To study the efficacy of romiplostim in chemotherapy-induced thrombocytopenia in head and neck cancer patients

INTRODUCTION

Thrombocytopenia is a common symptom of cancer patients and can be brought on by the disease, its therapy, tumor infiltration of the bone marrow (BM), or other etiologies such as liver disease or infection. Chemotherapy-induced myelosuppression and subsequent thrombocytopenia is a common finding with chemotherapeutic agents like gemcitabine, taxane, or platinum.^[1] Significant delay in chemotherapy can happen due to low platelet counts, and transfusion of platelets often yields temporary increments only. The delay or interruption of chemotherapy has been shown to affect outcome in a negative way.^[2] Apart from chemotherapy delay, very low platelet counts also increase the risk of bleeding and thus deterioration of patient’s general condition. The remedial measures in chemotherapy-induced thrombocytopenia (CIT) setting were not well defined in the past, except for platelet transfusion and delay or dose reduction of chemotherapy. Recent decade has seen emerging reports of use of thrombopoietin agonists (TPO-A) in the setting of CIT in a variety of malignancies.^[3–5] TPO-A has been widely used for immune thrombocytopenia (ITP), hepatitis C-induced thrombocytopenia, and thrombocytopenia of other reasons.^[6–8] TPO-A have been used across all ages and no major safety concern was noted. Cases of thromboembolism with TPO-A put a serious safety concern question in cancer setting, which is itself a prothrombotic state, thus in need of vigilance on platelet counts while using it.^[9] This study was planned to retrospectively analyze the practice of using romiplostim and its effect on platelet count in locally advanced head and neck cancer squamous cell carcinoma (LAHNSCC) cases that developed CIT.

MATERIAL AND METHODS

RESULTS

During the study period of six months, total of 110 cases were enrolled in the locally advanced head and neck squamous cell carcinoma induction chemotherapy program. Six cases opted out or defaulted and were excluded from analysis. One case died with aspiration pneumonitis before chemotherapy and was excluded. Out of 103, 18 cases (17.4 %) received romiplostim support at least once in chemotherapy cycles. Table 1 shows patients’ baseline characteristics. All cases were locally advanced and planned for induction chemotherapy followed by surgery (n = 6) or Concurrent chemoradiotherapy (CTRT) (n = 12). Median platelet counts before starting romiplostim was 76,000 cmm (range 35,000–96,000 cmm). Platelet counts were low even before the first chemotherapy among three cases, with a median 80,000 cmm. All three were diagnosed with peripheral platelet destruction, possibly ITP, with normal BM examination report.

As protocol, all cases were planned for three cycles of paclitaxel (175 mg/m²) and carboplatin (Area Under Curve (AUC) 7)-based induction chemotherapy with locally advanced HNSCC cases, planned at 21 days cycle gap; however, three cases received fourth cycle of chemotherapy as well while awaiting definitive local treatment. Three patients received all chemotherapy cycles after romiplostim as their baseline platelets were low. Among six cases, romiplostim was required before the second cycle, while 15 cases required romiplostim before the third cycle of chemotherapy. A median delay of ten days was noted among these cases where romiplostim was introduced after the first cycle of chemotherapy. Patients receiving romiplostim only after the second cycle (n = 6) showed a median delay of 11.5 days (6–18 days) in the initiation of subsequent chemotherapy. Three patients received two cycles only and proceeded for definitive surgery thereafter, while one case got interruption after two cycles and shifted to palliative radiation. None of them was shifted out of chemotherapy plan due to low platelet count. No dose reduction was noted among any of the cases.

Romiplostim was given as 3–8 μg/kg dosing, weekly schedule. Round off to the available strength (250 μg and 500 μg) was done. Patients who once required romiplostim were placed on prophylactic romiplostim dosing for the subsequent duration of chemotherapy. For platelet counts more than 200,000 cmm, the dose was skipped and platelet count was followed weekly. Any fall below 150,000 cmm was taken as a trigger to restart romiplostim injection. Median doses of romiplostim were five shots at weekly intervals. Platelet counts were checked weekly in a majority of cases and chemotherapy was given on platelet counts more than 100,000 cmm on the day of chemotherapy. For one case, chemotherapy was given at platelet count >90,000 cmm. Romiplostim was given after chemotherapy on the same day. Among cases with <50,000 cmm of platelet counts, median two doses (range 1–4) of romiplostim were required to raise platelet counts >100,000 cmm. Among cases with platelet counts >50,000 cmm, five cases showed platelet count >100,000 cmm after one dose of romiplostim, while the remaining nine cases required two doses for this desired increment [Table 2]. No thrombotic event was noted among any of the cases. Post chemotherapy, two cases noted platelets of <20,000 cmm despite romiplostim. Both were supported with platelet transfusions, a total of three episodes. No chemotherapy dose reduction was done. Four cases received red blood cell transfusions as well for anemia.

DISCUSSION

As per global cancer observatory statistics, head and neck malignancies constitute 10.3% of all adult malignancies.^[10] Head and neck cancer accounts for about 4% of all cancers in the united states. This year, an estimated 66,470 people (48,520 men and 17,950 women) will be diagnosed with head and neck cancer. Worldwide, an estimated 562,328 people were diagnosed with head and neck cancer in 2020.

Induction chemotherapy has been planned in stage III or IV, where upfront surgery seems difficult with the desired negative surgical margin. Paclitaxel and carboplatin have been used as chemotherapy in such cases.^[11] Incidence of thrombocytopenia with platinum chemotherapy as well as taxane has been well documented.^[12] Use of TPO agonists in such settings has shown encouraging results.

TPO agonists used in CIT have been elaborated in a few studies and encouraging results have been noted. Parameshwaran et al. described the use of romiplostim among 20 solid tumor cases where prolonged CIT was noted. They found encouraging results with desired platelet increment in most of the cases.^[13] In a multicentric study of romiplostim use in CIT, including lymphomas and solid tumors, a noticeable response in the form of raised platelet count, decreased duration of thrombocytopenia, and reduced delay in chemotherapy was noted among solid tumors.^[14] Hanny Al-Samkari et al. also noted similar results with romiplostim.^[5] This study elaborated about the variable time lag of platelet count increment. While 59% cases achieved the desired platelet count of >100,000 cmm in one week of romiplostim, 18% cases required 7–12 weeks of therapy for such effect. This study noted a relatively quick and uniform romiplostim response and a platelet response in 1–2 weeks among most of the romiplostim group cases. It also noted prompt response among ITP cases.

CIT involves chemotherapy dose reductions and treatment delays; reduced relative dose intensity of chemotherapy may have a negative impact on optimal management of the malignancy and may lower overall and progression-free survival.^[2] Our study noted no need for dose reduction among romiplostim patients, although a delay in next cycle was observed. Effect of delay and dose reduction in such subset of head and neck malignancy is not known precisely.

Romiplostim-induced thrombotic events are not noted in our study. Incidences of vascular thrombosis with romiplostim in CIT setting are variable with none to few cases.^[9,14]

Our study also noted no thrombocytosis secondary to romiplostim.

There are certain limitations to our study. Retrospective, observational nature of study makes the finding less robust. This study has smaller sample size and has no control group, further making it small to draw any significant conclusion.

CONCLUSION

Romiplostim can be used effectively to raise platelet counts in CIT in head and neck cancers. A larger randomized controlled study is required to recommend this practice as standard.