The Effect of Prophylactic TPO Combined With BMS-IMRT to Esophageal Cancer Patients

Study Overview
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Brief Summary
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The goal of this interventional study is to explore the protective effect of prophylactic TPO combined with bone marrow sparing (BMS)-IMRT in patients with esophageal cancer undergoing concurrent chemoradiotherapy. The main purpose is to reduce the incidence of all grades of thrombocytopenia from 35% to less than 10% by the intervention of study. Participants will initiate concurrent chemoradiotherapy within 2 weeks after enrollment,and they will receive subcutaneous injection of recombinant human thrombopoietin (rhTPO) 15000U once a week during the radiotherapy.

Detailed Description
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Concurrent chemoradiotherapy (CRT) is one of the standard treatments to the patients who initiate neoadjuvant chemoradiotherapy or radical radiotherapy. Previous large phase III trials of preoperative concurrent chemoradiotherapy and definitive chemoradiotherapy (Dt 40-60Gy) in esophageal cancer have shown rates of platelet inhibition (grade 1-4) of 25-54%. Concurrent chemotherapy has been associated with a significant increase in acute hematologic toxicity (HT) associated with radiation therapy, increasing the risk of infections, blood transfusions, colony-stimulating factors, and length of hospital stay. More importantly, severe myelosuppression also delays or interrupts the delivery of chemotherapy and radiotherapy, potentially reducing efficacy. In addition, the efficacy of locally advanced patients is still not optimistic, and the intensity of treatment may need to be increased. Therefore, if hematologic toxicity can be reduced, it may lead to more intensive concurrent chemoradiotherapy in the hope of further improving the efficacy. Intensity-modulated radiation therapy (IMRT) has an absolute advantage over conventional radiotherapy in increasing the dose to the target volume and reducing the dose to normal tissues. Previous studies have shown a significant association between the volume of 10Gy (V10) and the volume received 20Gy (V20) of the pelvic and lumbosacral bone marrow and the development of acute HT when pelvic tumors are treated with IMRT. Thus, reducing the volume of bone marrow receiving low-dose radiotherapy may reduce the occurrence and severity of HT. Therefore, using the dosimetric advantages of IMRT, quantitative study of BMS-IMRT to reduce the toxic effects of concurrent chemoradiotherapy is a research hotspot at present. Thrombopoietin (TPO) promotes the proliferation and survival of hematopoietic stem cells and all hematopoietic progenitor cells, accelerates the entry of stem cells into the cell cycle, and subsequently promotes the mitosis and polyploidy formation of megakaryocytes, increases the volume and number of megakaryocytes, and works with other cytokines to regulate megakaryocyte maturation. It is a commonly used drug for the treatment of thrombocytopenia in clinic. The aim of this study is to explore the protective effect of prophylactic use of TPO on platelet inhibition in concurrent chemoradiotherapy using BMS-IMRT for esophageal cancer.

Official Title
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A Prospective Phase II Study of Prophylactic TPO Combined With Bone Marrow-Sparing Intensity-Modulated Radiotherapy to Reduce Platelet Inhibition in Patients With Esophageal Cancer Undergoing Concurrent Chemoradiotherapy

Conditions
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Esophageal Cancer, Intensity-modulated Radiation Therapy, Concurrent Chemoradiotherapy, Thrombocytopenia

Intervention / Treatment
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* Drug: rhTPO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than 18 years and less than or equal to 75 years Histopathologically confirmed esophageal squamous/adenocarcinoma, clinical stage I-IV A (according to the 7th edition of AJCC（American Joint Committee on Cancer） 2010; Concurrent chemoradiotherapy (≥45Gy) was planned (regardless of whether the patient had received induction adjuvant chemotherapy). Karnofsky performance status score ≥80 ·; Life expectancy >6 months; Meet the following laboratory diagnostic criteria: Hemoglobin ≥120g/L, white blood cell ≥4.0×109/L, Neutrophil ≥2.0×109/L, platelet ≥100×109/L; Participators had not used granulocyte colony-stimulating factor and thrombopoietin within 3 weeks before enrollment. Exclusion Criteria: A history of malignancy at other sites, excluding curable non-melanotic skin cancer and cervical carcinoma in situ; Previous radiotherapy to the chest; Patients with existing or suspected (thoracolumbar and pelvic) bone marrow or bone metastases, or a history of bone trauma in this region within 4 weeks; Allergy to Gadolinium-based contrast agent; Patients with active infection, or combined with rheumatic immune disease, long-term chronic infection, acute infection, etc., so that the body is in an inflammatory state; Blood system diseases with hematopoietic dysfunction;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: All patients are planned to receive concurrent BMS thoracic radiotherapy (>45Gy, 1.8Gy per fraction), chemotherapy (five cycles of weekly intravenous paclitaxel [50 mg/m²] and cisplatin/nedaplatin [25 mg/m²], or two cycles of intravenous paclitaxel [135-175 mg/m²] and cisplatin/nedaplatin [80 mg/m²]) , and rhTPO，15000U ih. qw(during the radiotherapy)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: prophylactic TPO<br>Prophylactic TPO combined with BMS-IMRT in the esophageal cancer patients undergoing concurrent chemoradiotherapy | Drug: rhTPO<br>* Standard treatment options: Radiotherapy: 95% planning target volume （planning target volume，PTV） ≥45Gy(without simultaneous boost). Concurrent chemotherapy: Weekly regimen: paclitaxel 50mg/m2 d1, nedaplatin/cisplatin 25 mg/m2d1, a total of 5 cycles. Three weeks regimen: paclitaxel 135-175mg/m2 d1, nedaplatin/cisplatin 80mg/m2, a total of 2 cycles. The active bone marrow was determined by magnetic resonance（magnetic resonance，MR）, and the dose limits are: V5<95%,V10<85%,V20<60%，V30<40%；95%PTV>45Gy. rhTPO，15000U ih. qw(during the radiotherapy course)<br>* Other names: concurrent chemoradiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The highest grade of thrombocytopenia (CTCAE 4.0) during the radiotherapy and 1 month after the radiotherapy. | For esophageal cancer patients, Grade 1-4 thrombocytopenia is considered as endpoints. | From start of radiotherapy and 1 month after the radiotherapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical dosimetry of active bone marrow in BMS radiotherapy plan. | Low dose volume, the volume of active BM receiving 5,10,20,30 and 40 Gy | The first day of radiotherapy. | 
| Conformity of BMS IMRT/VMAT (Volumetric Modulated Arc Therapy，VMAT) plan | Conformity Index (CI）was used to evaluate the conformity of IMRT/VMAT plan. | The first day of radiotherapy. | 
| Homogeneity of IMRT/VMAT (Volumetric Modulated Arc Therapy，VMAT) plan | Homogeneity Index (HI) was used to evaluate the homogeneity of BMS IMRT plan. | The first day of radiotherapy. | 
| The highest grade of leukopenia, neutropenia,anemia (CTCAE 4.0) during the radiotherapy and 1 month after the radiotherapy. | For esophageal cancer patients, Grade 1-4 leukopenia, neutropenia and anemia are considered as endpoints. | From start of radiotherapy and 1 month after the radiotherapy. |