Long-term renal function after treatment for malignant germ-cell tumours

S. D. Fosså1,+, N. Aass1, M. Winderen2, O. P. Börmer3 and D. R. Olsen4

Departments of 1Medical Oncology and Radiotherapy, 2Nuclear Medicine and 4Medical Physics, and 3Central Laboratory, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway

Received 25 June 2001; revised 11 September 2001; accepted 19 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective

To evaluate prospectively renal function in patients with malignant germ-cell tumours (MGCTs) >10 years after retroperitoneal lymph node dissection alone (RPLND), radiotherapy alone (RAD) or different schedules of cisplatin-based chemotherapy with or without surgery/radiotherapy (CHEM).

Patients and methods

In 85 patients, three groups were identified: RPLND, 14; RAD, 18; CHEM, 53, with subdivision of the latter group according to the cumulative cisplatin dose or the additional use of radiotherapy. Renal function was determined by 131Iodine Hippuran clearance or 99m DTPA glomerular filtration rate, and was assessed before treatment and four times during 14 years of follow-up. A value of <70% of the upper limit of the normal range identified impaired renal function.

Results

Twenty-five patients displayed long-term impaired renal function, 23 of them from the RAD or CHEM group. In the RAD group, renal function decreased by 8%, whereas a 14% reduction of renal function was observed in the CHEM group. In the CHEM group the cumulative dose of cisplatin, and in the RAD group the age at treatment, were associated with impairment of renal function. Combining all patients, age at treatment and the type of treatment were associated with impaired renal function.

Conclusions

In 20–30% of the patients with germ-cell tumour, standard radiotherapy and chemotherapy strategies are followed by long-term subclinical impaired renal function. These findings support current intentions to avoid overtreatment with these treatment modalities.

Key words: long-term renal function, testicular cancer, treatment


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Modern multi-modality treatment of malignant germ-cell tumours (MGCT) cures ~90% of patients, most of them presenting with testicular cancer (TC). According to the prevailing opinion, these young men’s post-treatment life expectancy is comparable to that of age-matched males without cancer. There is, however, a growing understanding that treatment for TC may lead to long-term sequelae that not only decrease the individual patient’s quality of life, but also cause life-threatening somatic morbidity. Abdominal radiotherapy of TC may cause major dyspepsia or peptic ulcer in 2–10% of patients [1, 2] and increases the risk of specific types of second cancer (upper gastrointestinal tract, bladder) [3, 4]. Several reports have claimed a raised incidence of cardiovascular risk factors after cisplatin-based chemotherapy, such as obesity and hypercholesterolemia [57], besides the specific sequelae of the applied treatment: ‘dry ejaculation’ after retroperitoneal surgery, and ototoxicity, peripheral neuropathy and nephrotoxicity after cisplatin-based chemotherapy [710].

Almost all studies of renal function in TC patients have dealt with side-effects after cisplatin-based chemotherapy [79, 11]. Most of these investigations have demonstrated an association between renal damage and the cumulative dose of cisplatin resulting in a decreased glomerular filtration rate (GFR), and hypomagnesemia and hypophosphatemia due to tubular salt wasting [7, 11, 12] 3–5 years after chemotherapy. Petersen and Hansen [8] did not observe further decrease of GFR beyond 4 years in 22 patients examined >10 years after cisplatin-based chemotherapy. In a comparative prospective study, Aass et al. [11] showed that infradiafragmatic radiotherapy, either given alone or in addition with chemotherapy, may be nephrotoxic 3–5 years after treatment in patients treated at an age of >=40 years, an observation that is confirmed in part by the findings of Bokemeyer et al. [7]. In discussing these results, Boyer et al. [9] emphasize that these observations require long-term follow-up with regard to eventual recovery stabilisation or worsening of the renal function. Long-term observations of renal function after routine infradiafragmatic radiotherapy of TC are, however, lacking.

The present report deals with long-term observations obtained in patients from the study by Aass et al. [11], 13–15 years after treatment. The data were collected during 1998–2000 as part of a systematic long-term follow-up study of patients with GCT treated at the Norwegian Radium Hospital (NRH). Of particular interest were the questions of whether chemotherapy-related reduced kidney function would recover >5 years after treatment of TC, and whether routine radiotherapy for TC influenced renal function.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During the period 1984 to 1988, 171 patients with newly diagnosed MGCT were prospectively evaluated with regard to their renal function before and up to 5 years after treatment. In 1998, surviving cancer-free patients from this cohort were identified and invited to undergo a new evaluation of their renal function if they were <75 years old at the scheduled outpatient visit. Due to administrative regulations of the Norwegian health care system, only patients from Southern Norway could be included in this long-term follow-up study. Furthermore, patients were excluded from the present study if they had received additional chemotherapy after 1988.

Principle management of testicular cancer
After the histological diagnosis of MGCT, in all but one patient consisting of unilateral orchiectomy, the clinical stage was determined according to the Royal Marsden staging system [13]. The present study discriminates seminoma from non-seminoma. Patients with seminoma stage I, stage IIa or limited stage IIb had abdominal radiotherapy. In the 1980s the target dose to a so-called dog-leg field [1] was 36 Gy (stage I) or 40 Gy (stage II), the daily fraction being 2 Gy applied 5 days per week. Either the posterior or anterior field was treated daily. If more than one-third of a kidney was included in the target volume, shielding of the most lateral parts of the lumbar part of the target field was performed after 20 Gy using individually adjusted lead blocks. Patients with advanced stage IIb or stage III or higher seminoma received four cycles of cisplatin-based chemotherapy, initially as CVB cycles: cisplatin 20 mg/m2, days 1–5; vinblastin 0.10–0.15 mg/kg, days 1 and 2; bleomycin 30 mg, days 2, 9 and 16 (maximum dose 300 mg), followed by radiotherapy or surgery of initially tumour-bearing regions (consolidation treatment). From 1983 vinblastin was gradually replaced by VP16 (500 mg/m2 per cycle), resulting in the so-called BEP cycles (bleomycin, etoposide, cisplatin), and consolidation treatment was omitted from 1985 onwards. All cisplatin-based chemotherapy cycles were given at 3-week intervals. Patients with initial seminoma stage I and stage II who developed a recurrence after previous abdominal radiotherapy were treated with four cycles of cisplatin-based chemotherapy. Patients with non-seminoma clinical stage I and stage II a underwent retroperitonal lymph node dissection (RPLND) followed by three cycles of cisplatin-based chemotherapy in case of histologically confirmed lymph node metastases. Patients with clinical stage IIb or higher underwent four cycles of the above chemotherapy followed by resection of residual tumour manifestations, most often as RPLND. If malignant tissue was found in the post-chemotherapy operation specimen, the patient received a further two or three cycles of adjuvant chemotherapy, which could contain ifosfamide. From 1984 to 1987, patients with high-volume metastases were defined as ‘high-risk cases’ and had a high-dose cisplatin regimen [BEP 60: cisplatin 180 mg/m2, days 1–3; VP16 120 mg/m2, days 1–3; bleomycin 30 mg, days 1, 5 and 15 (maximum cumulative dose 300 mg)]. During the period of chemotherapy, hydration was closely monitored. Magnesium was substituted in case of hypomagnesemia (serum Mg <0.7mmol/l). Guidelines given to the individual patient and his family doctor and/or local hospital included the advice not to use any cytotoxic drugs during the period of chemotherapy.

For the purpose of the present study patients were allocated to five groups according to their treatment:

Group 1 (RPLND): patients with RPLND only.

Group 2 (RAD): patients whose treatment consisted of abdominal radiotherapy only.

Group 3 (CH <850): patients with chemotherapy only and a cumulative dose of cisplatin <850 mg, comparable to three or four cycles of cisplatin-based chemotherapy.

Group 4 (CH >=850): patients with chemotherapy only and with a cumulative dose of cisplatin >=850 mg.

Group 5 (CH-RAD): Patients who had both cisplatin-based chemotherapy and abdominal radiotherapy, the latter either prior or after chemotherapy.

For some analyses, groups 3, 4 or 5 were combined into a single chemotherapy (CHEM) group.

For nine patients in the RAD group, pre-treatment abdominal computed tomography (CT) scans were available together with the simulator images of the posterior/anterior fields and detailed documentation of the shielding procedures. Based on this information, dose volume histograms for the kidneys could be established. The median radiation doses to each of the kidneys could thus be estimated.

Assessment of renal function
Patients within the present study had their first assessment of renal function 2–3 weeks after orchiectomy/diagnosis before further treatment (‘pre-treatment’). Except for group 5, the second assessment was scheduled 3 months after discontinuation of all chemotherapy. Further determinations of renal function were to be performed, respectively 1 and 3–5 years after treatment, followed by the assessment during the years 1998–2000 (‘long-term’).

Before 1990, renal function was assessed by 131Iodine Hippuran clearance according to Pixberg and Just [14] or Oberhausen [15]. At the long-term follow-up the GFR (ml/min) was evaluated with 99mDTPA [99mTc-diaethyl-triamin-penta-acetic acid (DTPA); IFE, Kjeller, Norway] and blood samples [16]. Previous studies have shown that the results of Hippuran clearance are comparable to that of GFR if a correction factor of 0.20 is used [17]. Each patient’s renal function was recorded as the percentage of the upper limit of the normal range of renal function related to age, sex and body surface of the individual patient. As in the previous study [11], the lower limit of the normal range was set to 70% of this value, which is in agreement with the lower limits of the normal ranges for the used methods. ‘Normal’ renal function was >=70%, whereas patients with renal function <70% were considered to have impaired renal function. In addition, the difference between the pre-treatment and long-term assessment of renal function was calculated for each patient (RFdiff).

In 1984 determination of serum magnesium (Mg) was not carried out routinely in all patients with MGCT. All patients in the long-term study had serum Mg and creatinine levels determined. In the 1984–1988 period, serum creatinine was measured by a modified Jaffe’s method on a Technicon SMA 6/60 analyser, while Mg was measured by atomic absorption spectrophotometry. During the long-term follow-up study, both parameters were measured with a Vitros 950 Chemistry System (Johnson & Johnson Clinical Diagnostics, Rochester, NY). Long-term comparability of results has been ensured by continuous participation in external quality assurance programs.

Statistics
Descriptive statistics [median, range, mean, standard deviation (SD)] were performed by the program SPSS, version 9.0. Differences of categorical parameters were assessed by the {chi}2 test or the Fisher’s exact probability test. Differences between treatment groups were assessed by ANOVA (with Bonferroni correction for multiple testing). Differences between time-dependent continuous variables within each group were evaluated by a general linear model (repeated measurements), or by a paired t-test for comparison of the first and last assessment of renal function. Parameters that displayed significance at the level of <0.1 in the univariate analysis were included in a logistic regression analysis, the dependent parameter being renal function (normal versus impaired). A P value <0.05 was regarded as statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 85 patients from the previous prospective study had an assessment of their long-term GFR during 1998–2000 after a median observation time since diagnosis of 14 years (Table 1). Patients from group 5 were significantly older than the other groups both at diagnosis and at long-term follow-up (P = 0.05). Six of the patients from group 4 had received ifosfamide, and BEP 60 chemotherapy had been given to three patients from the same group. The pre-treatment mean renal function was similar in all five groups (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 1. Patient demographics
 

View this table:
[in this window]
[in a new window]
 
Table 2. Renal function before treatment and at long-term follow-up
 
At the long-term assessment, patients from groups 4 and 5 had significantly lower renal function values than those from group 1 (P = 0.03 and P = 0.003, respectively) with no difference between groups 1, 2 and 3. ANOVA also revealed a significant difference in long-term renal function between the RPLND group and the CHEM group (P = 0.004). The number of patients with impaired renal function increased from 10 at diagnosis to 25 at the long-term follow-up. A total of 11 of 53 patients from the CHEM group developed impaired renal function as compared with four of 32 patients without chemotherapy (P = 0.02). For patients from groups 3 and 4, the cumulative dose of cisplatin was associated with RFdiff (Figure 1A; R = 0.35, P = 0.02).




View larger version (33K):
[in this window]
[in a new window]
 
Figure 1. (A) Reduction in renal function (%) and cumulative dose of cisplatin (mg) in patients receiving cisplatin-based chemotherapy with or without surgery (without radiotherapy) (R = 0.35). (B) Age at treatment start in patients receiving radiotherapy only (R = 0.54).

 
There was also a tendency towards reduced long-term renal function in the RAD group as compared with the RPLND group (P = 0.09). The analysis of the dose volume histograms revealed that in five of the nine evaluable patients, median doses of 3–4 Gy were given to the kidneys (Table 3). Two patients had renal radiation doses of >8 Gy, the kidneys of the remaining patient receiving 5.3 Gy. No statistically significant association was observed between the renal radiation dose and the development of impaired renal function. However, the two oldest patients (numbers 265 and 2232) developed impaired renal function after their radiotherapy, whereas the renal function was normal in all nine patients before treatment. This observation is in agreement with the result of the correlation analysis: in the RAD group, age at treatment was significantly associated with RFdiff (Figure 1B; R = 0.54, P = 0.02).


View this table:
[in this window]
[in a new window]
 
Table 3. Age, renal radiation dose and long-term renal function
 
Figure 2 displays in detail the development of changes in renal function for the five treatment groups (Figure 2A) and for the three groups, if groups 3–5 are combined (Figure 2B). In the RPLND group, no significant change in the pre-treatment renal function was observed during the years of follow-up. The limited number of patients in groups 4 and 5 prevents definite statements, but the relevant curves in Figure 2A do not reveal major recovery. For patients from the three chemotherapy groups combined, a significant decrease in kidney function at long-term follow-up was demonstrated (mean 14%). For the CHEM group, the mean renal function was found to already be impaired 3 months after chemotherapy, without significant recovery or further impairment thereafter. In the RAD group, the mean RFdiff was 8%, with an almost significant reduction between the pre-treatment and long-term assessment (P = 0.08). In fact, similar figures for long-term renal function were observed for the CHEM group and the RAD group. In contrast to the observations from the chemotherapy groups, the reduction in renal function in the RAD group developed gradually, and first became detectable 3–5 years after treatment. Thereafter, no further decrease in renal function was seen.




View larger version (41K):
[in this window]
[in a new window]
 
Figure 2. Renal function and post-orchiectomy treatment: long-term results (number of patients within each group). (A) Five treatment modalities: RPLND, retroperitoneal surgery only; RAD, infradiagragmatic radiotherapy only; CH <850, cisplatin-based chemotherapy with or without surgery (cumulative dose of cisplatin <850 mg); CH >=850, as CH <850, but cumulative dose of cisplatin >=850 mg; CH-RAD, cisplatin-based chemotherapy with radiotherapy with or without surgery. (B) Three treatment modalities: CHEM, cisplatin-based chemotherapy with or without surgery and with or without radiotherapy.

 
The mean serum Mg level was similar at long-term assessment in all groups. One patient in the RPLND group and two patients in CH <850 group had Mg levels below the normal range.

In the multivariate analysis, long-term impairment of renal function was predicted by age at treatment and type of treatment (Table 4).


View this table:
[in this window]
[in a new window]
 
Table 4. Multivariate analysis: prediction of long-term impaired renal function
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twelve to 17 years after cisplatin-based chemotherapy for MGCT renal function is significantly reduced, by a mean of 14%, related to the cumulative dose of cisplatin. After infradiafragmatic radiotherapy a tendency towards reduced renal function was observed (P = 0.08), dependent on the age of the patient at treatment.

In the present study two principally different methods for the evaluation of renal function were used, due to the change of the techniques in the laboratory during the 15 years of follow-up. While Hippuran clearance primarily assesses tubular function, GFR mainly detects glomerular dysfunction. Although previous studies from our laboratory have proven comparability of the two methods [16, 17], this change of methods favoured reporting of our patients’ renal function by relative figures (percentages) rather than absolute values (ml/min), as is usually done. Of particular importance for the present results is the fact that an individual patient’s renal function is estimated while taking into account the patient’s age, thus compensating for age-related decrease in renal function. The validity and reliability of our evaluations of renal function are supported by the measurements in the RPLND group: as expected, no reduction in renal function was observed at long-term follow-up. This group therefore represented a control cohort.

Our study confirms previous observations that cisplatin-based chemotherapy leads to decrease in renal function, with the lowest renal function values obtained immediately after treatment, and with no or only slight recovery during the first 3–5 years [7, 8, 10]. Thereafter, no further improvement takes place. Even after >10 years the mean values of renal function remain decreased compared with the pre-treatment situation. Our mean decrease in renal function of 14% confirms the observation of Osanto et al. [10], who reported a 15% reduction of creatinine clearance after five cycles of cisplatin-based chemotherapy. Our percentage of patients with impaired renal function after chemotherapy (14%) is in agreement with the range of 20–30% reported by Kollmannsberger et al. [18], considering that 19 of our 53 patients had high cumulative cisplatin doses or had also received radiotherapy.

Hypomagnesemia is a frequent finding during and immediately after cisplatin-based chemotherapy, and was also evident in 15 of 19 evaluable patients during the first year after chemotherapy (data not shown). Persisting low Mg levels have been reported repeatedly [7]. Huddart et al. [19] found, for ex-ample, low serum Mg levels in their patients examined ~10 years after treatment. Low Mg levels after cisplatin-based chemotherapy have been associated with Raynaud phenomena, long-lasting polyneuropathy and an increased risk of myocardiac infarction. Our finding of normal post-chemotherapy serum Mg levels in the vast majority of patients are in contrast to the above observations. As loss of Mg and other electrolytes is thought to mirror a tubular dysfunction (reduced re-absorption), our finding of normalisation of Mg values thus indicates the tubular epitelium’s ability to recover.

The pathogenesis of persisting cisplatin-related nephrotoxicity remains unclear. As expected, renal function impairment is most pronounced if high doses of cisplatin are given or if chemotherapy is combined with radiotherapy. Most investigators have described an association of the post-treatment renal function with the cumulative dose of cisplatin [7, 12].

The concentration of cisplatin during the days of chemotherapy has also been discussed as a predictor of the development of reduced renal function. Except for the three patients with high-dose BEP in group 4, the serum concentrations of cisplatin during the days of chemotherapy were probably very similar in our patients whose hydration was carefully monitored during the 5–7 days of hospitalisation when chemotherapy was applied. Particularly intensive hydration regimens have been used in our patients receiving BEP 60. Under these clinical conditions the cumulative dose rather than the serum concentration of cisplatin seems to be responsible for the reduction of renal function in TC patients. If the standard dose of cisplatin (100 mg/m2) is given over 2 days, as suggested by the results of a recently published large trial [20], renal function may become more impaired, even though only three chemotherapy cycles are applied. Long-term effects of continuously elevated serum concentrations of cisplatin [21] may also, over years, reduce renal function. In this regard, clinicians should be aware that serum levels of creatinine do not sufficiently mirror the changes in renal function, as demonstrated by previous reports [7, 10, 11] and also in the present study.

Radiotherapy for early seminoma was given as two opposing infradiaphragmatic target fields, which were considered standard in the 1980s. The upper part of the target field (from the XI thoracic vertebra to the first sacral vertebra) covers the median parts of the kidneys. Such adjuvant radiotherapy is usually considered to be without severe sequelae, although the target dose of 36 Gy for stage I seminoma may today be regarded as too high. However, larger prospective studies of the long-term human renal function after radiotherapy for stage I seminoma are so far lacking. Bokemeyer et al. [7] suggested that abdominal radiotherapy may add to cisplatin-induced nephrotoxicity, an observation that is confirmed in the present study. Using the above-described shielding policy of renal tissue, between 30% and 50% of each kidney could have been irradiated by 20 Gy and up to one-third of the renal tissue would have received at least 36 Gy. According to Markoe et al. [22], the tolerability of renal tissue for fractionated radiation to the whole kidney is 20–23 Gy. This is comparable to a single fraction irradiation of 8 Gy. But even after such low doses, long-term studies in primates have shown reduction of hematocrit and increase of creatinine per body weight comparable to decreased renal function [23]. Studies in patients with abdominal irradiation due to gynecologial tumours have also shown subclinical impairment of the renal function after doses of <20 Gy to the kidneys [24]. Our data indicate that subclinical renal dysfunction may develop even though only minor volumes of the kidneys are exposed to fractionated radiation doses of <20 Gy. As also described by Dewit et al. [25], the post-radiotherapy decrease in renal function develops gradually, and becomes detectable after 3–5 years, in agreement with late small vessel sclerosis as one possible cause for renal function impairment. Markoe et al. [22] did not observe a dose–effect relationship in their animal experiments. This is in agreement with our observations: more than the actual radiation dose received by the renal tissue, the age of the patient at treatment seems to determine the final reduction of the renal function, high age possibly impairing post-treatment recovery. The importance of age at treatment for post-irradiation impairment of renal function has also been emphasised by Irwin et al. [26] using a dose of <20 Gy. Furthermore, due to limited radiotherapy resources, only one field was exposed daily. This sub-optimal irradiation schedule may have contributed to increased renal tissue toxicity in our RAD group.

Our results on post-irradiation impairment of renal function support the current arguments to limit the use of adjuvant radiotherapy in seminoma stage I as much as possible. The application of the surveillance strategy or of one or two cycles of carboplatin may represent preferrable alternatives, whereas our data leave some doubt over whether the reduction of the target dose from 30 to 20 Gy reduces impairment of the renal function.

Twelve to 15 years after treatment renal damage remained subclinical in the patients evaluated, even though statistically significant or almost significant differences were found for the chemotherapy and radiotherapy groups. It is, however, unlikely that significant recovery will occur in the patient’s lifetime. Increasing age and age-related co-morbidity may rather worsen the kidney function. The consequence is that clinicians seeing patients with TC who have had radiotherapy and/or chemotherapy, even many years after their treatment, have to consider the presence of subclinical renal damage, which in some patients may become clinically relevant during the patient’s lifetime, for example during any therapy with drugs that are eliminated by the kidneys.

Our findings of persistent impaired renal function after treatment of GCT support the current treatment strategies, which avoid ‘overtreatment’ of this malignancy as much as possible, e.g avoiding unnecessarily prolonged chemotherapy in good prognosis patients with metastases or the current use of adjuvant radiotherapy in stage I seminoma.


    Acknowledgements
 
The authors wish to thank Anne Berit Murstad, Siri Lothe Hess and Vigdis Opperud (project secretary) for assistance during the study. B. Ericson, A. Munoz, G. Marthinussen, A. L. Hafne, O. G. Selvik and A. Danielsen are recognised for analysis of the dose volume histograms. The Norwegian Cancer Society and The Norwegian Foundation of Health and Rehabilitation are acknowledged for financial support.


    Footnotes
 
+ Correspondence to: Tel: +47-22-93-40-00; Fax:+47-22-93-45-53; E-mail: s.d.fossa@klinmed.uio.no Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Fossa SD, Aass N, Kaalhus O. Radiotherapy for testicular seminoma stage I: treatment results and long-term post-irradiation morbidity in 365 patients. Int J Radiat Oncol Biol Phys 1989; 16: 383–388.[ISI][Medline]

2. Vallis KA, Howard GC, Duncan W et al. Radiotherapy for stages I and II testicular seminoma: results and morbidity in 238 patients. Br J Radiol 1995; 68: 400–405.[Abstract]

3. Wanderas EH, Fossa SD, Tretli S. Risk of subsequent non-germ cell cancer after treatment of germ cell cancer in 2006 Norwegian male patients. Eur J Cancer 1997; 33: 253–262.[Medline]

4. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW et al. Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 1993; 11: 415–424.[Abstract]

5. Meinardi MT, Gietema JA, van der Graaf WT et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000; 18: 1725–1732.[Abstract/Free Full Text]

6. Raghavan D, Cox K, Childs A et al. Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 1992; 10: 1386–1389.[Abstract]

7. Bokemeyer C, Berger CC, Kuczyk MA, Schmoll HJ. Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 1996; 14: 2923–2932.[Abstract]

8. Petersen PM, Hansen SW. The course of long-term toxicity in patients treated with cisplatin-based chemotherapy for non-seminomatous germ-cell cancer. Ann Oncol 1999; 10: 1475–1483.[Abstract]

9. Boyer M, Raghavan D, Harris PJ et al. Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer. J Clin Oncol 1990; 8: 21–26.[Abstract]

10. Osanto S, Bukman A, Van-Hoek F et al. Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol 1992; 10: 574–579.[Abstract]

11. Aass N, Fossa SD, Aas M, Lindegaard MW. Renal function related to different treatment modalities for malignant germ cell tumours. Br J Cancer 1990; 62: 842–846.[ISI][Medline]

12. Hansen SW, Groth S, Daugaard G et al. Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988; 6: 1728–1731.[Abstract]

13. Peckham MJ, McElwain TJ, Barrett A, Hendry WF. Combined management of malignant teratoma of the testis. Lancet 1979; 2: 267–270.[Medline]

14. Pixberg HU, Just G. Determination of the effective renal plasma flow using 131I-hippuric acid whole-body clearance. Dtsch Med Wochenschr 1971; 96: 156.[ISI][Medline]

15. Oberhausen E. Grundlagen der Nuklearmedizinischen Clearancebestimmung. In Pfannenstiel P, Emrich D, Oberhausen E, Pixberg HU (eds): Nuklearmedizinische Verfahren bei Erkrankungen der Nieren und ableitenden Harnwege. Schnetztor-Verlag 1977; 21.

16. Cappelen T, Skretting A, Winderen M, Aass M. Measurement of glomerular filtration rate in connection with 99Tc-DTPA renography. Tidsskr Nor Laegeforen 1999; 119: 521–525.[Medline]

17. Lindegaard MW, Aass N, Bue ES et al. Glomerular filtration rate, 131I-hippuran clearance and estimated creatinine clearance in cancer patients. Br J Cancer 1991; 64: 401–405.[ISI][Medline]

18. Kollmannsberger C, Kuzcyk M, Mayer F et al. Late toxicity following curative treatment of testicular cancer. Semin Surg Oncol 1999; 17: 275–281.[ISI][Medline]

19. Huddart RA, Norman A, Coward D et al. The health of long-term survivors of testicular cancer. ASCO 2000; 19: 331a (Abstr 1301).

20. de Wit R, Roberts JT, Wilkinson PM et al. Equivalence of three or four cycles of bleomycin, etoposide and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organisation for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19: 1629–1640.[Abstract/Free Full Text]

21. Gerl A, Schierl R. Urinary excretion of platinum in chemotherapy-treated long-term survivors of testicular cancer. Acta Oncol 2000; 39: 519–522.[ISI][Medline]

22. Markoe AM, Brady LW, Swartz C et al. Radiation effects on renal function. Front Radiat Ther Oncol 1989; 23: 310–322.[Medline]

23. Neimer-Tucker MM, Sluysmans MM, Bakker B et al. Long-term consequences of high-dose total-body irradiation on hepatic and renal function in primates. Int J Radiat Biol 1995; 68: 83–96.[ISI][Medline]

24. Schneider DP, Marti HP, Von Briel C et al. Long-term evolution of renal function in patients with ovarian cancer after whole abdominal irradiation with or without preceding cisplatin. Ann Oncol 1999; 10: 677–683.[Abstract]

25. Dewit L, Anninga JK, Hoefnagel CA, Nooijen WJ. Radiation injury in the human kidney: a prospective analysis using specific scintigraphic and biochemical endpoints. Int J Radiat Oncol Biol Phys 1990; 19: 977–983.[ISI][Medline]

26. Irwin C, Fyles A, Wong CS et al. Late renal function following whole abdominal irradiation. Radiother Oncol 1996; 38: 257–261.[ISI][Medline]