Abstract

INTRODUCTION

Multimodality management either a combination of surgery followed by adjuvant radiation or radical chemoradiation is the standard of care in locally advanced oral cancers.[1,2] However, in spite of multimodality management, locally advanced oral cancers have high failure rates.[2,3] Unfortunately, majority of these failures occur in first 1-2 years posttreatment completion.[3,4] Palliative chemotherapy remains a treatment option in such scenarios.[5,6] However, patients who fail within 1-month of adjuvant radiotherapy (RT) or within 6 months of CTRT (within 6 months of last dose of platinum) have a very poor prognosis.[7,8,9] These biologically aggressive tumors are commonly excluded from the treatment defining studies.[10,11,12] Unfortunately, there is no dearth of such patients in our country. Cetuximab-based chemotherapy seems to be an option in these patients. However, < 1% of patients in the developing countries can afford it.[13]

Metronomic chemotherapy consisting of oral methotrexate and celecoxib has shown promising results in head and neck cancer patients.[14] We recently reported a randomized study which compared metronomic chemotherapy consisting of oral methotrexate and celecoxib with intravenous cisplatin in palliative head and neck cancer patients who had failed post 3 months of curative therapy.[8] Metronomic chemotherapy was found to be superior in terms of progression-free survival (PFS) and overall survival (OS). Hence, these patients with early failures are treated with a metronomic combination of celecoxib and oral weekly methotrexate on compassionate grounds when they cannot afford cetuximab at our center. This analysis was planned to study the efficacy of metronomic chemotherapy in this group of patients. We hypothesized that if 6 months survival would be 30% or more, then metronomic chemotherapy should be studied in a randomized Phase 2.

MATERIALS AND METHODS

This was a retrospective analysis. We maintain a prospective database of patients undergoing palliative chemotherapy in head and neck cancers. Cases were selected from this database subjected to following criteria.

RESULTS

DISCUSSION

Recurrent head and neck cancers have limited treatment options.[5] Salvage surgery provides the best chance of cure. Further, the results of salvage surgery are impressive if the DFI is >2 years and stage of recurrent tumor is Stage I or II.[5] Impressive 2-year DFS rates of 70% have been reported in such patients.[16] However, only 16% of recurrent patients are suitable for salvage surgery,[17] either the DFI is short or the disease is extensive. In our study, we have addressed such patients only. Hence, it's not a surprise that none of these patients was considered for salvage surgery by the multidisciplinary clinic. Re-irradiation is the next option available in recurrent head and neck cancers. However, again in the context of early failures as in the present study, re-irradiation is not a feasible option. Reirradiation is associated with 2 years OS 30-40% in different series; however, the series are limited to patients who had DFI of more than 1-year from previous treatment and the tumor volumes were small (< 27 cm³). [5] The cohort of patients in this study had extensive disease and the maximum DFI was 6 months hence palliative chemotherapy was offered.

Palliative chemotherapy in head and neck cancers has evolved over time. It started with a small study demonstrating a survival benefit of chemotherapy over patients treated with only supportive measures.[18] Over next 30-40 years, we have improved survivals modestly by adding targeted therapy to chemotherapy.[12] However, this benefit of targeted therapy, cetuximab was seen in a randomized study done in a selected cohort of patients. Likely, platinum-insensitive patients were excluded from this study and are routinely excluded from the treatment defining palliative chemotherapy studies.[10,11,12] Platinum-insensitive or resistant or refractory patients have never been systematically addressed.[19] The definition of this entity has also been variable. In general, patients who receive either cisplatin cumulative dose more than equal to 60 mg/m2 or carboplatin cumulative dose more than or equal to AUC-4,2 or more cycles of treatment with < 4 weeks among them and failure within 6 months of the last dose of platinum are considered as platinum-resistant.[15] Figure 1 depicts that 71 patients in our cohort who all had received platinum had failed within 6 months and cumulative doses were far beyond these recommendations. We have also included 29 patients who had failed within 1-month of surgery and adjuvant RT. These patients were included as these patients have a biological aggressive disease and even these patients are excluded from chemotherapy studies and hence are never addressed.[10,12]

The treatment options in the platinum-resistant and/or early failure patients studied are limited. Cetuximab as a single agent seems an appropriate option in this setting. In a study done by Vermorken et al., 117 patients who had progressed on platinum were treated with single-agent cetuximab. The disease control rate was 26%. The median time to progression and OS were 50 days and 178 days, respectively. This regimen had limited side effects and was well tolerated.[19] Similar results with a median PFS of 85 days and OS of 183 days with single agent cetuximab were reported in platinum refractory patients by Baselga et al.[7] Combination of cetuximab + cisplatin has shown similar survivals to single agent cetuximab in patients who had progressed within 90 days (3 months) on cisplatin-paclitaxel or cisplatin 5 FU combination.[20] Another combination tried in platinum-insensitive patients is weekly paclitaxel and cetuximab. This regimen in retrospective studies has consistently shown to have median OS around 10.0 months.[21,22] However, the cost of cetuximab precludes its use in most of the low and middle-income countries as a routine standard of care; hence, the search for cheaper alternatives.[13] The mechanism of the action of metronomic is by antiangiogenesis and its effects the endothelial cell of the vasculature supplying the tumor.[23] The endothelial cell is a genotypically stable cell hence it should be unaffected by somatic mutations in the tumor which leads to platinum-resistance.[24] Hence, metronomic chemotherapy theoretically should be equally effective in early failures or platinum-resistant patients. Metronomic chemotherapy combination of methotrexate and celecoxib, unfortunately, failed to meet its expectation in our study. The threshold considered by us for its further studies was 30% OS at 6 months, while the proportion of patients surviving was below this, 26.4% at 6 months.

The impact of time to failure post upfront multimodality treatment on OS with palliative chemotherapy was seen in this study. Patients with time to failure below 3 months had lower OS than patients who had failure between 3 and 6 months posttreatment completion. Previous treatment with radiation, poor PS, previous history of weight loss, nonoropharyngeal location, and poor differentiation are the known poor prognostic features in the patients treated with palliative chemotherapy in head and neck cancers. Patients having two or more of these features (poor risk status) have a survival of around 6 months with first-line platinum chemotherapy.[6] In our study, majority of patients (84 patients, 84%) had previous radiation and all had oral cancer primaries. In addition, nearly three-fourth of the patients had exposure to platinum and had failed within 6 months.

As this metronomic combination has failed to reach the prespecified proportion, we need to consider other options in the patients who cannot afford cetuximab. The mechanism of resistance to methotrexate in head and neck cancers is driven by ABCG2 protein.[25] This protein is overexpressed in 60% of head and neck cancers.[26] Erlotinib is a known potent inhibitor of this protein.[27] Addition of erlotinib to this combination of methotrexate and celecoxib seems a rational approach. Second-line treatment with erlotinib after first-line failure provides response rates of around 15-20% in our experience.[8] At this end, we now planned to study the combination of triple drug metronomic (methotrexate, celecoxib, and erlotinib) in this poor risk cohort.

CONCLUSION

Metronomic chemotherapy combination of methotrexate and celecoxib failed to meet its prespecified efficacy limit and hence should not be used in such patients.