In recent years, the incidence of cancer was continuously increasing in the global. With the progress of biomedical science, novel biotherapy and targeting therapy have provided more options for cancer treatment. However, for these therapeutic modalities, the high cost and specificity of patients, e.g. patients with specific receptors or genes, have restricted their clinical application to some extent. With relatively affordable price and broad-spectrum antitumor activity, chemotherapy remains as the major option for most cancer types. While inhibiting and killing the tumor cells, chemotherapeutic drugs would inevitably damage the normal cells and induce a variety of side effects [16, 17]. BMS is one of the most common systematic toxicity of chemotherapy. The occurrence of BMS will require the reducing dose of chemotherapy drugs, prolong the time of chemotherapy, and even have the possibility to terminate chemotherapy. What’s worse, BMS would increase the risk of visceral bleeding, infection, shock, etc., especially in elderly patients, which can be fatal and not conducive to the prognosis [18].
The current clinical treatment for BMS mainly focused on the symptomatic treatment. If BMS can be predicted before chemotherapy, it will greatly alleviate the economic and disease burden of patients. Recently, real-world studies (RWS) have been widely applied in the prediction of drug-related adverse effects [19–21]. However, due to the regional specificity of the incidence, esophageal cancer is relatively rare in the middle of China, and there are few RWS on the adverse effects of esophageal cancer after chemotherapy. Herein, in this project we established a prediction model involved in various comprehensive factors related to chemotherapy-related BMS for esophageal cancer. The AUC of the training and validation set was 0.883 (0.863–0.904) and 0.881 (0.85–0.912), respectively, indicating good accuracy of this newly developed model.
BMS after chemotherapy is largely determined by the chemotherapy regimen. Lobaplatin is the third-generation platinum compound developed by Germany. Compared with cisplatin, it reduces the occurrence of hair loss, nephrotoxicity, ototoxicity, etc., but hematological toxicity, especially thrombocytopenia, is more common [22]. Among the chemotherapy drugs analyzed in this study, lobaplatin, PTX and 5-F all have relatively hematological toxicities and lobaplatin has the most serious effect in inducing BMS. It has been reported that combination of multiple chemotherapeutic agents can improve the therapeutic efficacy as well as reduce the side effects [23]. Compared with mono-chemotherapy, combinational therapy by PTX + PCD and 5-F + PCD showed protective effects to BMS. Besides, the results of this study showed that multiple courses of chemotherapy have a wide variety of effects on BMS. It could be attributed to that multi-cycle chemotherapy would increase the cumulative toxicity of chemotherapeutic drugs, thereby exacerbating the risk of BMS [24].
The blood parameters were important risk factors in BMS. In the present research, the Hb, PLT and RBC counts of BMS were lower than that of Non-BMS (Table S1). According to Table 1, with increasing of Hb and PLT, the risks of BMS significantly reduced. The lower Hb and PLT counts before chemotherapy indicated the deficiency of hematopoietic function in the patient's bone marrow, which may be attributed by the patient's low hematopoietic reserve capacity [25]. However, our research showed no significant impact of RBC count on BMS, which could be attributed to the limited number of cases in this study.
To clarify the relationships of tissue functions with BMS, we investigated liver function, electrolytes, renal function and heart function of patients. After multivariate logistic regression analysis, BUN, Cr and urine protein for renal function and CK for heart function were included for developing the prediction model. Among the three markers for renal function, Cr played the most important role in the model, followed by BUN and urine protein (Fig. 3). With the elevating level of Cr and urine protein, the risks to induce BMS increased correspondingly. BUN showed no significant influence. As chemotherapy agents are excreted through the kidney. Injured renal function would diminish the renal clearance, reduce the drug elimination and increase the in vivo drug exposure time, thereby aggravating the systematic toxicities [26, 27]. The elevating of CK indicated the deficiency of heart function. According to our results, heart function showed no obvious impact on BMS. It could be resulted from that the baseline CK for BMS and Non-BMS were both in normal range.
Other factors including sex, concomitant use of drugs and age were also in our model. Male patients were more incline to occur BMS than the female, which could be related to the bad lifestyle habits of men, such as smoking and drinking, etc. The concomitant use of other drugs increased the risk while age showed no obvious effect in inducing BMS.
The present study had several limitations. First, it was a retrospective study, which was lack of standardized data collection. In fact, we had attempted to carry out a prospective study to obtain a better conclusion. However, owing to the limited patient number of esophageal cancer in the designed period of this study, the prospective study failed to draw a meaningful result. Second, this study was carried out in a single-center with sub-sufficient sample size. We had collected all the consecutive patients with esophageal cancer from 2013 to 2020 at our hospital, so the study population was still representative in the middle of China. Multi-center studies could be performed to establish models with wider application range. Third, the validation of this study used an internal validation method by separating 30% of the collected data. External validation was also needed to verify the prediction model.