Randomized trial on acute toxicities of weekly vs three‐weekly cisplatin‐based chemoradiation in head and neck cancer

Abstract Background The current first‐line treatment of locally advanced head and neck carcinoma (LAHNC) is concurrent chemoradiation with three‐weekly cisplatin 100 mg/m2. However, prescribing cisplatin at this dose increases the treatment toxicity, which may compromise the treatment results. An alternative schedule is weekly 40 mg/m2 cisplatin. Aim To compare the acute hematologic and renal toxicities of these two regimens. Methods This randomized clinical trial included 77 LAHNC patients who were allocated to a high dose (100 mg/m2 every 3 weeks) or low dose (40 mg/m2 weekly) cisplatin group concurrent with radiotherapy. Hematologic and renal indices were measured weekly during chemoradiation. Results The average age of patients was 55.3 years. Overall, 71.4% of patients were treated in a definitive setting. The incidence of severe hematologic events was not significantly different. However, the average estimated glomerular filtration rate (eGFR) was significantly greater in the three‐weekly group (67.85 vs. 58.57% mL/min per 1.73 m2; P‐value = .02). Cumulative cisplatin dose of ≥240 mg/m2 was significantly greater in the weekly group. Totally, treatment breaks occurred in 40.3% of patients due to treatment toxicity. Treatment interruption was primarily due to neutropenia in the three‐weekly and renal dysfunction and thrombocytopenia in the weekly group. Conclusions Severe acute hematologic toxicities were comparable for three‐weekly and weekly groups. The decrease in eGFR through treatment was more significant with weekly cisplatin. Further follow‐up, however, is needed to confirm its impact on delayed renal function.


| Participants
The inclusion criteria were: (1) previously untreated patients with clinical stage III-IV LAHNC [T3-4, N0-3, M0; based on the AJCC staging system (seventh edition)]; (2) patients aged at most 80 years and at least 20 years with an Eastern Cooperative Oncology Group (ECOG) of 0-2; (3) patients with adequate renal and bone marrow function (defined as the glomerular filtration rate of ≥60, an absolute neutrophil count of ≥1.5 Â 10 3 /mL, hemoglobin level ≥ 10 g/dL, and platelet count ≥100 Â 10 3 /mL). Patients with a synchronous or metachronous cancer, psychological disorder, uncontrolled underlying disease (e.g., diabetes mellitus, hypertension), or contraindications for treatment with platinum (including peripheral neuropathy, renal failure, and uncontrolled thrombocytopenia) were excluded. Patients who did not agree to stop smoking and/or drinking alcohol were also excluded from the study. Based on previous studies, 12 with an error of 5% and a statistical power of 80%, 50 patients were required for each group.

| Intervention and outcome
The initial assessment consisted of a complete history and physical examination, computed tomography (CT), and/or magnetic resonance imaging (MRI) for locoregional extension of disease (if patients were treated in definitive setting), chest X-ray, abdominal ultrasonography, complete blood cell count (CBC), and comprehensive blood chemistries, including serum creatinine (Scr), electrolytes, and liver function tests. Clinical examination, CBC, and blood chemistry were repeated before each course. To evaluate renal function, we used three parameters: the marked rise in Scr (defined as Scr ≥3.0 Â baseline), development of acute kidney injury (AKI; defined as Scr ≥3.0 Â baseline, increase to ≥4.0 mg/dL, or initiation to renal replacement therapy), 14 and marked drop in estimated glomerular filtration rate (eGFR; refer to Table S1). Figure 1 shows the consort diagram of the trial. Radiotherapy was delivered using the three-dimensional conformal technique at a daily dose fraction of 2 Gy for 5 days per week. Patients were randomly assigned to receive cisplatin as either a weekly 40 mg/m 2 regimen (AKA as the low dose group) or a three-weekly 100 mg/m 2 regimen (AKA as the high dose group), both concurrent with radiotherapy. In the weekly arm, participants were treated in the out-patient setting with 1 L of 0.9% normal saline administered intravenously during 1 h as prehydration followed by another 1 L of 0.9% normal saline containing cisplatin, which was infused over an hour.
Patients in the three-weekly schedule were treated in the inpatient setting. Prehydration included an infusion of 1 L of 0.9% normal saline containing 10 cc potassium chloride (%15) and 2.5 g of 50% magnesium sulfate administered in 3 h followed by 100 cc mannitol 20% and 20 mg furosemide prescribed as an intravenous short infusion. The prescribed dose of cisplatin was given in 1 L of normal saline 0.9% for 4 h followed by 1 L of normal saline containing 10 cc potassium chloride and 2.5 g magnesium sulfate for 3 h as posthydration.
Dose adjustments were based on blood counts and creatinine clearance that were taken prior to each cycle. Creatinine clearance was evaluated with the Cockcroft-Gault formula (eGFR). Dose adjustment and delay in treatment were performed using British Columbia cancer (BC cancer) institute protocol 15 (Tables S1 and S2).

| Follow-up
After the treatment, patients were assessed at 12 weeks and then every 3 months for the first 2 years.

| Evaluation criteria
To evaluate and grade the treatment-induced toxicities, the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 was utilized. 16 Dose-limiting toxicity was defined as the occurrence of at least one of the following events: (1) renal toxicity in the form of eGFR less than 60 mg/mL; (2) hematological toxicity in the form of absolute neutrophil count (ANC) ≤800 mL À1 and/or platelet count ≤100 Â 10 3 mL À1 ; or (3) death.

| Statistical analyses
The primary objective of this trial was to compare the rate of hematological and renal toxicities of three-weekly cisplatin with weekly cisplatin-concurrent with radiotherapy-in patients with LAHNC. The data management and analysis were performed using SPSS v21.0 (IBM Corp., Armonk, NY) software. The Chi-square test and Fischer's exact test were used to evaluate the difference between the control and experimental groups. Moreover, the Mann-Whitney U test and independent t-test were conducted to analyze continuous variables.
The generalized estimating equation (GEE) was run to assess the patients' eGFR over the trial. The statistical significance level was set to .05.

| RESULTS
We screened 101 participants with LAHNC for eligibility. Of these, 92 patients (91.1%) were randomly assigned to the study groups ( Figure 1). The patients were followed up for at least 12 weeks. The final analysis included 39 and 38 patients who assigned to weekly and three-weekly cisplatin regimens, respectively.

| Treatment and evaluation details
The results obtained from the preliminary analysis of both treatment schedules are summarized in Table 2

| Radiotherapy details
All patients completed the planned radiation course. The median chemoradiation duration was 50.54 days for the weekly arm and 49.03 days for the three-weekly arm, respectively, without significant difference (P-value = .28). Radiotherapy break occurred in four cases of weekly group (three cases due to thrombocytopenia and one case due to severe mucositis) and six cases of three-weekly group (three cases due to neutropenia, one case due to neutropenia and thrombocytopenia, and two cases due to severe mucositis). The maximum duration of the treatment break was 8 and 11 days for the weekly and three-weekly groups, respectively.

| Chemotherapy details
The median cycles of concurrent chemotherapy were 6.5 cycles in the weekly arm and 2.5 cycles in the three-weekly arm. The number of patients who completed all planned chemotherapy was 16 (41%) and 15 (39.5%) for the weekly and three-weekly groups, respectively. Dose adjustment was required in 33.3% and 42.1% of the participants in the weekly and three-weekly groups, respectively, with no significant difference between arms (P-value = .42). The leading cause of dose adjustment in the weekly group was thrombocytopenia (92.3%) while neutropenia was the most common cause (68.7%) in the threeweekly group. Delay or discontinuation in the administration of chemotherapy was reported in 38.4% and 42.1% of the patients in the weekly and three-weekly group, respectively (P-value = .70). This was mainly due to renal dysfunction (73.3%) in the weekly arm and neutropenia (81.2%) in the three-weekly arm (  In subgroup analysis, this difference was consistently significant in a definitive therapy setting (P-value = .004).
The overall rate of grade 3-4 hematological toxicities was 61%.  Table 3. The difference between weekly and three-weekly regimens was nonsignificant in terms of either grade 3-4 creatinine rise (0.0% vs.
Generally, one patient experienced a marked Scr rise (who had received a three-weekly schedule) and two patients, one in each group, developed stage 3 AKI. Among patients who received ≥240 mg/m 2 of cisplatin concurrent with radiotherapy, the rates of grade 3-4 creatinine rise (0.0% vs. 4.5%, P-value = .24) and stage 3-4 AKI (3.4% vs. 4.5%, P-value = .84) were almost similar in weekly and three-weekly regimens. Figure 3 shows an overview of the eGFR between the weekly and three-weekly groups. Although the mean eGFR level at the beginning of therapy was the same between the groups (86.44 and 87.76 mL/min/1.73 m 2 for the weekly and three-weekly schedules, respectively), a significant decrease of mean eGFR occurred over the course of treatment for both groups (Figure 3(A)). Based on the GEE F I G U R E 2 Kaplan-Meier curves of the time to occurrence of chemotherapy delay/cessation due to neutropenia (A), thrombocytopenia (B), renal dysfunction (C), and all three causes (D) in weekly and three-weekly schedules analysis, the decrease in eGFR was more profound and statistically significant in the weekly arm compared to the three-weekly arm (Pvalue = .02). In the subanalysis, however, this difference was not observed in patients who received ≥240 mg/m 2 of cisplatin concurrent with radiotherapy (P-value = .11; Figure 3(B)).

| DISCUSSION
Compelling evidence regarding toxicity profiles of various schedules of cisplatin administered in the form of chemoradiotherapy for LAHNC is lacking. Other agents (e.g., carboplatin, fluorouracil, cetuximab, or gemcitabine) may also be administered concurrently with radiotherapy. [17][18][19] However, published literature supports the use of these agents as alternatives for patients who are not eligible for cisplatin. 17 The current understanding of this topic is confined to retrospective and a few small prospective studies. 10 In this trial, we aimed to compare the acute toxicity profile of the meta-analysis did not support our findings regarding delayed or interrupted chemotherapy. According to Guan's meta-analysis, delay or interruption of chemotherapy was more common in weekly CCRT. 20 In current study, the rate of delay/interruption of chemotherapy for weekly-and three-weekly CCRT was 38.4% and 42.1%, respectively, and showing no statistically significant difference between groups.
The main reasons for chemotherapy delay in weekly and three-weekly CCRT arms were renal disorders and neutropenia, respectively. Uygun et al. reported chemotherapy interruption of 35% and 26% in weeklyand three-weekly CCRT, respectively, without significant differences.
The main reasons for the interruption were hematologic toxicity (85%) for the weekly group and both hematologic (50%) and renal toxicity (50%) for the three-weekly group. 21   for three-weekly groups. In contrast, in Noronha et al.'s trial, the rate of dose reduction was much lower in that for weekly-and threeweekly CCRT arms, the rates were 9.3% versus 8%, respectively, without significant difference. In their study, the underlying toxicity was not mentioned. 22 Their results may be due to the utilization of a lower weekly dose of cisplatin (30 mg/m 2 ). In Driessen et al.'s trial, the rate of renal toxicity was greater in the three-weekly CCRT arm. In that trial, the rise in Scr was used as the criteria for renal toxicity. 23 In our study, we used various criteria to evaluate the effect of cisplatin on renal functions, considering the uncertainty of the relation between Scr and eGFR. 24 In this regard, the two criteria (i.e., Scr and AKI) were not significantly different across the two arms. However, the trend in eGFR reduction was significantly steeper in the weekly CCRT arm during the course of the trial (Figure 2 Tables S1 and S2, the BC cancer guidelines suggest either "dose modification" or "treatment delay" options for three-weekly CCRT (based on the renal function) while including only "delay in chemotherapy" option for weekly CCRT (based on the renal function). This specification may have biased the results of our trial regarding the difference in the effect of arms on renal function as we employed a "delay in treatment" (in case of creatinine clearance <50) only for weekly CCRT arm. This may have had some negative effects on the renal function of the weekly CCRT arm. Future trials with alternative dose adjustment criteria can address this issue. The third limitation of this study is related to the number of participants. The final sample comprised 15 cases less than the estimated number (eight cases for the experimental and seven cases for the control arms). Likely, this notion resulted in some statistically insignificant results. Therefore, future trials with more participants can reveal more accurate differences between the two arms. The fourth limitation of current study is that we restricted our evaluation only to renal and hematologic toxicities based on laboratory findings. We did not analyze other acute toxicities (e.g., mucositis). This may have affected the results. Considering other issues in future trials, including other toxicities and the measure of the quality of life, among others, could provide more reliable results.

| CONCLUSIONS
The results showed that the weekly schedule of concurrent cisplatin has its pros and cons in comparison with the three-weekly arm, which should be considered in clinical practice. Its advantages over the three-weekly regimen include a larger cumulative dose and less chemotherapy delay/interruption because of neutropenia. However, its important drawback is related to renal impairment. From a methodological perspective, the study emphasizes the necessity of ad hoc randomized clinical trials with larger sample sizes to validate these findings.