Introduction

Over 500,000 new cases with head and neck squamous cell carcinoma (HNSCC) are diagnosed worldwide annually, the majority of them with locally-advanced disease [1]. Chemoradiotherapy (CRT) is nowadays the standard of care for locally-advanced HNSCC (LA-HNSCC). The meta-analysis of chemotherapy in head and neck cancer (MACH-NC) included a total of 16,485 patients in 87 randomized trials conducted between 1965 and 2000, showed an overall survival (OS) benefit of 4.5% at 5 years; hazard ratio (HR) for death = 0.88, p < 0.0001 by the addition of chemotherapy to radiotherapy (RT), compared to RT alone. The meta-analysis also showed a more profound benefit of concomitant as compared to induction chemotherapy (50 trials; 9615 patients), with an absolute OS benefit of 6.5% at 5 years in case of concomitant chemotherapy (HR for death 0.81, p < 0.0001). There was also a decreasing benefit from the addition of chemotherapy with increasing age (p = 0.003, test for trend) [2]. Regarding the type of chemotherapy, the same meta-analysis showed that OS benefit did not differ significantly between poly- and monochemotherapy. However, inferior results were seen using single-agent chemotherapy drugs other than cisplatin and, therefore, should not be recommended for the daily clinical practice.

The rationale for the addition of cisplatin to the RT is its radiosensitizing effect and the fact that radiation- and cisplatin-related toxicities are mostly not overlapping. Most institutions use the 3-week regimen, preferably giving a cumulative dose of 300 mg/m2 during the course of RT. However, considerable proportion of these patients did not receive a second or third course of cisplatin [3] because of cisplatin-related toxicity such as renal insufficiency, severe gastro-intestinal symptoms, ototoxicity, and hematological toxicity.

Despite the wide use of cisplatin, data on the optimal regimen and cumulative dose are scarce and frequently conflicting. The recently published systemic review by Strojan et al. [4] supports the idea that the cumulative dose of cisplatin for HNSCC is quite important. However, no solid conclusions were drawn with regard to the optimal dose and schedule, as the currently available data are mainly collected from retrospective studies and provide, therefore, a low level of evidence. We performed a retrospective analysis on patients treated by four different dose levels of cumulative cisplatin (300, 200, 150, and 100 mg/m2) and patients who did not receive any type of cisplatin at all (as control group). Therefore, we believe that the findings of the current study would increase the bulk of the slowly growing evidence about the cut-off cumulative dose level of concurrent cisplatin as monotherapy in combination with RT in LA-HNSCC.

Patients and methods

Between January 2008 and December 2015, 279 consecutive patients with histologically proven primary squamous cell carcinoma of the oropharynx, hypopharynx, and larynx scheduled for concomitant chemoradiotherapy (CCRT) according to the institutional guidelines were identified. All patients were treated in one tertiary referral institution with curative intentions.

Pre-treatment evaluations consisted of complete history and physical examination, including examination under general anesthesia. All patients had a chest X-ray, ultrasound with fine needle aspiration cytology (FNAC) when indicated, and head and neck MRI or CT scan. P16 and P53 staining was performed on the tissue blocks obtained during examination under general anesthesia. An 18-FDG-PET was performed in all stage III/stage IV patients, and all patients were discussed at the weekly multidisciplinary head and neck tumor board. Tumor classification was done according to the seventh edition of the American Joint Commission on Cancer. Based on the joint recommendations of the multidisciplinary board, patients were scheduled for RT with or without chemotherapy. Patients will subsequently be evaluated by the medical oncologist whether they are fit enough to be planned for three courses of 3-week high dose of cisplatin. Based on our institutional guidelines, chemotherapy will be added to radiotherapy concomitantly in all patients with T3, T4, N2c, N3 disease, or any node-positive disease with extra-capsular extension, with one exception; bulky T3 laryngeal cancer will receive CRT, and patients with non-bulky T3 laryngeal cancer will be treated with RT alone. Furthermore, all patients with node-positive disease hypopharyngeal cancer, irrespective of T classification, will receive CCRT in our institution. None of these patients received induction chemotherapy.

Radiotherapy

Patients were immobilized in supine treatment position in a custom-made head-and-neck mask. For planning, contrast-enhanced CT-scan simulation was performed in all patients. The planning treatment volume (PTV) included a margin of 5 mm beyond the clinical target volume (CTV) of the primary tumor and the involved neck to account for different geometric uncertainties. All patients were treated with intensity-modulated radiotherapy (IMRT) or volumetric modulate arc therapy (VMAT). The radiation treatment consisted of 46 Gy of elective irradiation to both sides of the neck (levels II–IV in case of node-negative neck and levels I–V in case of cervical lymph node metastases), followed by a boost of 24 Gy in 12 fractions to the primary tumor and the involved nodes in case of node-positive disease, to a total dose 70 Gy.

Chemotherapy

Patients were scheduled for a 3-week intravenous high-dose cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) CCRT regimen as a hospital admission. Before and after each cisplatin infusion, patients received at least 3.5 L of saline with 60 mmol/L of KCl and 30 mmol/L of MgSO4, as well as antiemetics (aprepitant). Patients who could not receive the third course of cisplatin no further chemotherapy were given, whereas those who could not receive the second and third courses were treated by combining the RT with weekly carboplatin (AUC = 3), as from the fourth week of CCRT. Low-dose daily cisplatin was given in a daily dose of 6 mg/m2 for 5 weeks (weeks 1–5 of RT) (cumulative dose of 150 mg/m2). The reason why patients did not receive any type of cisplatin schemes or received low-dose daily cisplatin or only two or one course of 100 mg/m2 is illustrated in Fig. 1. The following baseline patient’s demographics were tested for the correlation with compliance for ≥two courses of cisplatin: WHO status, serum creatinine level, glomerular filtration rate (GFR), hemoglobin level, smoking status, diabetes mellitus, and hypertension.

Fig. 1
figure 1

Flow chart illustrating the number of patients received different schemes and dose levels of cisplatin and those who did not received any type of cisplatin and the reason why patients did not received any type of cisplatin schemes, received daily cisplatin or only two or one course of 100 mg/m2 instead of the intended three courses of 3-week cisplatin with a total intended cumulative dose of 300 mg/m2

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Follow-up

During CCRT, patients were seen twice weekly at the out-patient clinic to monitor the acute radiation- and cisplatin-related toxicities. After completion of treatment, patients were seen every 2 weeks until the acute radiation-induced toxicity had subsided. At 10–12 weeks after treatment, response evaluation was done by means of MRI or CT scan and ultrasound, with FNAC when indicated. In patients with residual disease after the (chemo)radiation, the possibility of salvage surgery will be evaluated by the head and neck surgeon. The type of surgery will depend on the site and extent of the residual disease. After the response evaluation, patients were seen at least 3 months for the first year, 4 months for the second year and 6 months thereafter. At each visit, history and clinical examination (including flexible endoscopy) were performed. In case of any doubt about the presence of recurrent disease, examination under general anesthesia will be done.

Statistical analysis

The recurrence and survival analyses were performed using the Kaplan–Meier method. Univariate testing was done by Chi square, Kruskal–Wallis or Fisher’s exact test. Variables included in the univariate analysis are: age, gender, smoking, T site, T classification, N classification, AJCC stage, P16 status, ACE-27 score, extra-capsular extension, and dose of cisplatin. Multivariate survival analyses including age, gender, AJCC stage, P16 status, and dose of cisplatin was performed using the Cox regression analysis. All tests were two-sided, and P-values <0.05 were considered statistically significant. Statistical programs used were SPSS (version 22.0, IBM Chicago, IL) and STATA data analysis and statistical software (version 10.0, StataCorp LP, TX, 1996).

Results

Patient’s demographics are shown in Table 1. The median follow-up of all patients is 31.6 months (range 2.1–106.3) and for those still alive at the time of the analysis (n = 161) is 50.8 months (range 13.1–106.3).

Table 1 Patient’s characteristics (n = 279)
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Of the whole study population (n = 279), 40 patients (14%) did not receive any cisplatin whereas 72 patients (26%) received daily cisplatin. All other patients (n = 167) were scheduled for the three courses of 3-week cisplatin with a total intended cumulative dose of 300 mg/m2.

Feasibility of 3-week cisplatin

Of patients who were planned for three courses of cisplatin (n = 167), only 93 patients (56%) received the intended three courses, 34 patients (20%) received two courses, and 40 patients (24%) received only one course of cisplatin. All patients who received one course of cisplatin received carboplatin AUC = 3 as from the fourth week of CCRT. From the tested variables, only borderline GFR (60–70 mL/min) at baseline was significantly predictive for the compliance for two or three courses. Significantly more patients with borderline GFR (60–70 mL/min) at baseline could not receive the second and the third courses as compared to those with baseline GFR > 70 mL/min (24 vs. 6%, respectively, p = 0.003). The correlation between compliance and other baseline characteristics were statistically not significant: WHO status (p = 0.601), serum creatinine level (p = 0.335), hemoglobin level (p = 0.201), smoking status (p = 374), diabetes mellitus (p = 0.958) and hypertension (0.773). Grade 3 toxicity was the most important reason why patients did not receive the second or the third course of cisplatin. The reported grade 3 toxicities in patients received 3-week intravenous high-dose cisplatin are renal insufficiency in 52%, sever nausea and vomiting in 9%, hematological in 8% and pneumonia and sepsis in 9% of patients.

Outcome

Table 2 shows the outcome of patients received different dose schemes and dose levels of cisplatin. The actuarial OS rates at 3 years were not significantly different between patients who received three or two courses (74 and 72%, respectively, p = 0.531). The same is true for DFS, LRC, and DMFS. The actuarial OS rates at 3 years for patients received ≥200 mg/m2 (three or two courses) was significantly better as compared to those received <200 mg/m2, regardless of the scheme used (74 vs. 51%, p < 0.001) (Table 2; Fig. 2). The actuarial rates of DFS, LRC, and DMFS at 3 years for patients received at least 200 mg/m2 were significantly better as compared to those who received <200 mg/m2 (one course of cisplatin or daily cisplatin); 73 vs. 49% for DFS, 80 vs. 58% for LRC (all p < 0.001), and 85 vs. 76% for DMFS (p = 0.034). Furthermore, no OS benefit was observed in patients who received <200 mg/m2, as compared to those who did not receive any type of cisplatin (51 vs. 56%, p = 0.507) (Table 2; Fig. 3).

Table 2 Actuarial incidence of different outcome measures at 3 years, comparing different dose schemes of cisplatin
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Fig. 2
figure 2

Actuarial rates of overall survival at 3 years for patients received ≥200 mg/m2 as compared to those who received <200 mg/m2

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Fig. 3
figure 3

Actuarial rates of overall survival at 3 years for patients received two or three courses of cisplatin as compared to those who received one course cisplatin, daily cisplatin, or no cisplatin at all

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Cancer-specific survival was also significantly related to the dose of cisplatin. The actuarial cancer-specific survival at 3 years for patients received ≥200 mg/m2, compared to those received <200 mg/m2 were 78 and 65%, respectively (p = 0.009).

Table 3 shows the results of univariate and multivariate analyses using different variables to predict OS in these patients. In the multivariate analysis, the cumulative dose of cisplatin (≥200 vs. < 200 mg/m2) was, beside P16 status, and AJCC stage, significantly predictive for OS (HR 1.79; 95% CI 1.17–2.73, p = 0.007). When the analysis was repeated without P16-positive patients, the dose of cisplatin retained the significant correlation with OS (HR 1.65; 95% CI 1.09–2.51, p = 0.019), beside the AJCC stage (HR 2.22; 95% CI 1.33–3.71, p = 0.002), and extra-capsular extension (HR 1.73; 95% CI 1.10–2.73, p = 0.019).

Table 3 Univariate and multivariate analyses for overall survival of the whole group and the whole group without P16-positive patients
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Discussion

Despite the fact that cisplatin is the most commonly used radiosensitizer in combination with RT for LA-HNSCC for long time, data on the optimal dose and regimen are scarce and frequently conflicting [2]. However, there is slowly growing evidence that a cumulative dose level around 200 mg/m2 might be sufficient to achieve reasonable outcome and weighted out against detrimental side effect [4]. In the current study, 2 dose levels (1 with cumulative dose <200 mg/m2 and 1 with cumulative dose of 200 mg/m2 or more) were evaluated and compared to a control group which was treated with RT alone. Our results are in line with the findings of recently published systemic review by Strojan et al. [4] and support the idea that a cumulative cisplatin dose of at least 200 mg/m2 might be sufficient to achieve reasonable oncologic outcome. Furthermore, our study clearly shows that lowering the cumulative dose of cisplatin below 200 mg/m2 may be detrimental and should not be recommended in the daily clinical practice. We found that the OS, DFS, LRC, cancer-specific survival, and DMFS of patients received only RT or a cumulative dose <200 mg/m2, independent of the given regimen (low-dose daily cisplatin or one course of cisplatin) were significantly worse as compared to those receiving ≥200 mg/m2 (two or three courses) (Table 2). However, the conclusion with regard to the impact of the cisplatin dose on OS should be interpreted with caution since patients received low-dose daily cisplatin or no chemotherapy might have lower OS rates at baseline because of the competing risk of death from their comorbidity. However, the impact of cumulative dose of cisplatin was very obvious for other end points not directly influenced by comorbidity, such as cancer-specific survival, LRC, and DMFS. The comorbidity score was not significantly predictive for OS in the univariate analysis. This is probably because the impact of cancer-related death on the whole survival was stronger than the risk of death from intercurrent disease, since cause-specific survival was significantly better in patients received ≥200 mg/m2.

HPV-positive oropharyngeal cancer patients have better outcome, compared to the HPV-negative group.

Ang et al. [5], showed that the 3-year OS of HPV-positive oropharyngeal cancer was significantly better, compared to HPV-negative patients (82.4, vs. 57.1%; p < 0.001). These patients might be candidates for treatment de-intensification and lower dose of cisplatin might be sufficient to cure these patients. To exclude the possible confounding effect of better outcome of this group, we repeated the analysis without the P16-positive patients. Nevertheless, the dose of cisplatin retained the significant correlation with OS (HR 1.65; 95% CI 1.09–2.51, p = 0.019), beside the AJCC stage, and extra-capsular extension.

In our study, 72 patients were treated by daily cisplatin (cumulative dose 150 mg/m2). The outcomes of these patients are in line with results from the only negative randomized study included in the MACH-NC, the study of the intergroup trial of the Eastern Cooperative Oncology Group [6], where RT in combination with weekly cisplatin dosed at 20 mg/m2 (cumulative dose of 140 mg/m2) was compared to RT alone. The addition of a cumulative dose of 140 mg/m2 cisplatin to RT did not significantly improve outcome, compared to 70 Gy of RT alone.

The randomized Swiss trial [7], comparing RT alone with RT in combination with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5, rather than 100 mg/m2 given in a single administration), reported 51 and 46% LRC and OS rates, respectively, in the CRT arm. Compared to other CRT trials, the use of this cisplatin regimen seems to reduce cisplatin-related toxicity without jeopardizing the oncologic outcome. These findings are consistent with the notion that the cisplatin radiosensitization is more dependent on the cumulative dose than on the scheme.

Our conclusions with regard to the optimal dose level are also in line with the results of the literature-based meta-analysis published by Ghi et al. [8] in an abstract mentioned in the systemic review of Strojan et al. [4]. The survival outcome of patients treated with high cumulative cisplatin dose (300 mg/m2) was similar to those treated with cumulative cisplatin dose <300 mg/m2. However, there was significant difference in HR for death between intermediate cumulative cisplatin dose (200–225 mg/m2) and low cumulative cisplatin dose (<150 mg/m2) (HR for death 0.68 and 1.04, respectively).

Since the prognosis of patients scheduled for 3-week cisplatin will depend on the ability to receive at least two courses (≥200 mg/m2), careful selection of patients regarding their expected compliance is of utmost importance. Although no validated tools to date are available to identify patients at risk of low compliance, we investigated different baseline patient’s demographics with regard to the compliance for two or three courses. The only possible predictive factor for reduced compliance is the baseline GFR. Significantly, more patients with borderline GFR (60–70 mL/min) at baseline could not receive the second and the third courses as compared to those with baseline GFR > 70 mL/min (24 vs. 6%, respectively, p = 0.003). The explanation might be that patients who are not able to receive two or three courses might have a latent renal insufficiency, expressed by the borderline GFR (60–70 mL/min), who subsequently decompensate after the first course of cisplatin and will not be timely recovered enough to receive the second and the third course of cisplatin. Therefore, caution is needed before 3-week cisplatin will be scheduled in patients with borderline GFR, especially in combination with other comorbidities were silent renal insufficiency might be elicited, such as diabetes, hypertension, or heavy smoking as indirect indicators of microvascular disease. Furthermore, there is slowly growing evidence that sarcopenia in cancer patients might be cisplatin dose-limiting factor. Sacropenic cancer patients seem to have increased incidence of chemotherapy-related toxicity and a shorter time to tumor progression [9, 10]. By identifying these patients at risk of low cisplatin compliance, other alternative treatment options might be considered instead of 3-week cisplatin. Several studies have shown that renal toxicity might be reduced and compliance might be improved by modulating the cisplatin scheme. Although different retrospective studies comparing the compliance of weekly with 3 weeks showed conflicting results [11,12,13,14,15], some of studies showed that nephrotoxicity and mucositis were significantly higher with 3-week cisplatin, compared to the weekly scheme [9, 10]. The randomized trial conducted by the Swiss group [7] showed that two cycles of cisplatin were well tolerated and associated with reduced renal toxicity without jeopardizing oncologic outcomes.

Another strategy for reducing chemotherapy-related toxicity is the replacement of cisplatin with cetuximab. Bonner et al. [16] confirmed in randomized trial that the addition of cetuximab to primary RT in patients with locally-advanced HNSCC significantly improves median survival and OS at 5 years as compared to RT alone. This is meanwhile the standard of care in many institutions in patients who are unfit for cisplatin. The only randomized trial conducted [17] to compare the outcome of RT with concomitant cisplatin vs. concomitant cetuximab was, unfortunately, discontinued early due to slow accrual. However, the published results on the treated patients showed lowered compliance by the addition of cetuximab to RT and increased acute toxicity while the outcomes of both arms were comparable. The study raised the importance of appropriate selection of patients for treatment with cetuximab. The RTOG-0522 trial randomly assigned patients with locally-advanced HNSCC to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Cisplatin radiation combined with cetuximab, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy and more grade 3–4 radiation-related toxicity without improvement of OS, DFS, LRC, or DMFS [18].

Another promising approach to improve outcome is decreasing radioresistance by the concomitant use of new radiosensitizers, for example, drugs inhibiting DNA repair, such as poly ADP ribose polymerase (PARP) inhibitors [19]. Currently, a phase I trial is ongoing at our institution to investigate the safety and tolerability of RT with concurrent olaparib in stage II–III laryngeal and stage II–III HPV-negative oropharyngeal cancer. Another study on novel radiosensitizers in HNSCC is the TRYHARD study [20]. In this placebo-controlled randomized phase II study, the addition of lapatinib (a dual tyrosine-kinase inhibitor) to platinum-based CRT in HPV-negative locally-advanced HNSCC is evaluated.

Different studies are nowadays conducted to investigate the benefit of adding immunotherapy to RT in patients with recurrent or metastatic HNSCC. Ferris et al. [21] published the results of the randomized trial comparing the efficacy of nivolumab (human IgG4 anti-PD-1 monoclonal antibody) among patients with recurrent and metastatic HNSCC who had disease progression after platinum-based chemotherapy, compared to standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The treatment with nivolumab resulted in significantly longer survival, compared to treatment with the standard therapy. This treatment option might also be promising for the primary treatment of HNSCC, especially when low cisplatin compliance is expected, such in case of sacropenic HNSCC or patients with borderline GFR at baseline. Several ongoing prospective studies are investigating this approach at the primary setting by combining the radiation treatment with anti-PD-1 or anti-PDL-1 (programmed death-ligand 1). At our institution, in patients unfit for cisplatin-based chemoradiotherapy, the RT will be given in combination with weekly cetuximab and 2-week avelumab (anti-PDL-1) (programmed death-ligand 1) followed by adjuvant 2-week avelumab for 6 months. The results of these studies need to be awaited.

Conclusions

Of all patients scheduled for three courses of cisplatin, 24% received only one course of cisplatin. The outcome of patients received ≥200 mg/m2 was significantly better compared to patients received <200 mg/m2, regardless of the cisplatin regimen. Patients receiving a cumulative dose <200 mg/m2 (one course or daily cisplatin) have comparable outcome to those who did not receive any chemotherapy at all. The findings of the current study increased the bulk of the slowly growing evidence about the cut-off dose level of concurrent cisplatin as monotherapy in LA-HNSCC of around 200 mg/m2 and support the idea that a cumulative dose of cisplatin <200 mg/m2 might be detrimental and should not be recommended.

Although no validated tools are available to date to identify patients with poor compliance, caution is needed before 3-week cisplatin will be scheduled in patients with borderline GFR (60–70 mL/min), especially in combination with other comorbidities which might elicit latent renal insufficiency, such as diabetes, hypertension, heavy smoking, and atherosclerotic disease. However, this tool should be validated in prospective clinical studies.