INTRODUCTION
Head-and-neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignant tumors, developing in the mucous membranes of the mouth, nose, and throat. It constitutes more than 90% of all head-and-neck cancers[ 1 ] and 30% of all cancers in India.[ 2 , 3 ] It is commonly diagnosed in the older population and amongst people of lower socio-economic status. However, more than 70-90% of patients present with disease in the locally advanced stage.[ 4 ] The standard treatment for locally advanced HNSCC utilizes a multimodal approach consisting of surgical tumor resection followed by chemoradiotherapy in patients at high risk of recurrence. However, despite receiving curative intent therapy, a significant proportion of these patients inevitably metastasize or recur within 2 years.[ 5 , 6 ]
Standard palliative intent therapy for advanced HNSCC consists of systemic treatment with either cetuximab, nivolumab, or pembrolizumab,[ 7 ] with or without chemotherapy. However, in a developing country like India, cetuximab or nivolumab-based regimens are not economically feasible and therefore, can be only administered to less than 5% of the eligible patients.[ 8–12 ] Hence, most patients with metastatic, recurrent, or relapsed HNSCC who are planned for palliative treatment either receive intravenous cisplatin or oral metronomic chemotherapy (OMCT); both of which are low-cost treatments.[ 13 ] Nevertheless, even with the availability of affordable treatments, the prognosis of this disease remains poor.
Bendamustine is a cytotoxic alkylating agent,[ 14 ] which is Food and Drug Administration (FDA) approved for treating patients with chronic lymphocytic leukemia and B-cell non-Hodgkin’s lymphoma who have progressed on rituximab or rituximab-containing regimens. This drug has shown promising results in various solid tumors, both as a stand-alone treatment and in combination with other chemotherapeutic agents.[ 15 ] Bottke et al . in their phase I study combined bendamustine with radiation therapy in patients with recurrent HNSCC and reported that 62% of patients who received the treatment had a partial response.[ 16 ] A study combining bendamustine with cetuximab in 28 patients with relapsed HNSCC reported partial responses in 10 (36%), stable disease in 10 (36%), and progression in 8 (28%) patients after 28 weeks of treatment. Moreover, this combination therapy was well tolerated and showed minimal hematological toxicities.[ 17 ] In another study, bendamustine was administered concurrently with palliative radiotherapy in 14 patients with recurrent HNSCC, with the intent of studying the remission status, time to progression, side effects, and overall survival. The regimen resulted in partial remissions in 8 (53.3%) and complete remissions in 4 (26.7%) amongst the 15 treated patients; additionally, up to 70% improvement in the tumor-related symptoms was also documented. The duration of remission was between 2 and 104 weeks, with a median of 2 weeks. Grade 3 to 4 toxicities were noted in 2 patients (14%), while 71% of the patients experienced no significant side effects.[ 18 ]
Considering these results, we offered bendamustine on compassionate grounds as a third-line treatment or beyond, to patients with relapsed HNSCC who had failed on multiple lines of standard palliative therapy. The aim of our study was to evaluate the efficacy and safety parameters of bendamustine in these patients.
MATERIALS AND METHODS
General study details
This was a single-center, retrospective, observational study conducted between October 2020 and January 2021 in the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary cancer care center in Mumbai, India. The study was approved by the Institutional Ethics Committee (IEC)-3 on September 6, 2021 (project #900835, Supplementary appendix 1 ). The IEC waived the requirement to obtain written informed consent, as it was a retrospective study. We did not register the study in a publicly accessible clinical trials database, given the retrospective observational nature of the study. We adhered to the ethical guidelines included in the Declaration of Helsinki, the International Committee on Harmonization Good Clinical Practice guidelines, and the Indian Council of Medical Research. No funding was received for this study.
Supplementary Appendix 1
Participants
Patients over the age of 18 years, who had been planned for palliative systemic therapy, and had received treatment with bendamustine for metastatic, recurrent, or relapsed HNSCC were deemed eligible. A total of 25 such patients were identified from the database and were included in the study.
Objectives
We aimed to evaluate the safety and efficacy of bendamustine in patients with metastatic, recurrent, or relapsed HNSCC in the palliative setting. Our primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS) and toxicities.
Study methodology
We screened all the patients who had received systemic therapy for head-and-neck cancers between the years 2020 and 2021 from the database maintained by the Department of Medical Oncology. We raised a search query consisting of the following terms – ”head and neck squamous cell carcinoma (HNSCC),” “palliative therapy,” and “bendamustine” to identify the eligible patients. The demographics, histopathology, and previous treatment details of all the patients were retrieved from the case files and electronic medical records. The dose and line of bendamustine, the number of cycles administered, treatment-related toxicities, and clinical as well as radiological responses were recorded. Toxicities were charted in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Definitions
The primary endpoint of our study was progression-free survival (PFS) measured in months from the date of starting bendamustine till the occurrence of an event such as disease progression or death, whichever occurred first. The secondary endpoint was overall survival (OS) which was calculated from the date of starting bendamustine to the date of death from any cause.
Platinum-refractory disease was defined as cancer with documented tumor progression during the course of platinum-based treatment or recurrence within 6 months of platinum-based chemotherapy. Taxane-resistant disease was defined similarly, i.e., tumor progression during the course of taxane-based treatment or recurrence within 6 months after taxane-based chemotherapy.
Statistics
A sample size calculation was not performed given the retrospective nature of the study. All eligible patients were included within the time frame of the study. Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp., Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, USA: IBM Corp.) was used for the analysis. We performed descriptive statistics and estimated both PFS and OS using the Kaplan-Meier analysis.[ 19 ] Patients lost-to-follow up were presumed dead within 30 days from their last clinic visit date and were coded as event occurred. The median with interquartile range was calculated for continuous variables, while proportions with 95% confidence intervals (CI) were calculated for non-continuous variables.
RESULTS
A total of 25 patients treated with bendamustine as palliative intent chemotherapy were included in the study [Figure 1 ]. The median age of the study cohort was 47 (range, 29-58) years and the most commonly reported histology was oral cavity carcinoma (n = 21, 84%) [Table 1 ].
Figure 1: Screening, enrollment and analysis (*Patients who were lost-to-follow-up [n = 3] were included in the OS analysis and were coded as dead one month from the date of last clinic follow-up). OS=Overall survival; PFS=progression-free survival
Table 1: Baseline characteristics of the patients with relapsed refractory head-and-neck cancer who were treated with bendamustine
Before the administration of bendamustine, 19 (76%) patients had received platinum-taxane combination chemotherapy, and 8 (32%) had received OMCT. There were 16 (64%) patients who had progressive disease as the best response to the previous chemotherapy regimens, while 5 (20%) had disease recurrence after attaining remission. Of the 25 patients reviewed, 21 (84%) had platinum-refractory disease and 20 (80%) had taxane-resistant disease. The average time to failure for the previous treatments was 5.4 months (95% CI, 0.7-28.4) [Table 2 ].
Table 2: Previous treatment details of the patients with relapsed refractory head-and-neck squamous cell carcinoma
Bendamustine was administered at a dose of 100 mg/m2 intravenously every 3 weeks until progression or intolerable side effects. All patients received at least one cycle of bendamustine; the majority (16, 64%) completed only one cycle of bendamustine. Nine (36%) patients died while receiving treatment with bendamustine; all deaths were attributed to disease progression. There were 16 (64%) patients who developed progressive disease, of which 13 (52%) patients were planned for best supportive care, 2 (8%) patients were treated with low dose nivolumab, and 1 (4%) patient received treatment with OMCT.
All 25 (100%) patients treated with bendamustine developed disease progression; the median PFS was 1.3 months (95% CI, 0.9-2.0) [Figure 2 ]. At the time of analysis, 21 (84%) patients had died of progressive disease, 1 (4%) patient was alive, and 3 (12%) patients were lost to follow-up post-disease progression; the median OS was 2.2 months (95% CI, 1.6-3.6) [Figure 3 ].
Figure 2: Progression free survival of the patients with locally advanced, metastatic, recurrent or relapsed head-and-neck squamous cell carcinoma treated with bendamustine after failing multiple lines of prior therapy
Figure 3: Overall survival of the patients with locally advanced, metastatic, recurrent or relapsed head-and-neck squamous cell carcinoma treated with bendamustine after failing multiple lines of prior therapy
The most common side effects of any grade were constipation (n = 7, 28%) followed by neuropathy (n = 5, 20%), and fatigue (n = 4, 16%). Bendamustine was permanently discontinued in two patients (8%) due to toxicities; one patient experienced grade 3 hypercalcemia and grade 2 creatinine increase while the other patient had grade 2 diarrhea and grade 2 chemotherapy-induced nausea and vomiting [Table 3 ].
Table 3: Adverse events of bendamustine in patients with relapsed refractory head-and-neck squamous cell carcinoma
DISCUSSION
To the best of our knowledge, this is the first study evaluating the role of bendamustine as a third-line agent or beyond in head-and-neck cancers. Our study suggests that a median PFS of 1.3 months (95% CI, 0.9-2.0) and a median OS of 2.2 months (95% CI, 1.6-3.6) could be achieved with the use of bendamustine. Overall, these outcomes are dismal, but they need to be interpreted in light of the type of patients included in the study. The overwhelming majority of the study population had oral cavity cancer (84%), platinum-refractory disease (84%), taxane-refractory disease (80%), and over half the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Each of these factors has been independently linked to a poor prognosis.[ 20 , 21 ] Considering this heavily pretreated group of patients who had multiple negative prognostic features, the outcomes achieved by bendamustine appear reasonable.
Bendamustine was a well-tolerated drug. The most common toxicity observed was constipation (28%). Since these patients had been previously treated with multiple lines of therapy, administering a therapy with low toxicity was important. The safety of bendamustine was also demonstrated by other authors like Bottke et al .[ 16 ] who reported that amongst the 13 patients who received bendamustine along with radiotherapy, only 1 (7.7%) patient experienced grade 3/4 toxicity.
In developing countries like India, the use of immunotherapy is limited in the palliative setting and the accessibility is below 5%.[ 8–10 ] As observed in our study as well, only a minority of patients could receive immunotherapy and/or cetuximab. In such situations, especially in community practice, taxanes, platinum, and metronomic combinations are used. Following the use of these chemotherapy regimens, very limited treatment options are available as patients are unable to afford cetuximab or checkpoint inhibitors. Therefore, bendamustine can be offered as an alternative treatment to such patients after explaining the benefits of the drug.
Since this was a retrospective study conducted at a single center, there are limitations which exist such as a small sample size. However, this study provides real-world evidence regarding the use of bendamustine in the palliative setting in patients who have already received multiple treatment regimens and cannot afford expensive alternatives. Furthermore, there is a clear lack of literature on bendamustine and its role in head-and-neck cancers. Our study provides practical insights into the efficacy and safety parameters of bendamustine as a palliative drug in patients with HNSCC.
CONCLUSION
Bendamustine is a reasonably effective and well-tolerated drug that can be used as a third-line treatment or beyond in patients with metastatic, recurrent, or relapsed HNSCC, who have previously failed on multiple therapies.
Author contributions
Study conception and design: VP; data collection: VP, SA, VN, NM, GKS, KP; analysis and interpretation: VP, SA, VN, NM, GKS, KP; manuscript writing: VP, SA, VN; approval of the final article: all authors; accountability for all aspects of the work: all authors.
Data sharing statement
Individual de-identified participant data that are related to the results of this study and the statistical analysis plan will be made available on reasonable request, by Dr. Vijay Patil (email ID: [email protected] ) starting from the date of publication, until three years following publication. Requests beyond this timeline will be considered on a case-by-case basis.
Financial support and sponsorship
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The authors declare that they have no conflicts of interest.
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