Chinese expert consensus on the application of pegylated recombinant human granulocyte colony‐stimulating factor during concurrent chemoradiotherapy (2020 edition)

Concurrent chemoradiotherapy (CCRT) is an important treatment modality for malignancies.1, 2 Neutropenia the most common hematological toxicity of CCRT and can often lead to febrile neutropenia (FN), toxic shock, even death, which not only seriously impact clinical survival cancer patients, but also increase their medical expenses.3-5 Numerous national international organizations have published guidelines on standardized management chemotherapy-related neutropenia. These recommend prophylactic use pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF, pegfilgrastim) within 24–72 h after chemotherapy completion, as it effectively reduce incidence, duration, severity chemotherapy-induced neutropenia.6, 7 However, these lack recommendations PEG-rhG-CSF during CCRT, been helpful in solving problems encountered by radiation oncologists practice. a purified long-acting (rhG-CSF) with 20 000 Da polyethylene glycol cross-linked N-terminus rhG-CSF. was first approved marketing China 2011, marked start era treatment. To promote reasonable this treatment, Chinese Association Therapeutic Radiation Oncologists has re-evaluated safety efficacy based relevant recent data, formed expert consensus (pegfilgrastim) application provide reference oncologists. primary adverse event myelosuppressive therapies, such therapy. serious dose-limiting chemotherapy. Bone marrow highly sensitive radiation, degree tissue damage depends dose, range, location, duration radiation. therapy mainly affects lineage, more tumor radiotherapy. defined absolute neutrophil count (ANC) <2.0 × 109/L peripheral blood. There are four grades CTCAE 5.0; namely, grade 1 (1.5 ≤ ANC < 2.0 109/L), (1.0 1.5 3 (0.5 1.0 4 (ANC <0.5 109/L). FN accompanied fever. Serious or expected 48 h. Fever oral temperature ≥38.3°C single measurement ≥38.0°C over h.7 A meta-analysis 19 randomized-controlled trials involving 2728 stage I–III non-small cell lung patients showed that incidence 3.53- 1.38-fold higher than radiotherapy alone sequential chemoradiotherapy, respectively.8 Stratified analysis radiotherapy-induced myelosuppression MacManus et al. found volume irradiation main risk factors moderate severe FN.9 In particular, highest its odds ratio (OR) up 42.1. The incidences ≥3 be high 77% 16% non-resectable III receiving vinorelbine plus cisplatin respectively.10 CONVERT trial 3–4 (84% vs. 70%; P = 0.02) among small (SCLC) >70 years CCRT.11 addition, 45.7% esophageal + neoadjuvant CCRT. For unresectable cancer, 30.3% 31.6% radical (paclitaxel cisplatin), respectively.12, 13 It previously reported toxicities cause (88%) interruption, local control rate interruption.14 Furthermore, overall significantly lower myelosuppression-induced interruption those without interruption.15, 16 Therefore, prevention extremely malignant patients. Prophylactic should considered, particularly high-risk (e.g. aged >65 had previous neutropenia) standard-dose 1995 study 215 SCLC combined granulocyte-macrophage increased toxicities.17 As result finding, subsequent versions American Society Clinical Oncology National Comprehensive Cancer Network recommended routine (CSF) while acts upstream granulocytes, specifically targets progenitors. guideline much debated. contrast, advancements technology allowed precise delivery high-dose affecting adjacent normal tissues, greatly reduced radiation-induced toxicities. worthy re-evaluation. 38 limited-stage (3-D conformal radiotherapy), prophylactic, secondary therapeutic (G-CSFs) did risks acute advanced pulmonary esophagitis nor treatment-related deaths patients.18 phase 547 Among 33% were given at least one cycle G-CSFs, 41% G-CSFs. Similar findings II trial, G-CSFs beneficial completion.19 result, statement “prophylactic CCRT” removed from Guidelines Hematopoietic Growth Factors (2020 v1).6 show modern technology, safe Myeloid Cytokines Treatment Acute Exposure Myelosuppressive Doses Radiation: Subsyndrome Syndrome (H-ARS) US Department Health & Human Services Emergency Medical Management 2015. This recommends (6 mg, single-dose, subcutaneous) (weighing >45 kg) who might experience ≤500/mm3 persistent neutropenia.20 Likewise, Expert Consensus Application Pegylated Recombinant Granulocyte Colony-stimulating Factor (2016 edition) post-chemoradiotherapy neutropenia.21 Guideline Standardized Induced Chemotherapy Radiotherapy (2017 CCRT-induced under close monitoring patient's parameters.22 whose regimen (FN >20%), regardless whether intended cure, prolong survival, improve disease-related symptoms (Table 1). (10%–20% FN), evaluation physician recommended. considered 2). low <10%), required. other treatments may FN-related negative prognostic factors, bone metastasis invasion. CDE (cyclophosphamide doxorubicin etoposide) Topotecan ICE (ifosfamide carboplatin Paclitaxel Docetaxel TCH (docetaxel trastuzumab) ddAC-2wP (dose-dense cyclophosphamide cycles paclitaxel) ddAC-1 wP TAC cyclophosphamide) TE epirubicin) TC FEC (fluorouracil epirubicin High-dose docetaxel thiotepa VeIP (vincristine ifosfamide cisplatin) VIP (etoposide TIP BEACOPP (bleomycin etoposide vincristine procarbazine prednisone) Brentuximab-vedotin AVD (doxorubicin dacabarzine) Dose-adjusted EPOCH prednisone doxorubicin) Dose-dense CHOP ± rituximab MINE (mesna mitoxantrone DHAP (dexamethasone cytarabine( ESHAP methylprednisolone cytarabine) HyperCVAD dexamethasone) Dacarbazine-based combination (dacarbazine vincristine) IL-2 IFN-α) methotrexate Doxorubicin (neoadjuvant) Methotrexate (advanced initial diagnosis) Cisplatin (arterial intervention) (intravenous drip) MAID dacarbazine) Standard-dose Ifosfamide DT-PACE thalidomide VTD⁃PACE (DT-PACE bortezomib) CAV Etoposide cisplatin/carboplatin Age received sufficient dose intensity Previous Presence before Tumor involvement Recent surgery and/or open trauma Liver dysfunction (bilirubin >2.0 mg/dL) Renal (creatinine clearance <50 mg/min) Malignant hemolymphatic diseases Female patient (small cancer) Cardiovascular disease (non-Hodgkin's lymphoma) TP NP (cisplatin vinorelbine) DP docetaxel) CP (carboplatin Irinotecan Epirubicin fluorouracil capecitabine topotecan Docetaxel-based trastuzumab CMF fluorouracil) AC-T docetaxel, cycle) AC-TH (sequential FEC-T 21-day paclitaxel ddEC-T E-CMF XT (capecitabine standard regimen) BEP GDP (gemcitabine dexamethasone rituximab, including liposomal substitute CHP bentuximab Bendamustine if observed First, subcutaneous administration completion (administration 14 days 24 cytotoxic recommended). Second, 6 mg (>45 kg adults) 100 μg/kg (<45 children, etc.) per Third, weekly there no evidence support PEG-rhG-CSF, then consensus. 163 neutropenia-related hospitalization (4.44% 14.62%, 0.002) delay (5% 17.69%, 0.001) compared delayed antibiotic (by 78.1%), neutropenia, FN, (P 0.05).23 comparing rhG-CSF head neck 3/4 (3.85% 19.5%, (0.96% 8.53%, 0.023), favorable implementation scheduled time dose. both well-tolerated patients.24 mean half-life 47 h, required effect last 12 days. Neutrophil metabolism prevent excessive elevation maintain stable range. pharmacological properties suitable use, they adherence workload staff.25 current involves early administration, measures poor adherence.26 non-special conditions, tumor, ensures neutropenic following conditions: (i) sepsis; (ii) age years; (iii) 109/L; (iv) possibility prolonged neutropenia; (v) complicated pneumonitis infections; (vi) invasive fungal (vii) fever hospitalization; (viii) FN.20, 27 Patients continue until above trough value restores level near laboratory receive PEG-rhG-CSF. generally additional If persists days, salvage considered. (not chemotherapy). adult) children) proliferation group group. already detectable 12–24 improved 36 h.28 either resulted comparable ANC, recovery various points caused > 0.05). decrease neutropenia.29 complex scenarios, in-depth patients’ conditions maximize differentiation, effective concentration toxicities, large number newly-generated naive neutrophils killed chemotherapeutic drug, resulting dysfunction. regimen. pain: pain reaction similar between (19.7% 19.0%), mild-to-moderate does require Non-steroidal anti-inflammatory drugs, ibuprofen naproxen, used symptomatic cannot tolerate pain. post-PEG-rhG-CSF naproxen (500 bid) 5–8 d PEG-rhG-CSF-induced pain.31 Allergic reactions: Skin, respiratory, cardiovascular allergies. reactions relatively rare do anti-allergic Splenomegaly/splenic rupture: Although exact mechanism G-CSFs-induced splenomegaly/splenic rupture still unclear, state some hematopoietic transient splenomegaly splenic event. abdominal (especially upper left abdomen), nausea, vomiting, gradual exacerbation anemia, change spleen closely monitored timely associated type, drug intensity, volume, site. reduction, delay, consequently prognosis. parameters provided successful ensure authors declare read article competing interests. List experts During Chemoradiotherapy Member advisory group: Yu Jinming (Shandong Hospital) Leader writing Li Baosheng Members (in alphabetical order family name): Fu Xiaolong (Shanghai Chest Hospital), Han Chun (Fourth Hospital Hebei University), Hui Zhouguang (Cancer Academy Sciences), Lang Jinyi (The Affiliated School Medicine, UESTC/Sichuan Guang (First Lu Bing Guizhou University/Guizhou Wang Jun Junjie (Third Peking Luhua Sciences, Shenzhen Center), Ping (Tianjin University Institute Xiaohu (Lanzhou Heavy Ion Hospital/Institute Modern Physics, Wu Yongzhong (Chongqing Zhang Fuquan (Peking Union College Zhen (Fudan Shanghai Zhu Guangying (China-Japan Friendship Written by: University)