Modified bi‐weekly cetuximab‐cisplatin and 5‐FU/leucovorin based regimen for effective treatment of recurrent/metastatic head and neck squamous cell carcinoma to reduce chemotherapy exposure of patients

Abstract Background The standard chemotherapy treatment protocol for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) requires as long as 56 days of hospitalization over six months. Where the 5‐Fluorouracil (5‐FU) pump is available, most treatment will be on outpatient bases, however patients will still be under chemotherapy treatment for a comparable period of time (around 50 days). Aim A modified protocol was assessed to decrease hospitalization and/or chemotherapy treatment time without sacrificing outcomes, to potentially increase patient quality of life. Methods and results A retrospective analysis (2005–2018) of recurrent/metastatic HNSCC patients with a modified treatment protocol was performed. Treatment consisted of cisplatin, cetuximab, 5‐fluorouracil bolus and leucovorin administered on day 1 of a 2‐week cycle, and a continuous infusion of 5‐fluorouracil on days 1–2 of the cycle. Outcomes were measured by progression‐free survival, overall survival, and patient hospitalization time. Analysis was done using the Kaplan–Meier survival function curve. The study cohort consisted of 27 patients. The modified treatment protocol resulted in a median progression‐free survival of nine months and median overall survival of 14 months, while hospitalization time was reduced by almost 80% in the first six months of treatment. Conclusions Modification of the cisplatin, cetuximab, 5‐FU and leucovorin protocol to a bi‐weekly regimen utilizing alternative drug delivery methods, significantly reduced patient hospitalization from 56 days to 12 days in the first 6 months of treatment. This was achieved without compromising treatment outcome, while significantly reducing the days patients were exposed to chemotherapy, and thus potentially improving quality of life.

nificantly reducing the days patients were exposed to chemotherapy, and thus potentially improving quality of life.  1,2 Up to 60% of recurrences are locoregional and are the leading cause of death, while metastatic recurrences are less frequent and account for up to 30% of cases. 3,4 The median overall survival (OS) of these cancer patients is approximately 6 months without chemotherapy. [5][6][7] In the seminal study described by Vermorken  In the region of Israel where this study took place, it is standard of care to provide 5-fluorouracil (5-FU) pumps for outpatient use for a maximum of two days, where longer treatment durations require hospitalization. The expected duration of hospitalization for patients treated with this cetuximab-based protocol is 48 days over six months.
In certain countries however, due to hospital regulations, fluorouracil is given from days 2 to 5 of the cycle thereby extending this hospitalization to 56 days in 6 months. Such a prolonged hospitalization is a concern, especially regarding patient quality of life, and risk of COVID-19.
In this study, the HNSCC treatment protocol was modified to reduce patient hospitalization duration. Briefly, this modified protocol consisted of administering cisplatin and cetuximab on day 1 of a 2-week cycle, with a 5-FU bolus plus leucovorin also given on day 1 of the cycle, and a continuous infusion of 5-FU on days 1 and 2. The rationale for this modification was derived from experience with cetuximab and fluorouracil in other indications, such as metastatic colorectal carcinoma, or with other combinations, such as docetaxel, in metastatic HNSCC. 9 In colorectal cancer, cetuximab has shown similar response rates when given in a biweekly or weekly regimen. 10,11 The modified protocol of this study altered the standard 5 days of 5-FU continuous infusion to reflect that of the de Gramont protocol, which was effective in colorectal cancer treatment. [12][13][14] The aim of this study was to successfully utilize a modified, alternative treatment protocol for recurrent and metastatic HNSCC to substantially decrease patient hospitalization duration and subsequently improve patient quality of life.

| Study population
The study was reviewed and approved by the institutional ethics com-  Table 1).

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| Treatment regimens
The modified treatment protocol comprised administration of 40 mg/m 2 cisplatin, 500 mg/m 2 cetuximab, 400 mg/m 2  In the modified protocol however, cisplatin is administered for as many cycles as tolerated rather than being limited to only 6 cycles.

| Patient monitoring
Patients were monitored every 2.

| Measurable outcomes
The primary endpoint of the study was OS, defined as the period between starting the modified protocol and death. The secondary endpoint was progression-free survival (PFS), defined as the period from the first treatment of the modified protocol until proven disease progression.

| RESULTS
Of the 238 patients recorded with recurrent or metastatic HNSCC, 27 (70.4% males) were identified as having been treated utilizing the modified protocol and were included in the study. Majority of the study cohort suffered from local regional recurrences of HNSCC (77.8%). The primary cancer sites are summarized in Table 1. The most common site of primary tumors was the oral cavity (63.0%).
Median treatment duration was 6 months. Kaplan-Meier survival analysis showed that median PFS was 9 months with a range of 5-18 months (Supplementary Figure 1). At the time of data cut-off, four  Figure 2).
Of the 27 patients treated according to the modified protocol, one patient discontinued treatment due to a moderate allergic reaction that was medically managed. An additional patient suffered an anaphylactic reaction to one of the drugs and refused to continue with treatment. Another patient suffered from necrotizing fasciitis of the neck while receiving treatment. This side effect can be attributed to the cancer, the radiation or the treatment received.
Due to the fact that only three patients suffered from grade 3/4 adverse events for which the treatment regimen had to be stopped, no adverse event profiles were included in the study results. The reason that a higher rate of severe adverse events was not seen is most likely related to the fact that the dose intensity of the highly toxic cisplatin was lower in our treatment regimen as compared to the standard regimen. Limitations of this study include the fact that this was a non-randomized, one-armed study, with a relatively small study cohort. Moreover, the clinical diversity of the patients participating in this study was broader than the reference study used for comparison.
Reduction of hospital or outpatient chemotherapy exposure is an aim to achieve across all treatment modalities. This study has shown that modification of the standard cisplatin, cetuximab, 5-FU HNSCC treatment protocol to a bi-weekly regimen using alternative drug delivery methods, significantly reduces patient chemotherapy time exposure from approximately 56 days to 12 days in the first 6 months of treatment, without compromising treatment outcome or desired results. Decreasing the time that a patient spends under chemotherapy may not only improve quality of life and reduce total healthcare costs but may improve patient compliance. A prospective clinical trial is warranted to confirm these findings.