tu¨bingen University approved the study protocol, which was in accordance with the Helsinki Declaration of 1975.
Patients The eligibility criteria were complete (R0) or microscopically incomplete (R1) resection of histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction; Stage II-IV disease according to the International Union Against Cancer (1997); Eastern Cooperative Oncology Group performance status of 0–2; age 18–65 years; adequate hematologic, renal, and hepatic function (hemogram with normal limits, bilirubin concentration not exceeding twice the normal upper limit, creatinine clearance $60 mL/min); and written informed consent. The start of adjuvant treatment had to be within 6 weeks after surgery. The exclusion criteria were severe concurrent, insufficiently treated diseases such as heart, renal, or hepatic failure, acute infection, previous chemotherapy, and a second malignant disease, with the exception of basal cell carcinoma or carcinoma in situ of the cervix. All patients underwent computed tomography of the chest and abdomen, a complete physical examination, complete blood count, serum chemistry, creatinine clearance determination, electrocardiography, and an audiogram. Before RT, renal scintigraphy with technetium-99m-mercaptoacetyltriglycine was required to allow for modification of the beam arrangements if significant difference in function was found between the two kidneys and to allow for accordance with the dose constraints, described below.
Treatment The treatment schedule is detailed in Fig. 1.
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Chemotherapy. All patients had a permanent venous access implanted and, therefore, could be treated on an outpatient basis. Dose reductions were applied if toxicity (Common Toxicity Criteria) of Grade 2 or more occurred. One cycle of 5-fluorouracil, leucovorin (folinic acid), cisplatin, and paclitaxel consisted of a 2-h infusion of 500 mg/m2 folinic acid followed by a 24-h continuous infusion of 2,000 mg/m2 5-FU on Days 1, 8, 15, 22, 29, and 36. Paclitaxel was given as a 3-h infusion of 175 mg/m2 on Days 1 and 22. Cisplatin was administered at a dose of 50 mg/m2 within 1 h on Days 8 and 29. All patients received dexamethasone and ranitidine, as well as diphenhydramine, as premedication to paclitaxel. Adequate hydration was administered in combination with the cisplatin. Chemoradiotherapy. Radiotherapy was administered in 25 fractions with 1.8-Gy/d, resulting in an overall treatment time of 5 weeks and a total dose of 45 Gy. Patients received concomitant 5-FU as a continuous 24-h infusion on all RT days in a dosage of 225 mg/m2. An oral 5-HT3 antagonist was recommended during chemotherapy. Patients with residual gastric tissue received a proton pump inhibitor. Radiotherapy was administered with linear accelerators using 15-MV photons after three-dimensional planning according to International Commission on Radiation Units and Measurements Reports 50 and 62. The clinical target volume (CTV) included the regional (perigastric, celiac axis, prevertebral, para-aortic, hepatoduodenal, and pancreaticoduodenal, including the splenic and hepatic hilus) lymph nodes, the anastomosis region, and a minimal 4-cm safety margin in respect to the formerly involved mucosal site. If a proximal T3 tumor was treated, the CTV also encompassed the medial part of the diaphragm. In the case of involvement of the gastroesophageal junction, a 5-cm safety margin in this direction, as well as the inclusion of the paraesophageal lymph nodes in the CTV, was used. For distally localized tumors, the safety margin was 5 cm in the aboral direction. The planning target volume (PTV) included the CTV with an additional 12-mm margin in every direction. Both kidneys and the liver, heart, and spinal cord were considered organs at risk and had the following dose/volume restrictions: kidneys, #12 Gy to <37.5% of the functional volume for both kidneys using functional scintigraphy for calculation; liver, <30 Gy to <60% of the liver volume; heart, <40 Gy to <30% of the volume defined by the outline of both ventricles; and spinal cord, <47.5 Gy (single dose <1.9 Gy). The kidneys were contoured, excluding the renal pelvis. RT planning was done using one computed tomography scan with normal breathing and without correction for breathing-induced kidney movement. Whenever the dose constraints were met, an anteroposterior–posteroanterior technique was chosen. In the case of violation of these constraints, more complex beam arrangements were used. An example of a five-beam plan with a cranial and caudal half-beam-arrangement is shown in Fig. 2. If the prescribed dose to the PTV still caused a violation of these restrictions, the CTV was reduced in favor of the organs at risk.
Endpoints and follow-up The endpoints for the assessment of renal function were the changes in the urea, creatinine, and creatinine clearance values and clinical signs of nephrotoxicity such as anemia or arterial hypertension. The calculation of creatinine clearance was done according to the formula of Cockcroft and Gault (5): creatinine clearance ¼ ½ð140 ageÞ weight=72 serum creatinine, with age in years, weight in kilograms, and serum creatinine in milligrams per deciliter. The results were adjusted for body surface area and female gender (6)—adjustment for body surface area: creatinine
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Fig. 1. Study design. FLPP = 5-fluorouracil, leucovorin (folinic acid), cisplatin, paclitaxel; CHX = chemotherapy; RTCHX = chemoradiotherapy. clearance 1:73=body surface area ðin meters squaredÞ; and adjustment for female gender: creatinine clearance 0:85. During follow-up, the data for 14 patients only showed that the serum creatinine level was ‘‘normal,’’ meaning within the normal laboratory range. We, therefore, calculated clearance according to the above-mentioned formula using the upper laboratory range value (1.2 mg/dL) for creatinine when the exact value was unknown.
Follow-up examinations were done at 3-month intervals for 2 years followed by 6-month visits for another 3 years, and yearly thereafter.
Statistical analysis Statistical analysis was done using Statistical Analysis Systems software (Statistica) for uni- and multivariate analysis.
Fig. 2. Example of radiotherapy plan with (a) cranial (three beams) and (b) caudal (two beams) half beams. Corresponding dose–volume histogram for (c) left and (d) right kidney.
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Table 1. Patient characteristics
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A total of 27 evaluable patients were treated within these studies at Tu¨bingen University Hospital. The median age was 50 years (range, 25–66). All patients received the prescribed radiation dose, but 26% received less than the intended cisplatin dose. Additional information on patient characteristics is given in Table 1. To encompass the primary tumor region, as well as the adjacent lymphatic tissue, and to meet the dose constraints for the liver, spinal cord, and kidneys, it was necessary to apply more complex beam arrangements than anteroposterior– posteroanterior beams in about two-thirds of all patients.
However, even with these techniques (Fig. 2) and with moderate reductions of the PTV in favor of the organs at risk when necessary, in 11% of patients, the dose to the kidneys exceeded the recommended dose–volume histogram restrictions. Figure 2 displays an example of a beam arrangement and the resulting absorbed doses of both kidneys. Figure 3 shows the distribution of the absorbed dose per kidney volume for all patients. All creatinine values were normal (i.e., lower than the upper laboratory range of 1.2 mg/dL) before the start of adjuvant therapy. Patients with unilateral renal function impairment were excluded from the study. Figure 4 displays the creatinine values from the start of therapy to the longest available followup examination in absolute values, and Fig. 5 illustrates the change in creatinine (delta) with the months of follow-up. Whenever the creatinine value obtained from the study management center could only be classified as ‘‘normal,’’ we assumed the worst possible case (i.e., a value of 1.2 mg/dL). For the creatinine and creatinine clearance values, 37% and 41% of all patients were at risk of not reaching the 2 years of follow-up. Most patients experienced a slight increase in creatinine, but only one had a value that was greater than the upper laboratory range. Almost all patients had a decreased calculated creatinine clearance value at the longest available follow-up point. The worst outcome was a reduction of about 50%. The same tendency was true for the urea values (data not shown). We defined a high-risk group of patients (n = 10) who received a dose of >12 Gy to >50% (median, 59%; range, 54– 87%) of the functional renal volume. The median absorbed renal dose in this subgroup was 12.8 Gy. All but 1 patient (95%) received 100% of the intended cisplatin dose. The patients in this group are indicated separately in Figs. 4 and 5. The results for this subgroup with a follow-up period for the clearance and creatinine values of 24 and 26 months,
Fig. 3. Dose distribution of both kidneys indicating volume cluster of kidneys receiving dose of >12, >15, >18, or >22.5 Gy in which percentage of patients.
Fig. 4. Change in creatinine values before therapy and at longest available follow-up point. Many latter values were worst-case assumptions (see text). Bold lines and large icons indicate high-risk group.
Characteristic
Value
Gender (n) Male Female Age (y) Median Range Radiation dose (ICRU 50/62) (Gy) Stage (UICC 1997) (%) II III IV Gastric adenocarcinoma (%) Pathologic grade (%) G2 G3 Complete resection (%)
21 6 50 25–66 45 37 30 33 100 15 85 96
Abbreviations: ICRU 50/62 = International Commission on Radiation Units and Measurements Reports 50 and 62; UICC = International Union Against Cancer.
RESULTS
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Fig. 5. Difference between creatinine values before therapy and at longest available follow-up point (delta). Circles indicate high-risk group.
respectively, were not significantly different from those of the whole population. Univariate analysis considering the change in creatinine and creatinine clearance over time compared with the volume of the kidneys irradiated showed no significant dose– volume relationship in the tested dose range. No patient had signs of clinically relevant nephrotoxicity, including arterial hypertension or nephritis. DISCUSSION For patients with high-risk, completely resected gastric cancer, adjuvant chemoradiotherapy has been shown to significantly improve overall survival in a randomized trial (1). However, the high rate of distant metastases still needs to be addressed further. In this regard, new chemotherapy regimens have been introduced, which included the use of drugs such as the nephrotoxic cisplatin, which has been shown to be effective against this disease (2). Adjuvant RT in gastric cancer targets the area in which the stomach itself was located with the primary tumor site, as well as the locoregional lymphatic pathways along both former curvatures, the splenic hilus, liver hilus, and pancreaticoduodenal lymphatic area. The boundaries of the resulting, complex-shaped CTV are usually in direct contact with the surface of both kidneys, on the left side to a greater extent than on the right. Setup errors and breathing-induced organ motion require margins between the CTV and PTV of $1 cm in the axial and $1.5 cm in the craniocaudal direction. In most cases, a substantial overlap of the PTV and kidney
volumes is the result. Hence, it is inevitable, even if one uses optimized three-dimensional planning or intensitymodulated RT, to irradiate large parts of the kidneys with a considerable dose (Table 2). The effect of RT on renal function was reviewed by Emami et al. (3), who made assumptions concerning the doses tolerated by the kidneys according to retrospective patient data. Their conclusion was that the 5% risk at 5 years (for nephritis) is 23 Gy and the 50% risk at 5 years is 28 Gy for irradiation of the whole kidney. On the basis of these data, constraints on the absorbed doses by the kidneys were defined. Because the kidney is an organ with a parallel functional structure, the assessment of the effects of partial volume irradiation is difficult. Even less is known about the renal toxicity of the combined approach of sequential cisplatin chemotherapy and RT on renal toxicity. Data from an animal model study, which investigated the influence of cisplatin on mouse kidneys exposed to multifractionated irradiation (4), suggested additive toxicity with the two nephrotoxic treatments. The investigators calculated an enhancement factor of 1.2–1.4 for the addition of cisplatin to fractionated irradiation. They also found that renal tolerance was dependent on the sequence of RT and chemotherapy. The administration of cisplatin before RT yielded a greater tolerance dose for RT than when cisplatin was administered after RT. However, in the protocol used in the present study, cisplatin was a part of the chemotherapy regimens both before and after RT (Fig. 1). The patients described in our study were treated in the AIO/ARO/ACO protocol (2), detailed in the ‘‘Patients and
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Table 2. Radiotherapy/chemotherapy parameters Parameter
Value
Patients receiving 45-Gy RT (%) Median PTV (cm3) Median no. of beams used Patients receiving beam no. and configuration (%) Two AP–PA Angled AP–PA AP–lateral Three (AP–lateral opposing) Four or more Patients with median absorbed dose for both kidneys (%) >12 Gy >15 Gy >18 Gy >22.5 Gy Accordance with renal constraints* (%) 5-FU chemotherapy during RT (%) Cisplatin dose received (%) 100 $75 Median follow-upy (mo) Creatinine Creatinine clearance
100 1,326 (670–2,477) 3 (2–5)
37 4 7 19 33 44 (19–87) 39 (14–61) 32 (12–56) 25 (5–55) 89 100 74 100 30 (13–55) 26 (6–56)
Abbreviations: RT = radiotherapy; PTV = planning target volume; AP = anteroposterior; PA = posteroanterior; FU = fluorouracil. Data in parentheses are ranges. * Renal constraints: #12 Gy to <37.5% of functional volume. y Difference in median follow-up for creatinine and creatinine clearance occurred because clearance not always measured with creatinine.
Methods’’ section. The constraints on the radiation doses absorbed by the kidneys within these studies were derived from the data from Emami et al. (3) and Stewart et al. (4). However, because no data were available for the sequence of sequential cisplatin, RT, and cisplatin, we assumed a lower tolerance than did those studies. Each patient underwent functional renal scintigraphy before chemoradiotherapy. However, only a few patients underwent this examination after the end of therapy, so it could not be used for recalculation. We, therefore, used the creatinine values and calculated creatinine clearance to measure the renal function during follow-up. Creatinine values were readily available for all patients. However, in many cases, the records of the study management center displayed only ‘‘normal’’ creatinine levels, without giving the exact number. In these cases, we used the upper normal laboratory range (i.e., 1.2 mg/dL) to calculate the creatinine clearance. It is important to note that this resulted in a worst-case calculation of renal function. The data concerning renal function after irradiation mostly come from the investigation of patients who had undergone total body irradiation (TBI). Igaki et al. (7) investigated 109 patients treated with TBI of 12 Gy at a dose rate of 5 Gy/ min. TBI was part of a conditioning regimen containing predominantly busulfan and cyclophosphamide. Renal shielding limited the renal dose to 10 Gy in 39 patients. The investiga-
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tors found a renal dysfunction-free rate of 78.5% without shielding and 100% if the renal dose was restricted to 10 Gy. van Kleef et al. (8) found only mild morphologic renal damage after TBI with single doses or two fractions in rhesus monkeys after 6 to 8 years of follow-up. The dose needed for morphologic changes was equivalent to 12–13 Gy (assuming an a/b ratio of 6 to 8 Gy [9]) or 19 Gy (assuming an a/b ratio of 2.5 [10]) with conventionally fractionated RT. Lawton et al. (11) investigated renal dysfunction after TBI in 72 patients who had received 14 Gy in nine fractions (1.5 Gy/fraction). Renal shielding had limited the absorbed doses to 14, 11.9, and 9.8 Gy. After 2.5 years, 29.4%, 14.1%, and 0% of all patients had measurable renal dysfunction, indicating that the renal dose should be restricted to 10 Gy in this setting. Miralbell et al. (12) obtained similar results with TBI doses of 19, 12, and 13.5 Gy, which yielded a renal dysfunction-free rate of 95%, 74%, and 55%, respectively, after 18 months. These data clearly indicate a dose dependency for renal damage after RT and suggest a dose of 10 Gy to the whole functional renal volume to be entirely safe. Doses of 12–19 Gy (dependent on the assumed a/b ratio) result in minor renal toxicity. When an enhancement ratio of 1.2–1.4 (4) for the addition of cisplatin is taken into account, a safe dose for the irradiation of the whole functional volume of the kidneys should be in the range of 7–16 Gy. According to the data of Emami et al. (3) with a 5% risk at 5 years of 23 Gy, one would not expect these doses to cause renal damage. The answer could be that the TBI patients received additional nephrotoxic chemotherapy during conditioning and nephrotoxic cyclosporine as maintenance, as well as nephrotoxic antibiotics in the case of infection. In our study population, a maximal irradiated volume of 37.5% of the functional renal volume was allowed to be irradiated with #12 Gy. Because a dose–volume relationship is not known, the aim of this study was to investigate whether these constraints would really yield no significant renal toxicity. At a median renal absorbed dose of 9.9 Gy (range, 2.5– 24.1) and constraints of #12 Gy to 37.5% of the functional volume of both kidneys, no measurable deterioration in renal function was detected. In 11% of all patients, the dose constraints to the kidneys could not be kept. These patients received 12 Gy to 64%, 68%, and 87% of their functional renal volume. However, no renal damage was observed in this small subgroup of patients at a corresponding followup of 24, 16, and 21 months. The same was true for a highrisk subgroup of patients who received >12 Gy to >50% of the functional renal volume. Furthermore, our calculated results represent a worst-case scenario, with the true impairment of renal function as measured by creatinine/urea or creatinine clearance being smaller than shown in our results (Fig. 4). Therefore, it can be concluded that our restrictions in the setting with sequential 200 mg/m2 cisplatin and RT were entirely safe. We were unable to show any dose dependency for renal damage with an absorbed dose per functional volume in the tested dose range, indicating that we were still below the
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critical dose range even with the combination of sequential administration of a cumulative cisplatin dose of approximately 200 mg/m2. CONCLUSIONS The dose restriction of 12 Gy to 37.5% of the functional renal volume in addition to two cycles of full-dose sequential chemotherapy with cisplatin in adjuvant chemoradiotherapy for gastric cancer in this study yielded no relevant renal toxicity after 2 years of follow-up. Our results must be confirmed
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with longer follow-up. The morphologic equivalent of radiation nephropathy are glomerular lesions resulting from alteration of capillary tissue as late effects (10, 13), which were found to be dose dependent in animal studies. Because no recovery from induced damage can occur and even slow progression with time is assumed (10), a median follow-up of 2 years is too short to draw final conclusions. However, the absence of significant renal toxicity observed at 2 years is reassuring for the use of this aggressive multimodal therapeutic approach against gastric cancer.
REFERENCES 1. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730. 2. Kollmannsberger C, Budach W, Stahl M, et al. Adjuvant chemoradiation using 5-fluorouracil/folinic acid/cisplatin with or without paclitaxel and radiation in patients with completely resected high-risk gastric cancer: Two cooperative phase II studies of the AIO/ARO/ACO. Ann Oncol 2005;16:1326–1333. 3. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21: 109–122. 4. Stewart FA, Oussoren Y, Bartelink H. The influence of cisplatin on the response of mouse kidneys to multifraction irradiation. Radiother Oncol 1989;15:93–102. 5. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. 6. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:863. 7. Igaki H, Karasawa K, Sakamaki H, et al. Renal dysfunction after total-body irradiation: Significance of selective renal shielding blocks. Strahlenther Onkol 2005;181:704–708.
8. van Kleef EM, Zurcher C, Oussoren YG, et al. Long-term effects of total-body irradiation on the kidney of rhesus monkeys. Int J Radiat Biol 2000;76:641–648. 9. Safwat A, Bentzen SM, Nielsen OS, et al. Time-course of the hazard of murine nephropathy induced by total-body irradiation. Int J Radiat Biol 2000;76:979–983. 10. Trott KR, Herrmann T, Do¨rr W. Strahlenwirkung auf Normalgewebe. Munich: Urban and Vogel; 2002. p. 53–55. 11. Lawton CA, Cohen EP, Murray KJ, et al. Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 1997;20:1069–1074. 12. Miralbell R, Sancho G, Bieri S, et al. Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: A prospective assessment. Int J Radiat Oncol Biol Phys 2004;58: 809–816. 13. Down JD, Berman AJ, Warhol M, et al. Late complications following total-body irradiation and bone marrow rescue in mice: Predominance of glomerular nephropathy and hemolytic anemia. Int J Radiat Biol 1990;57:551–565.