2L triple metronomic chemo shows more efficacy in comparison to systemic therapy for head and neck cancer

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Published: 5 Jun 2023
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Dr Rushabh Kiran Kothari (PI, CRSF group) - Narayana Multispeciality Hospital, Ahmedabad, India

Dr Rushabh Kiran Kothari speaks to ecancer about a phase 3 randomised study for evaluating the physician's choice of treatment compared to triple metronomic chemotherapy as second-line therapy in head and neck cancer.

Triple metronomic chemotherapy is oral, affordable and requires minimal resources. In this study, the efficacy endpoints were overall survival, progression-free survival, quality of life and adverse events. 

The study found that triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician-choice therapy.

It was also discovered that the adverse event rate was lower with metronomic chemotherapy. Furthermore, being an oral treatment, triple metronomic chemotherapy is easy to administer. 

Head and neck cancer is a significant challenge in our country, it is the second most common malignancy. Globally we know that with chemotherapy in second line or beyond relapsed metastatic head and neck cancer patients we don’t have a good treatment to offer. Most of our patients with chemotherapy have a dismal outcome and median overall survival is less than seven years. 

Immunotherapeutic agents like nivolumab and pembrolizumab have shown statistically significant benefit in median overall survival and a fraction of patients do get long and durable response. But, unfortunately, most of our patients, less than 3% of patients can access immunotherapeutic agents. So we, as a group, have prior published literature on metronomic chemotherapy and triple metronomic therapy which comprises an oral regimen of erlotinib, methotrexate and celecoxib which in the palliative setting has shown a reasonable first line and second line response rate, overall survival and progression free survival. Also it has shown improvement in quality of life and decreasing adverse events. Based on this background, we have tried to compare metronomic chemotherapy with physician’s choice of treatment in second line or platinum refractory head and neck cancer patients.

In the trial we have taken… very pragmatic patients were taken. We have taken all the patients who were more than or equal to 18 years of age, all patients who were planned for second line treatment or were platinum refractory, all patients with ECOG performance status 0-2. Taking ECOG performance status 2 is not a usual thing in routine clinical trials. Here the patients were randomised 1:1 to metronomic chemotherapy and physician’s choice of treatment and our efficacy endpoints were overall survival, progression free survival, quality of life and adverse events. 

The primary endpoint of overall survival improved from 4 months to 6 months with a hazard ratio of 0.50, the confidence interval not crossing unity and a significant p-value. Similarly, progression free survival improved from 70 days to 120 days, again with a hazard ratio of 0.49 not crossing unity and a significant p-value. Thus it is an efficacious regimen when compared to physician’s choice of treatment. 

The second important thing which we found was the adverse event rate was lower with metronomic chemotherapy and grade 3-5 adverse events were also lower with metronomic chemotherapy. The third important thing was it, being an oral treatment, is easy to administer. The compliance rate was around 98% with that regimen. So, an efficacious treatment with lower adverse events and a treatment which can be taken by patients in an appropriate form is something which we always look for as oncologists.

How could this research impact the future treatment of head and neck cancer?

There are two aspects to it. In low and middle income countries such as ours, most of our patients are not able to access immunotherapeutic agents. For them, this is potentially standard of care in second line treatment because when compared with physician’s choice of treatment, which was a very broad range, we allowed chemotherapeutic agents like paclitaxel, docetaxel, 5FU, capecitabine, immunotherapy agents like nivolumab, pembrolizumab, targeted therapeutic agents like cetuximab and afatinib. When it was compared with such a broad range of agents it has shown improvement in overall survival and decrease in adverse events. So it is likely to be standard of care in low and middle income countries, especially where access to immunotherapy is low.

In high income countries where access to immunotherapy is not an issue, most of the patients will now receive immunotherapy in first line treatment. Hence, second line treatment is again an unmet need there where the given physician’s choice treatment, when compared with metronomic chemotherapy, is inferior. So metronomic chemotherapy is something which can be considered even in the setting where immunotherapy has been exposed in first line.