Medical technology errors.

There were six aspects of medical technology errors involved in this study. Errors involving ADRs control accounted for nearly half of the medical technology errors. Therefore, in the clinical application of NADs, the primary task is to control the ADRs of NADs. The study of litigation cases highlighted several errors in this scope. The causes of litigation are generally acute and serious ADRs to NADs. The most frequent errors were inadequate prevention and preparation, inadequate disposal and treatment, and inadequate observation and monitoring, accounting for 13.24%, 10.29%, and 6.62% of the total medical errors, respectively.

Errors in the management of NAD-related ADRs.

Rituximab. All five cases were associated with serious ADRs to rituximab, including one infusion related reaction (IRR), three lung injuries and one hepatitis B virus reactivation (HBVr).

IRRs. Case 1. A 55-year-old male patient with lymphoma developed chest tightness and discomfort during the first infusion of rituximab for 100 minutes, but the delivery of the drug was not stopped. At 120 minutes, the patient’s discomfort worsened. Subsequently, the patient developed cardiac arrest and died of cardiogenic shock after rescue. The occurrence of IRRs, especially during the first infusion, is a main concern of rituximab [35]. The clinical manifestations of a rituximab-induced IRR typically occurs within a few minutes to 120 minutes after the start of infusion. Reactions may vary widely, from mild adverse events (AEs) to life-threatening reactions. Fatalities occurred in 0.04% to 0.07% of patients [36]. According to the GPCANADs, it is recommended to pay attention to the risk of an IRR during the use of brentuximab vedotin, inetetamab, ramucirumab, carfilzomib, daratumumab, camrelizumab, and penpulimab [8].

Based on the errors we identified and related literature, several measures are required to prevent and manage the occurrence of IRRs: 1) Special monitoring of patients with cardiac or pulmonary conditions [37]; 2) Systematic administration of prophylaxis to reduce the occurrence and severity of IRR. Anti-allergenic drugs should be used before each infusion of rituximab. If the treatment regimen used does not include glucocorticoids, glucocorticoids should also be used in advance; 3) Monitor the infusion speed during the first infusion [8] and evaluate and manage the patient’s discomfort in a timely manner, such as discontinuation of the offending drug; 4) Availability of anticipated prescriptions for nurses to begin urgent care prior to the arrival of the doctor; 5) All supportive care should be immediately available [38].

Lung injury. Case 2. A 35-year-old male patient with systemic lupus erythematosus / megaglobulinemia died of respiratory failure due to acute pulmonary edema following the fourth infusion of rituximab. Case 3. A 30-year-old male patient with Hodgkin’s lymphoma developed dyspnea and died on the 52nd day after starting rituximab, and was identified as being associated with respiratory failure caused by rituximab induced lung injury. Case 4. A 78-year-old female patient with anti-neutrophil cytoplasmic antibody associated vasculitis developed a fever within 24 hours after the second infusion of rituximab, resulting in respiratory failure due to severe pneumonia. At present, the discovery, diagnosis, and treatment of acute lung injury caused by rituximab chemotherapy remains a challenge [39]. Zheng D et al. [39] reported that the onset chemotherapy time was mainly distributed in two to four courses, the time between the onset of symptoms and the infusion of rituximab was eight to 49 days. Fever is the most common clinical manifestation of the disease, followed by cough and chest tightness [39]. Due to the lack of specificity of its early clinical symptoms, it often fails to attract people’s attention [39]. The severity of acute lung injury ranges from hypoxemia to respiratory failure. In severe cases, fatal lung disease can occur. According to its severity, different treatment methods need to be taken [40]. For patients with symptoms of acute lung injury, rituximab and chemotherapeutic drugs should be stopped immediately, and glucocorticoids should be used instead [41]. Patients with severe cases often require mechanically assisted ventilation [41]. Therefore, chest imaging should be performed and evaluated before using rituximab, especially in patients with existing pulmonary insufficiency or tumor lung infiltration. The patient should be observed for fever, cough, and other related premonitory symptoms during administration of the medication.

HBVr. Case 5. A 57-year-old male patient with non-Hodgkin’s lymphoma (B-cell lymphoma) who was hepatitis B surface antigen positive, experienced HBVr after the second infusion of rituximab. The use of rituximab enhanced the patient’s liver injury, cirrhosis, splenomegaly, and other sequelae, which constituted grade seven disabilities. The amount of compensation in this case ranks second among the 39 cases, and the number of lawsuits is at least more than 6 times. The medical institution was responsible for 90% of the liability for compensation and reserves the right of patients to follow-up litigation. This result is similar to findings in our previous studies on severe cutaneous ADRs [21]. Disability often leads to higher compensation levels, which may be related to the increased indirect costs caused by patient disability.

The manufacturers of rituximab added black box warnings to the product labels identifying rituximab as a high HBVr risk in 2013 [42]. HBVr is an overlooked but significant complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death [43]. HBVr is defined as a sudden and rapid increase in HBV DNA levels by at least 100-fold in those with previously detectable HBV DNA or a reappearance of HBV DNA viremia in individuals who did not have viremia prior to the initiation of immune suppressive or biological modifier therapy or cancer chemotherapy [44]. Prevention and treatment of HBVr is complex but is now a well-recognized and preventable complication in clinical practice. HBVr can be identified in a timely manner by combining ALT levels with HBV DNA and HBsAg. In HBsAg[+] patients, a dramatic rise in HBV DNA concentrations (usually 100-fold or more) are indicative of HBVr, while in patients with resolved HBV infection (HBsAg[−] and HBcAb[+]), HBVr usually means the reappearance of HBsAg or an increase in serum HBV DNA concentrations with or without HBsAg seroconversion and ALT exacerbation [45].

Imatinib.

HBVr. Case 6. A male patient under 60 years old presented with a gastric stromal tumor had HBVr after imatinib treatment, which induced and promoted liver function injury. According to the GPCANADs, in addition to above drugs, it is also recommended to be aware of the risk of HBVr during the use of zanubrutinib, orelabrutinib, daratumumab, and Obinutuzumab [8].

Therefore, it is necessary to establish a comprehensive plan to manage the process when using NADs that have a risk of HBVr according to the errors mentioned in the aforementioned litigation case. These actions include: 1) Host-related, virus-related, and medication-related risk factors assessment. Patients with current or previous hepatitis B viral infections, the medical service providers should consult a hepatitis specialist before starting treatment and pay attention to monitoring during treatment; 2) Screening for viral hepatitis prior to initiation of NADs, such as conduct quantitative examination of hepatitis B virus DNA; 3) Monitoring liver function indicators; 4)Management of HBVr in individuals receiving immunosuppressive agents. The two strategies for targeting HBVr are antiviral prophylaxis and preemptive therapy. Antiviral prophylaxis means treating patients (usually at least 1 week before immunosuppressive therapy) with HBsAg[+] or HBcAb[+] regardless of viral load or whether or not there are clinical symptoms of HBVr. Preemptive therapy refers to the close surveillance of HBV DNA, in which antiviral therapy begins at the first sign of an increase in the HBV DNA load [45]; 5) Duration of therapy and monitoring. The optimal duration of prophylactic antiviral therapy remains controversial. Data derived from multiple sources indicate that antiviral prophylaxis should last for at least 6 months after the cessation of immunosuppressive therapy and should be lengthened to 12 months for patients receiving regimens with B-cell-depleting therapies or antiviral prophylaxis [45]. Due to space constraints, we will not be discussing the risk prevention and control strategies in detail and refer the readers to reviews on the topic [43–45].

The two HBVr cases cited above have been confirmed by judicial institutions as HBVr, but given that a large number of DILI cases are attributed erroneously to nondrug alternative causes, the lack of RUCAM evaluation results should not be disregarded [46]. We recommend conducting RUCAM assessments on patients with liver function injury. In these two patients, laboratory data covering liver function indicators were not disclosed in the court documents, which makes it difficult for us to draw any further conclusions.

In the other two cases, no hepatitis virus was detected, but the patients’ liver was seriously injured.

Sorafenib.

Drug-induced liver injury (DILI). Case 10. A male patient (age unknown) with a renal malignant tumor stage T3 had severe liver function injury during the use of sorafenib, which was diagnosed as DILI. After treatment, the patient’s liver function returned to normal. According to the appraisal opinion given by identification institution, the patient’s liver function damage was caused by sorafenib, and the DILI was not found in time, resulting in the aggravation of liver function injury. The healthcare services compensated 20% of the patient’s medical expenses, which included hospitalization food allowance, transportation, nursing, nutrition, lost wages, and appraisal fees, totaling $830. Unfortunately, this case occurred in 2015, and the liver function indicators of the patient before and after treatment had not been published, which made it impossible to conduct further RUCAM scoring.

Alfatinib.

DILI. Case 11. A 79-year-old patient with advanced left lung adenocarcinoma (Phase IV B c (T2N3M1c) was diagnosed with DILI after taking alfatinib with a RUCAM score of 6 points. The patient was treated with ondansetron tablets due to ADRs of nausea and vomiting during oral afatinib treatment. The doctor mistakenly wrote the prescription for a single dose of 8 mg as 8 tablets, and the patient took 32 mg of ondansetron orally at one time, resulting in or aggravating the injury to the patient’s liver function. This resulted in the discontinuation of afatinib. The appraisal opinion believed that the patient’s liver function injury was mainly related to the ADRs of alfatinib, and there was also a certain correlation with the single overdose of ondansetron. Because the patient’s liver function was damaged and alfatinib was a hepatotoxic drug, the treatment of anti-tumor drugs was stopped. It had a slight causal relationship with the development of the patient’s disease to death, and a $10,587 of compensation was assumed by the healthcare services.

The compensation reasons for two cases of DILI were not completely identical. In Case 10, the DILI was not discovered in a timely manner, leading to increased liver function injury. The healthcare services undertook DILI treatment related compensation. In Case 11, the patient suffered from tumor-targeted-treatment interruption due to DILI and died, and the healthcare services also undertook death-related compensation. In the published judgment document, although DILI was identified, the evaluation method was not published. We used RUCAM to reevaluate this case. Case 10 was unable to be re-evaluated with RUCAM because liver function data was not published in the court documents. Current pharmacotherapy options of DILI remain under discussion, but the use of the offending drug must be stopped as soon as DILI is suspected [46]. Therefore, it is important to clarify the DILI diagnosis. RUCAM is the most used causality assessment tool worldwide for the diagnosis of DILI and herb-induced liver injury (HILI) in many epidemiological studies, case reports, and case series [47]. Therefore, it is recommended that, for cases involving DILI, both medical and judicial expertise institutions use RUCAM scoring to: 1) avoid not detecting DILI in a timely manner, which may lead to increased liver function injury, or 2) avoid incorrectly evaluating DILI leading to unnecessary discontinuation of drug.

Although we only reported the liver injury of rituximab, imatinib, sorafenib and alfatinib, which are four NADs in our study, the hepatotoxicity of immune checkpoint inhibitors (ICIs) should also be considered by users [48]. In recent years, ICIs, including programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors, cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors, were approved for the treatment of various malignities [49]. ICIs have an immunotoxicity to various organ systems, that is, immune-related adverse events (irAEs), which has also become an unavoidable new complication in clinical practice. ICIs-related irAEs, especially high-grade irAEs, pose a significant threat to patients’ lives, with an incidence ranging from 54% to 76% [50]. One important side effect of all three classes of ICIs is DILI, and they also increase the risk of idiosyncratic DILI of co-administered drugs. Its occurrence often leads to the discontinuation of therapy and might require treatment [51,52]. Immune tolerance plays a dominant role in the immune response of the liver, and impairment of immune tolerance with ICIs increases DILI in both humans and other animals [52]. Therefore, it is necessary for medical service providers to familiarize themselves with diagnostic steps and management plans for patients with liver injury. When assessing for possible ICIs induced hepatotoxicity, it is of utmost importance to use a formal scoring system such as the RUCAM to assess for risk factors, alternative causes, and response to cessation and re-exposure of a given drug [53]. It is hoped that the use of RUCAM will further increase confidence in the studies performed for DILI detection with new drugs, herbs, and dietary supplements, and in the identification of risk factors and new biomarkers to be able to take the appropriate measures to reduce the risk of hepatotoxicity [54].

Toripalimab.

Lung injury from irAEs. Case 12. A male patient over 75 years old with esophageal cancer and lung cancer after surgery developed lung injury and other irAE side effects on the sixth day after treatment with teriprizumab and died after resuscitation attempts. It was identified that the medical service providers had some defects in the process of diagnosis and treatment, such as insufficient communication, attention, observation, and monitoring of the patient’s condition. According to literature reports, there is an overall incidence of 4.5% for ICI-associated pneumonia, and the incidence of severe pneumonia (grade 3 or higher) was 0.8–1.5% [50]. Chen Y et al. [50] reported two Chinese patients with advanced tumors suffering from severe multisystem irAEs. Both patients developed myocarditis and one patient was also diagnosed with organizing pneumonia after receiving toripalimab treatment. They proposed that improved awareness and an early identification of multisystem irAEs are of great importance in management of patients undergoing treatment of ICIs. In addition, we suggest that medical service providers should also improve communication and notification of related risks.

Nivolumab.

Adverse cardiac reactions from irAEs. Case 13. A 40-year-old male patient with lung cancer was not carefully monitored for adverse cardiac reactions during treatment with nivolumab. Specifically, the myocardial zymogram was not rechecked after two sinus tachycardia. Immune-associated myocarditis is the most serious ADRs among all organs with immunotoxicity, and the fatality rate may be as high as 50% [55]. Moslehi’s [56] study on 101 cases of severe myocarditis showed that dosing information was available in 59 patients; 64% received only one to two doses before myocarditis onset. The precise timing of myocarditis onset in relation to ICI initiation was available in 33 patients. Of these, the median onset was 27 days (range 5–155 days) with 76% occurring in the first six weeks. Further, concurrent severe irAEs occurred in 42% of patients, most commonly myositis (25%) and myasthenia gravis (11%). Among all cases, death occurred in 46 (46%). Fatality rates were higher with a combination of anti-PD-1/PD-L1 plus anti-CTLA-4 than with anti-PD-1/PD-L1 monotherapy (67% vs. 36%, p = 0.008). Deaths also occurred in three of five patients with ipilimumab monotherapy associated myocarditis.

Nivolumab, as a PD-1 inhibitor, should be investigated for its irAEs, such as: 1) Before and during the administration of drugs, perform cardiac related examinations, which include cardiac biomarkers and ECG 2) While monitoring and observation some irAEs prodrome symptoms, including dyspnea, myalgia, fatigue, blepharoptosis, and myasthenia; 3) The induction period of irAEs is different so management of the entire process is essential, and any abnormality findings should be addressed quickly. For details, please refer to the ‘Management of immunotherapy-related toxicities, Version 1.2022 [57].

Bortezomib.

Five cases related to bortezomib were all diagnosed as multiple myeloma, which were associated with ADRs. ADRs occurred during the first course of treatment with bortezomib, among which Cases 14, 15, and 18 occurred after the second (day four) drug treatment. Complications involving: 1) Transient acute ADRs (including blood pressure decline, thrombocytopenia), and peripheral neuropathy; 2) Acute lung injury, including severe pneumonia, dyspnea, ARDS; 3) Cardiac failure. Among these cases, four patients died while one case resulted in grade three disability. Among the death cases, the autopsy confirmed that the cause of death of one patient was consistent with multiple myeloma complicated with infection, secondary drug-induced diffuse alveolar injury of both lungs, and multiple organ failure caused by DIC.

Bortezomib is an important part of current anti-myeloma therapy with a good clinical efficacy and manageable side effects [58]. However, the characteristics of bortezomib-related severe AEs need to be monitored. A comprehensive analysis from the Japanese Adverse Drug Event Report database showed that 13 of the 26 bortezomib AEs extracted presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and tumor lysis syndrome (TLS) (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately 1 month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively [59]. These AEs had a higher rate of fatal clinical outcomes after onset than other AEs and exhibited a greater onset tendency in the early post-dose period. Domestic literature analysis [60,61] on ADRs caused by bortezomib showed that the first two organs involved in ADRs are respiratory system damage (28.89–33.3%), followed by central and peripheral nervous system damage (13.33–13.33%). The mortality rate is 19.51–25.81%, among which the mortality rate of lung injury is as high as 50%. A total of 53.23% of the ADRs occurred in the first course of chemotherapy. The remaining ADRs occurred in the second to eighth courses with 3.23% occurred on the day of chemotherapy, and the rest occurred on or after the next day. Lung injury occurred in the first 3 weeks [60,61]. A Japanese study [62] reported that before bortezomib approval in Japan, four (30.7%) of 13 patients with myeloma who were treated with privately imported bortezomib experienced fatal pulmonary complications. Of these four patients, two (15.4%) died from respiratory failure. Another study [63] reported that of the 1,010 patients registered, 45 (4.5%) developed lung disease, five (0.50%) of whom had fatal cases. The median time to lung disease onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. In some cases [64], a pre-existing cardiac disease was an associated risk factor for further bortezomib-related cardiac disorder, while another case report highlighted a patient with no previously known cardiac disorder or any cardiovascular risk factor who suffered from bortezomib-related heart failure.

Therefore, combined with medical errors and literature, we suggest that: 1) Systematic cardiac and lung screening should be performed before and during administration of bortezomib; 2) There is a need to monitor signs of cardiac failure, lung disorder, and pneumonia, potentially resulting in serious outcomes; 3) The usage and dosage of bortezomib should be standardized to reduce the risk of medication; 4) Focus on high-risk groups prone to ADRs and appropriately extend the stay for observation, and 5) Fully explain the benefits and risks of medication and off-label use, and obtain informed consent.

Apatinib.

Both patients with lung cancer (Cases 19 and 20) died of massive hemoptysis, and two patients with gastric cancer (Case 21) and cervical cancer (Case 22) died of massive gastrointestinal bleeding.

Massive hemoptysis. Hemorrhage or abnormal clotting time is one of the main side effects of anti-angiogenic drugs, and it often occurs within 1 month after taking the drugs. Wang W et al. [65] reported that two patients with advanced esophageal cancer developed fatal hemoptysis (grade 5) after treatment with apatinib. During the treatment, both patients showed an abnormal coagulation function, APTT of one patient was slightly prolonged after 3 weeks of treatment using apatinib orally, and another patient showed a significant increase in PT and APTT after 2 weeks of treatment. However, no obvious abnormality was found in liver and kidney function except for the low plasma protein. It was suggested that the abnormal blood coagulation function should be associated with the side effects of apatinib. Further, the treatment with apatinib caused tumor necrosis, and the tumor continued to progress and invaded the bronchial artery, leading to hemoptysis by rupture of vessels [65]. Lung cancer is a cause of hemoptysis, and central lung squamous cell carcinoma (LSCC) is prone to cavity formation and sudden fatal hemoptysis. Apatinib may induce or aggravate hemoptysis [66]. Yang D et al. [67] reported that apatinib treatment was used for three patients with advanced non-small cell lung cancer (two cases of adenocarcinoma and one case of squamous cell carcinoma). The squamous cell carcinoma case died of sudden hemoptysis (grade 5). Although they have no definite conclusion regarding the causality between hemoptysis and apatinib treatment, a potentially increased risk of squamous cell lung cancer should be considered when using apatinib in non-small cell lung cancer (NSCLC) patients. The risk of hemoptysis in squamous NSCLC patients is inconclusive and current limited data suggest that squamous NSCLC may not be a contraindication of apatinib. A single-arm, open-label, investigator-initiated phase II prospective study demonstrated that the incidence of hemoptysis treated with low-dosage apatinib monotherapy in advanced LSCC was 18.4% (n = 38, grade 1 or 2) [68]. However, another phase II single-arm trial study revealed that the incidence of hemoptysis treated with apatinib as a maintenance therapy following standard first-line chemotherapy in extensive disease small cell lung cancer (SCLC) was 8.3% (n = 12, grade 1–2) [69]. Zeng DX et al. [70] reported that four advanced lung adenocarcinoma patients with a KRAS mutation were orally administered apatinib (250 mg/d) after second-line treatment, and one patient developed manageable hoarseness and hemoptysis (grade 1).

Gastrointestinal bleeding. Xu Z et al. [71] reported that four patients with a clinical diagnosis of stage IV gastric adenocarcinoma were treated with apatinib (500 mg/d) combined with paclitaxel and 5-fluorouracil, and one patient had gastrointestinal bleeding (grade 1). Li X et al. [72] reported that microwave ablation combined with apatinib and carbamazumab was treated in patients with advanced hepatocellular carcinoma and the incidence of gastrointestinal bleeding (grade 3 or 4) was 14.3% (n = 14, grade 3–4). Li XF et al. [73] reported that a 55-year-old Chinese woman with advanced gastric cancer suffered from gastrointestinal bleeding and perforation on the nineteenth day of apatinib administration. Considering the patient’s disease and history of drug use, the author thought that the most possible causes of patient’s upper gastrointestinal bleeding and perforation included drug resistance and cancer progression, in combination with adverse effects of apatinib.

In summary, apatinib has the potential to increase the risk of bleeding, therefore, we have learned that apatinib should be administrated with caution. To address these risks: 1) Hemorrhage and hemoptysis are both emergencies that need immediate treatment. Therefore, it is necessary to establish and prepare corresponding rescue procedures before using these drugs. 2) The blood clotting function should be monitored regularly. Patients on anticoagulant therapy combined with warfarin should be routinely monitored for prothrombin time (APTT) and internationalized normalized ratio (INR). Bleeding should be closely monitored when using the drug, especially when administered to patients undergoing additional treatment. Close attention should be paid to clinical signs of bleeding. The patients with hematemesis, hemoptysis, or black stool should reduce their dosage or stop the medicine. Additionally, for patients with severe bleeding (grade 3 or 4), it is recommended to temporarily stop the use of apatinib. If a severe hemorrhage reoccurs after the medication is resumed, the drug can be continued after the dose is lowered. If the adverse reaction persists, it is recommended to stop the drug [74]. 3) Special attention should be paid to the possibility of massive bleeding caused by tumor erosion and necrosis. Physicians should focus on choosing suitable candidates, detailed assessment, close surveillance, and active management to minimize lethal cancer-related complications besides yielding ideal tumor control [75]. 4) Physicians should use drugs according to the indications of the drugs. In the event of off label use of apatinib, communication should occur, as well as notification of drug risks in all links.

Bevacizumab.

Gastrointestinal bleeding. Case 23. A 56-year-old female patient with glioma was given bevacizumab intravenously while blood pressure was not controlled within the normal range. It was determined that the timing of administration was improper, and the indications were insufficient, which led to gastrointestinal bleeding, hematemesis, airway obstruction, and asphyxia.

Case 24. A patient with primary liver cancer had a history of gastrointestinal hemorrhage, and the doctor failed to fully explain the reasonable off-label use of drugs under special circumstances, which was a contributing factor in the death of the patient along with hemorrhagic shock caused by drug-induced gastrointestinal bleeding. The most serious adverse effects of bevacizumab are gastrointestinal perforations, surgery and wound healing complications, and hemorrhage [76]. A study in France showed that the most common adverse reactions of bevacizumab involved the gastrointestinal system (21.9%), in which hypertension and gastrointestinal hemorrhage accounted for 2.7% and 2.7%, respectively [77]. Therefore, all patients on bevacizumab treatment are recommended to have blood pressure monitored every two to three weeks.

Crizotinib.

An increased risk of PE in patients receiving crizotinib treatment was also reported in clinical trials but was easily neglected due to relatively low incidence [78].

Pulmonary embolism (PE). Case 26. A patient with lung cancer using crizotinib had a PE during treatment. It was identified that the medical service provider did not give corresponding information about the potential risks of the drug, and there was no communication record of special drugs. The patient possessed multiple risk factors, including advanced age and reduced mobility, which increased the risk of pulmonary embolism for crizotinib. Therefore, communication and risk notification should be strengthened for high-risk and other special groups.

Errors in off-label drug use.

Outside of direct medical damage caused by ADRs, medical errors can also cause indirect medical damage. Off-label drug use is particularly common for treatment of malignancies due to the existence of numerous cancer subtypes, difficulties involved in performing clinical trials, rapid diffusion of preliminary results, and delays in approval of new drugs by regulatory bodies [79,80]. Off-label drug use refers to prescribing medicines in a manner that is inconsistent with prescribing information published by regulatory authorities. Off-label drug use can be classified into different categories which include unapproved indication, use in a special population, an unapproved route of administration, or with a dose not specified on the FDA-approved label [81]. In our study, errors in off-label drug use ranked second among medical technology errors, with the primary errors being errors in the management of off-label use.

Case 14. Unapproved dose involved an overdose of bortezomib chemotherapy. A 67-year-old patient with multiple myeloma developed symptoms of hypoxia soon after using bortezomib with a dose approximately 1.46 times that of the recommended dose in the manual, and the hypoxia continued to progress. It was identified that the medical service providers did not anticipate the possible drug toxicity after the overdose of bortezomib, and the patient’s respiratory symptoms were not identified in time. This led to a missed diagnosis and the failure of timely and effective treatment of patients with ALI / ARDS, resulting in further development and deterioration of the patient’s condition. As a result, it was decided that the medical service providers shall bear 65% of the liability for compensation.

Case 17. A case from 2017 of unapproved route of administration involved a patient who died suddenly after treatment with bortezomib for multiple myeloma. It was confirmed that the patient’s death was caused by a combination of the original disease and from possible heart failure caused by a drug-induced injury. The doctor used an unapproved route of administration, injecting the drug subcutaneously, rather than intravenously, per instructions. While there was no causal relationship with the death, it was considering medical errors. The appraisal and court required the hospital to assume 20% of the liability for compensation. In 2017, there was sufficient evidence for the subcutaneous administration of bortezomib. The study found that subcutaneous bortezomib offered non-inferior efficacy to standard intravenous administration, with an improved safety profile [82] and alternative subcutaneous administration should be considered instead of intravenous administration in use of bortezomib for patients with multiple myeloma [83]. However, the court and appraisal opinion held that the medical service providers had not fulfilled the corresponding procedures for off-label use resulting in the 20% assignment of responsibility.

Unapproved indication included: a) apatinib (unapproved for: cervical cancer, early-stage gastric cancer, lung squamous cell carcinoma), b) bevacizumab (liver cancer, brain glioma, diffuse astrocytoma), c) gefitinib (undifferentiated large cell lung cancer), d) pezopanib (carcinoma of renal pelvis), and e) trastuzumab (breast cancer).

Case 28. A patient with renal pelvis cancer with multiple metastases was treated with pezopanib, and it was identified that the medical behavior of the healthcare services did not violate diagnostic and therapeutic norms. However, the healthcare services did not comply with the corresponding procedures and fully inform the obligation to use the drug in accordance with off-label use of NADs. Based on later examinations, it was demonstrated that the use of this drug had a certain effect on alleviating the patient’s condition. The patient had renal pelvis cancer with multiple metastases, with poor prognosis, and a lack of clear targeted drugs for treatment. There is no significant causal relationship between the outcome and the diagnosis and treatment behavior of the healthcare services, but it is caused by the patient’s own illness. There is a causal relationship between the medical errors behavior and the medical expenses incurred by the patient using pezopanib. It is recommended that the magnitude of the causal force be the main reason.

The doctor law of the people’s Republic of China [84], which came into force on March 1, 2022, wrote medication off-label use into the law for the first time. According to Article 29 of the law, "1) doctors should adhere to the principle of safe, effective, economical and reasonable drug use; 2) follow the guiding principles of clinical application of drugs, clinical diagnosis and treatment guidelines, drug instructions and other rational drug use; 3) in the absence of effective or better treatment methods and other special circumstances; 4) after doctors obtain the clear informed consent of patients; 5) the use of drugs not specified in the drug instructions but with evidence-based medical evidence can be used for treatment. It should be noted that the GPCANADs also propose that medical service providers should formulate corresponding management systems and technical specifications to strictly manage the use of drugs that are not specified in the drug instructions but have data to support evidence-based medicine. Under special circumstances, the right to use NADs should be limited to doctors with senior professional and technical titles authorized by the tertiary hospital, and drug use monitoring and tracking observation should also be performed [8]. Pharmacists should examine the suitability of doctors’ prescriptions and medication orders and strictly regulate doctors’ medication behavior. Taking the judgment of cases of off-label use into consideration, when assessing NADs for off-label use, medical service providers should maintain usage in accordance with the provisions of the national laws and regulations to avoid medical disputes caused by such errors.

Errors in condition evaluation during diagnosis and treatment.

There was one case of MAM (Case 29) and three cases of II (Cases 30, 31, and 33) caused by errors in condition evaluation.

Case 29. The doctor mistakenly diagnosed the patient as suffering from pancreatitis and stopped using chidamide, leading to the deterioration of lymphoma, which was identified as having a causal relationship with death.

Case 30. A patient with post-operative metastasis of undifferentiated large cell carcinoma of the (right) lung (upper lobe) received targeted drug therapy with gefitinib. It was identified that the monitoring and evaluation of the efficacy of patients during diagnosis and treatment, as well as the treatment of ADRs, are not timely. There is a lack of scientific and accurate relevant records.

Case 31. A patient with adenocarcinoma of the right lung who had previously failed to use gefitinib for treatment outside the hospital, and subsequently switched to other chemotherapy regimens, but was re-treated with gefitinib without a systematic assessment of the patient’s condition by the healthcare services. It was identified that the healthcare service examination before treatment was incomplete, the evaluation of medication indications was insufficient, and the notification was insufficient. There was an improper treatment, which had a causal relationship with the patient’s death.

Case 33. A patient with undifferentiated carcinoma of the nasal sinuses and nasal cavity was identified as having a high possibility of death due to bilateral lung metastasis, bone marrow suppression, secondary lung infection, and ultimately respiratory and circulatory failure after treatment. The main errors of the healthcare services are: 1) For the treatment of advanced head and neck tumors, there is no multidisciplinary consultation to jointly determine the treatment plan. As radiotherapy is a commonly used treatment method for head and neck tumors, the healthcare services should also request the radiotherapy department to consult, determine the treatment plan, inform the patient of the different plans and risks, and seek the patient’s opinions before treatment. There are shortcomings in the healthcare service diagnosis and treatment and nimotuzumab was given without informing the radiotherapy plan. 2) The healthcare services are at fault for not fully informing the patient’s condition, treatment plan, and prognosis. 3) The doctor did not perform gene testing before treatment, and the paraffin section tissue test showed normal expression levels. The doctor made a mistake in using the drug.

Therefore, in the diagnosis and treatment process, timely monitoring and evaluation of the efficacy of patients treated with NADs should be carried out, and relevant records should be scientifically and accurately kept. When reusing drugs that have failed treatment, the patient’s condition and indications for NADs should be fully reassessed. For the treatment of advanced head and neck tumors, and the need to interrupt the treatment of NADs, it is recommended to negotiate and jointly determine the treatment plan among medical professions in multiple disciplines.

Errors in molecular target detection.

There were two cases of II (Cases 27 and 32) and two cases of MAM (Cases 9 and 35) caused by errors in molecular target detection.

Case 27. A patient with primary bronchogenic lung cancer (stage IV of left upper central type high to moderately differentiated adenocarcinoma) was treated with crizotinib when the ALK gene deletion mutation was shown. It was identified that the ALK gene deletion mutation was not the result of driving gene fusion mutation. In light of the positive ALK results, the patient has used the targeted drug crizotinib for nearly one year, even no further detection and confirmation efforts were made. There was an incomplete analysis of the medical condition during the diagnosis and treatment process. The errors included unclear medication indications, incomplete handling opinions, or incomplete medical advice.

Case 32. A patient with stage IV right lung adenocarcinoma was advised to take gefitinib without genetic testing, which was inappropriate. It was identified that there was no direct causal relationship with the patient’s death, but it could be considered as a minor cause of death.

Case 9. When the results of pathological and gene mutation tests are not available, a patient with low-grade malignant potential mesenchymal tumor was advised to take imatinib orally and consider surgical treatment after the tumor shrank. One month later, the c-KIT/PDGFRa gene mutation test results showed that the c-KIT gene in the sample was of wild type in exons 11, 9, 13, and 17, and the PDGFRa gene was of wild type in exons 12 and 18. Compared with previous MRI scans, the tumor was slightly plump and enlarged. The appraisal and court held that the medical authorities had delayed further treatment of the tumor.

Case 35. A patient with breast cancer (cT1N0M0 and HER2 negative) was wrongly recorded as positive, which led to the incorrect use of trastuzumab. The appraisal and court held that there was a causal relationship between the use of the drug and the costs incurred.

Therefore, for drugs with clear targets of action, the principle of target detection must be followed before use. Attention should also be paid to the relevant detection methods and the correct interpretation of the detection results. Before prescribing NADs for target detection, it is necessary to review and clarify the target detection report again to avoid errors in this process.

Errors in histopathological diagnosis.

There were four cases of MAM caused by errors in histopathological diagnosis.

Case 34. A patient with nasopharyngeal carcinoma was misdiagnosed as having a recurrence in the parotid region after radiotherapy and chemotherapy, and the postoperative pathology suggested that "no tumor was found". The appraisal and court judgment identified that there was a causal relationship with the patient’s repeated treatment with three cycles of nimotuzumab.

Case 37. A 42-year-old female patient presented with a left lung mass accompanied by mediastinal lymph node enlargement, as indicated by a plain CT scan and enhancement. Physical examination revealed that an enlarged lymph node about 2 × 1 cm in size could be palpated on the left clavicle. Biopsy and cytological examination of the lymph node revealed metastatic poorly differentiated lymph nodes (adenocarcinoma). Therefore, left lung cancer with mediastinal and supraclavicular lymph node metastasis (CT2N3M0 stage IIIB) was diagnosed, and radiotherapy, chemotherapy, and erlotinib targeted treatment were given. Three years and seven months later, due to the discovery of enlarged left axillary lymph nodes, Hodgkin’s lymphoma (mixed cell partial nodular sclerosis) was diagnosed after biopsy and immunohistochemical examination. The appraisal and court held that cytological diagnosis was not sufficient to determine clinical diagnosis, and the medical team did not conduct further tumor histopathological examination to confirm the diagnosis. In the absence of diagnosis of lung adenocarcinoma and target testing to determine whether EGFR was positive, oral erlotinib treatment was received. These errors led to an extension of the patient’s treatment cycle in the later stage, as well as more uncertain factors in the treatment in the later stage. The appraisal held that the healthcare services should carry 40% of the responsibility. However, the court ruled that the healthcare services should bear 100% of the responsibility. The disability appraisal was not carried out at the time of the judgment, and the patient reserved the right to further litigation. This case resulted in the largest compensation settlement of all 39 cases at $97,301.

Case 38. A patient with invasive ductal carcinoma of the left breast was not treated with endocrine and targeted anticancer therapy. The appraisal and court held that the lack of comprehensiveness and accuracy of immunohistochemical detection, pathological molecular typing diagnosis, and a misdiagnosed of triple negative breast cancer, led to incomplete treatment plans. At the time, it was not determined that the patient’s breast cancer was a hormone dependent tumor with a high expression of estrogen receptor (ER). Endocrine therapy was not given, and targeted anti-cancer treatment was lacking. There was a certain causal relationship between inhibition, reduction, and avoidance of tumor recurrence and metastasis, or the effect of prolonging the patient’s survival was ultimately affected.

Case 39. Without pathohistological diagnosis, Fanconi Syndrome (after treatment with adefovir dipivoxil for hepatitis B) was misdiagnosed as bone metastasis of liver cancer, and sintilimab targeted therapy was wrongly used. The appraisal and court held that there was a slight to secondary causal relationship with related cost losses.

The lessons learned from the study support following these principles: 1) Treatment can be used only after histopathological diagnosis, 2) Drugs with clear target can only be used after target detection, and 3) Indications must be strictly followed.

Inappropriate treatment of NADs.

There were three cases of DDAT caused by improper timing of the administration of NADs and delayed treatment.

Case 7. A patient with Philadelphia chromosome positive acute lymphocytic leukemia (Ph + ALL) did not consider timely addition of TKI drugs such as imatinib.

Case 8. A patient with gastrointestinal stromal tumor was not informed to take imatinib after surgery to reduce chance of recurrence.

Case 36. A patient with infiltrating ductal carcinoma (right breast) was treated with trastuzumab only after finding cervical lymph nodes and liver metastases due to cost reasons. The appraisal and court judgment ruling found that incomplete chemotherapy, especially the delayed treatment of trastuzumab, and the failure to fully fulfill the obligation to inform during the treatment period, had a causal relationship with metastasis, recurrence, and death.

Therefore, during the treatment process, medical service providers need to understand the timing of treatment for NADs.