Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin

Three-weekly high-dose cisplatin (100 mg/m²) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) [1‐3]. The additional absolute benefit in overall survival of adding cisplatin chemotherapy has been best estimated as 6.5% at 5 years when compared with radiotherapy alone [4]. However, concurrent high-dose cisplatin is associated with significant acute and late toxicities [5, 6]. Acute kidney injury (AKI) is a common and serious side effect of high-dose cisplatin-based concurrent chemoradiation (CRT). AKI is a predictor of immediate and long-term adverse outcomes. Even a minor acute reduction in kidney function has an adverse prognosis [7].

The incidence of cisplatin-induced AKI has been reported before [5, 8‐10]. However, development of AKI during high-dose cisplatin-based CRT is underreported using the Kidney Disease Improving Global Outcomes (KDIGO) criteria [11], which are the most recent and preferred criteria for diagnosis and staging of AKI. Also, little is known about the impact of AKI on long-term renal function and treatment outcomes in patients with LA-SCCHN. Early detection of AKI enables early intervention, which might lessen treatment burden and improves efficacy and cost-effectiveness of care [12]. Therefore, it is clinically relevant to identify potentially modifiable risk factors for cisplatin-induced AKI in this patient group.

The purpose of this study is to answer the following questions: (1) what is the incidence of AKI during treatment with high-dose cisplatin-based CRT for LA-SCCHN according to KDIGO criteria, (2) which predictors for development of cisplatin-induced AKI can be identified, and (3) what are the long-term consequences of cisplatin-induced AKI in this patient group?

A total of 124 patients were included in this study. The median age was 60 years (range, 30 to 74 years), 78% of patients were male, and 94% had ECOG performance status 0 to 1 (Table 1). Twenty percent of patients had hypertension, age-adjusted CCI score was 0 to 1 in 74% of patients. Most patients (74%) had a smoking history of ≥10 pack-years, and 20% indicated excessive use of alcohol. Median number of potentially nephrotoxic co-medications was 2 (range, 0 to 3). Primary LA-SCCHN tumor site was the oral cavity or oropharynx in 71% of patients, and the hypopharynx in 12%. Fifty-six percent of patients had T3 or T4 LA-SCCHN, and 85% had node-positive disease. Mean sCr value was 66 μmol/l (Standard Deviation, SD 12). Eighty-five patients (69%) were re-admitted at least once for AKI during CRT.

AKI was reported in 85 patients (69%) with 112 episodes of AKI. Sixty of 85 patients (71%) experienced 1 AKI episode; 20 patients (29%) experienced ≥2 AKI episodes. Ninety-three (83%) AKI episodes were stage 1, 13 (12%) were stage 2, and 6 (5%) AKI episodes were stage 3. Eighty-six patients (69%) received all 3 preplanned courses of cisplatin (cumulative dose 300 mg/m²) without dose adjustment (Fig. 1). Thirty-eight patients (31%) prematurely discontinued cisplatin treatment; 7 patients after the first cycle, and 31 patients after 2 cycles of cisplatin. Reasons for discontinuation was AKI in 28 patients (74%) and infection/sepsis in 4 patients (11%). Median cumulative dose of cisplatin was 259 mg/m² (86% of preplanned dose) in the AKI group and 269 mg/m² (90% of preplanned dose) in the non-AKI group (p = 0.36). All patients but 2 (sepsis, n = 1; patient refusal, n = 1) received the preplanned, scheduled radiotherapy dose.

The present retrospective cohort study shows that 69% of patients with LA-SCCHN developed AKI stage 1 or higher during treatment with high-dose cisplatin-based CRT, according to the KDIGO definition and staging criteria. Almost 30% of patients experienced 2 of more AKI episodes. The majority of AKI episodes (83%) was stage 1 according to KDIGO criteria; only 6% was AKI stage 3. Predictive risk factors for cisplatin-induced AKI included hypertension and uncontrolled CINV. Long-term impairment of renal function was observed in both AKI and non-AKI patients. However, renal function was significantly worse at 3 and 12 months in patients with AKI during CRT. DFS and DSM were comparable between AKI and non-AKI patients.

Cisplatin-induced AKI has been reported to occur in 1 to 46% of patients treated with high-dose cisplatin, depending on the described grade of nephrotoxicity and the used AKI definition and staging system [5, 8, 10, 16]. Previous studies often used the adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events (CTCAE). In early versions of CTCAE (version 2.0 and 3.0), grading of renal insufficiency was based solely on the x-fold increase of the sCr level with respect to the Upper Limits of Normal (ULN). CTCAE v2.0 and 3.0 have different cutoff values for renal insufficiency than KDIGO, and no provision of a time course, which complicate direct comparisons of AKI incidence and outcome. CTCAE version 4.0 (v4.0) was the first to define AKI as sCr exceeding 26.5 μmol/l. Cutoff values for AKI grade 1 to 3 in CTCAE v4.0 resemble those according to KDIGO. However, in contrast to KDIGO, there is no provision of a time course in CTCAE v4.0. In previous trials using CTCAE criteria, AKI grade 1 and 2 were seldomly reported; only AKI grade 3 (sCr > 3 x baseline or 354 μmol/l; hospitalization indicated) and grade 4 (life-threatening consequences; dialysis indicated) were reported. Consequently, the high incidence rate of AKI in the present study compared to previous studies is explained by the identification of low stage AKI by using the KDIGO system. KDIGO builds upon two earlier AKI classification systems: the Acute Kidney Injury Network (AKIN) and the Risk, Injury, Failure, Loss, End-Stage (RIFLE) criteria. Compared against AKIN and RIFLE, the incidence of AKI according to KDIGO is the highest due to the addition of an absolute increase criterion (≥0.3 mg/dl over 48 h) to the RIFLE definition and expansion of the time limit for percentage increase (≥ 50%) in the AKIN definition from 48 h to 7 days [17]. Therefore, AKI will be more frequently diagnosed at an early stage, if KDIGO is applied.

The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of intravenous (iv) isotonic saline (≥3 L/day) to induced diuresis during cisplatin administration. However, the optimal hydration solution and regimen to prevent nephrotoxicity associated with cisplatin administration is unclear. There are no randomized trials that have compared different regimens and/or types of iv fluids. In this study, all patients received 5 L/day of iv isotonic saline according to protocol. Forced diuresis with mannitol is frequently used, although there is no evidence that this is required. There is also concern that mannitol may over-diurese some patients, resulting in dehydration [18]. Therefore, mannitol was not used in this study. There is insufficient evidence to support using furosemide for forced diuresis, unless there is evidence of fluid overload, as was applied in our study. Hypomagnesemia can upregulate OCT-2, leading to increased cisplatin transport to the kidneys, resulting in nephrotoxicity [19]. Several systematic reviews suggest that magnesium supplementation (8–16 milliequivalents [mEq]) may limit cisplatin-induced nephrotoxicity [18, 20]. In this study, 2000 mg (= 16 mEq magnesium) was administered to all patients according to protocol. Potassium supplementation was also included in the protocol. Several other approaches have been evaluated to prevent cisplatin-induced nephrotoxicity, including N-acetylcysteine, anti-inflammatory drugs and antioxidant supplements, but none have an established role in patients being treated with cisplatin. Amifostine is the only FDA-approved agent for the reduction of cumulative renal toxicity in advanced ovarian and non–small-cell lung cancer patients receiving cisplatin [21]. However, use of this drug is limited by side effects (nausea, vomiting, hypotension). In addition, concerns about possible interference with the antitumor activity of cisplatin limits its use to clinical trials in tumors other than advanced ovarian and non–small-cell lung cancer patients.

Another strategy to prevent dehydration and cisplatin-induced nephrotoxicity, is to perform prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement in those patients deemed at greatest risk of becoming malnourished or dehydrated during the course of treatment. The indication for prophylactic PEG placement is discussed in the multidisciplinary tumor board on a case-by case basis. Malnutrition, dysphagia and bilateral neck irradiation are among factors considered. In this retrospective study, 90 patients (73%) were treated with prophylactic PEG placement. During treatment, patients were monitored by a nutritionist, and if indicated a nasogastric feeding tube was placed in patients without PEG, or with PEG in the case of PEG-related complications or dysfunction. In this study, 20 patients (10 patients without PEG; 10 patients with PEG) were treated with (short-term) nasogastric feeding tube placement. Despite nastrogastric feeding tube placement, AKI occurred in 17 of these patients. Prophylactic PEG and feeding tube placement were not associated with a lower risk of AKI.

Reported predictors of cisplatin-induced AKI included older age and hypertension [22‐24], female sex [22, 25], smoking, black ethnicity [22, 26], hypokalemia, hypoalbuminemia [23‐25], concomitant use of other anticancer drugs, and single dose versus fractionated dose radiotherapy [27]. This retrospective study confirms the association of hypertension with cisplatin-induced AKI. No significant association with female sex was found, although both sexes were adequately represented in the study. The association of older age with AKI could not be confirmed, because elderly patients were underrepresented in this study (median age 60 years, range 30 to 74). Ethnicity could not be selected as a primary variable; included patients were predominantly white in this study. This also applied to serum albumin values, which were not measured in this study.

This study clearly demonstrates that CINV remains poorly controlled in a significant number of patients receiving CRT with high-dose cisplatin for LA-SSCHN, despite the use of guideline-consistent antiemetic therapy. Adherence to antiemetics in order to optimize CINV control for patients undergoing emetogenic chemotherapy is important, because adequate control of emesis prevents intravascular depletion of fluids and electrolytes, and therefore decreases the potential for cisplatin-induced nephrotoxicity. We have no data on adherence to antiemetics used in days 2 to 4, due to the retrospective design of this study. We were also unable to determine the severity of nausea or vomiting using an assessment tool in this retrospective study. Despite these limitations, there seems to be a clear need for further improvements in the management of CINV to minimize its negative impact. The benefit of olanzapine in controlling nausea and emesis has been suggested in previous trials, which showed that nausea and emesis were significantly reduced when olanzapine was added to guideline-directed prophylactic agents [28, 29]. This antiemetic regimen should be further explored in patients treated with CRT including high-dose cisplatin for LA-SCCHN.

Our results confirm previous observational studies’ findings that AKI is an independent risk factor for the development of chronic kidney disease [30, 31]. Decline of renal function was observed in both AKI and non-AKI patients at 3 and 12 months post-treatment. However, long-term decline in renal function was significantly more severe in AKI patients. In the current study, AKI did not have a negative impact both in terms of DFS and DSM. On the contrary, DSM and disease recurrence rates were numerically (but not statistically) higher in non-AKI patients. This could have several reasons. First, we did not have access to survival and disease recurrence data of all patients, which could have led to underreporting mortality and disease recurrence in the present study. Second, due to the retrospective nature of this study, patients were not stratified by prognostic risk factors, like primary tumor site, tumor stage, age or comorbidity at diagnosis, which may have resulted in unbalanced groups. Third, the follow-up period of 29 months was relatively short. Patients with AKI did not have inferior survival rates. In addition to the arguments already mentioned, this could also be explained by our data, showing that the majority of AKI and non-AKI patients (94%) received cisplatin with a cumulative dose of ≥200 mg/m²; only in 6% of patients cisplatin was discontinued after 1 cycle. Median cumulative dose of cisplatin was > 250 mg/m² in both groups and not statistically different between treatment groups. This was well above the minimum dose of 200 mg/m², which confers a survival benefit in LA-SCCHN patients treated with high-dose cisplatin-based concurrent CRT [32].

One of the strengths of our study was that associations between potential risk factors for AKI and outcome were studied in a well-characterized study population. AKI was also defined and graded according to KDIGO criteria, making it possible to identify low grade – but nevertheless clinically relevant – AKI. This study identifies a strong association between AKI and CINV, which is an important and potentially modifiable risk factor. Limitations were the single center retrospective nature of the study, and the relatively short follow up period of 2.5 years. Also, possible dose-response associations between the stage of AKI and outcome were not assessed. Finally, the effect of AKI and CINV on patients’ quality of life, and patients’ adherence to antiemetics could not be assessed due to the study’s retrospective design.

AKI is a frequent complication of high-dose cisplatin-based CRT for patients with LA-SCCHN, despite adherence to guideline-consistent prevention therapy. CINV and hypertension are potentially modifiable and highly significant risk factors contributing to AKI. Studies investigating strategies to minimize AKI after high-dose cisplatin-based CRT for patients with LA-SCCHN are warranted.