Prescribing an approved anticancer drug beyond its licensed indications should be subdivided into two sectors: i) expanding to different cancer types, for example, oxaliplatin is approved for colorectal cancer but used for non-Hodgkin’s lymphoma, esophageal cancer, biliary tract cancer, stomach cancer, ovarian cancer, pancreatic cancer, NSCLC, testicular cancer, transitional cell carcinoma of the bladder, and hepatocellular carcinoma in clinical practice (Motzer et al., 2012; Eroglu and Fruehauf, 2013; Gore et al., 2019; Benson et al., 2021; Ajani et al., 2022, 2023; Horwitz et al., 2022; Huang et al., 2022; Ren et al., 2022; Li et al., 2023) and ii) expanding to a different stage (oxaliplatin with 5-Fu/calcium folinate is used as adjuvant therapy for stage II colon cancer in adults) (Baxter et al., 2022), subtype (trastuzumab for HER2-negative rather than HER2-positive breast cancer) (Ignatiadis et al., 2018), or treatment line of the same cancer type (pyrotinib switched from second-line to the first-line treatment for advanced HER2-positive metastatic breast cancer) (Xu et al., 2022). Regorafenib is approved for second-line therapy but used as a first-line agent alone for advanced hepatocellular carcinoma (Bai et al., 2023).

The use of anticancer drugs beyond their approved dosage could be illustrated by two sectors: i) unapproved single dose (higher, lower, or different expression of dosing). For instance, compared with the approved dose, high-dose carboplatin-based chemotherapy has demonstrated curative potential in several patients diagnosed with BRCA1 or BRCA2-associated metastatic breast cancer (Rottenberg et al., 2021). Pembrolizumab is administered at a dose of 100 mg (2 mg/kg) instead of the fixed dose of 200 mg in combination chemotherapy (the KEYNOTE-001 study illustrated that the dose range of pembrolizumab is 0.005 mg/kg∼10 mg/kg, with maximum antitumor activity achieved at 2 mg/kg, and pembrolizumab administered through weight-based dosing and fixed-dose regimens had comparable pharmacokinetics [PK]) (Chatterjee et al., 2016). Pembrolizumab could potentially decrease the potential financial toxicity if given with PK guidance in patients with advanced NSCLC (Wang et al., 2023). As for the different levels of expression of dosing, a fixed dose of trastuzumab was prescribed instead of the dose adjusted for body weight in practice (Levêque, 2008; Pivot et al., 2017); ii) unlicensed frequency (lower), where the regimen consists of capecitabine (2,000 mg/m² once daily on days 1–14 of each 21-day cycle) in combination with lapatinib (1,250 mg/d). A single-group phase 2 trial including 45 patients with previously untreated brain metastases from HER2-positive metastatic breast cancer has provided evidence supporting the use of capecitabine once a day as opposed to twice a day (Bachelot et al., 2013).

The unauthorized route for medication administration has two ways in practice: i) broadening the routes, for example, subcutaneous injection of alemtuzumab instead of intravenous infusion for the treatment of refractory chronic lymphocytic leukemia (CLL) (Lundin et al., 2002), intraperitoneal infusion of cisplatin for the treatment of malignant pleural effusion caused by conditions like NSCLC (Zhao et al., 2022), or subcutaneous injection of trastuzumab instead of intravenous infusion for HER2-positive breast cancer (Pivot et al., 2017; Heo and Syed, 2019; Denys et al., 2020), and ii) substituting the approved routes, such as the administration of recombinant human endostatin injection through infusion/pouring into the pleural cavity instead of intravenous drip for the treatment of advanced NSCLC or malignant pleural effusion (Wang et al., 2020).

The utilization of approved anticancer medications beyond their licensed patient groups can be classified into different pathophysiological conditions. One of the scenarios is using adult-approved agents in pediatric patients: children in the United States with high-risk neuroblastoma undergo five intensive chemotherapy cycles using adult-approved drugs, including vincristine, cyclophosphamide, topotecan, doxorubicin, cisplatin, and etoposide (Park et al., 2011, 2019; Granger et al., 2021). Another scenario has occurred in different physiological conditions in women: toremifene is indicated for the treatment of estrogen receptor-positive/or unknown metastatic breast cancer in postmenopausal women but can be extended to premenopausal patients with breast cancer (Gradishar et al., 2022). The scenario that has occurred in patients with hepatic or renal dysfunction is supposed to be considered. For instance, the prescribing instructions for vincristine recommend reducing the dosage by 50% when the patient’s serum bilirubin level is above 3 mg/dL. However, some clinical practitioners advise against using this medication when the serum bilirubin level is above 3 mg/dL or the aminotransferase level exceeds three times the upper limit of the normal level (Superfin et al., 2007). Sorafenib is not recommended to be dose-adjusted for patients with mild, moderate, or severe renal impairment without undergoing dialysis. However, a phase I study suggested that for patients with a creatinine clearance (CrCl) of 20–30 mL/min, the initial dose of sorafenib should be reduced to 200 mg twice daily, whereas for patients undergoing dialysis, it should be reduced to 200 mg once daily (Miller et al., 2009).

The use of an approved antineoplastic agent beyond its licensed regimen could be subdivided into four sectors: i) lengthen/shortening the treatment interval: the former situation where patients with cancer are frequently immunocompromised during the COVID-19 pandemic and acquiring COVID-19 may significantly affect the diagnosis and treatment of their primary disease. Breast cancer patients who are co-infected with COVID-19 may wish to consider putting off chemotherapy as an option to ensure the stability of their condition (de Azambuja et al., 2020; Dietz et al., 2020) and the latter situation, where taxane drugs are used every 2 weeks instead of every 3 weeks for adjuvant chemotherapy in breast cancer (Early Breast Cancer Trialists’ Collaborative Group [EBCTCG], 2019); ii) extending the number of days of medication within a course of treatment: for instance, replacing the usual dose of 75 mg/m² administered on the first day of a 3-week cycle with a split dose over 3 days (25 mg/m² each day on days 1–3) to treat advanced breast cancer with cisplatin may reduce the frequency of unwanted side effects such as nausea, vomiting, kidney toxicity, and hypomagnesemia (Zhang et al., 2020); iii) increasing the course of the treatment: the bevacizumab combination chemotherapy regimen can be extended from 6 to 10 cycles in patients with recurrent ovarian cancer that is sensitive to platinum (Aghajanian et al., 2015); and iv) shortening the course of the treatment: a comparison between 9 weeks and 1 year of trastuzumab adjuvant therapy in HER2-positive early breast cancer patients did not show non-inferiority, and the standard treatment also remains the 1-year trastuzumab regimen. Nevertheless, the 9-week regimen could lower the risk of severe cardiac toxicity. Therefore, patients with low recurrence risk or those experiencing cardiac events during the treatment could opt for the 9-week option (Conte et al., 2018).

Combination therapy is a common form of antitumor regimen. Examples of such unlicensed medication use include i) changing monotherapy into a combination. Larotrectinib has been approved as a monotherapy for patients with advanced colorectal cancer who are unsuitable for 5-Fu/leucovorin calcium. However, the off-label use here is based on a phase II clinical trial that confirmed the efficacy, convenience, and tolerability of the larotrectinib and irinotecan combination as a chemotherapy regimen for the second-line treatment of metastatic colorectal cancer (Cheng et al., 2022); ii) changing the combination into a single agent. Bevacizumab is approved for the treatment of metastatic colorectal cancer when used in combination with fluorouracil-based chemotherapy. However, studies indicate the bevacizumab alone is non-inferior to standard fluoropyrimidine plus bevacizumab. Switching from combination therapy to monotherapy is still within the clinically acceptable range (Hegewisch-Becker et al., 2015); and iii) transformed type of association. Trastuzumab is approved to be used in association with paclitaxel or docetaxel for patients diagnosed with HER2-positive chemotherapy-naïve metastatic breast cancer, but research has shown that when used with vinorelbine for the treatment of untreated metastatic breast cancer, trastuzumab has significantly fewer adverse effects and can serve as a first-line alternative treatment (Andersson et al., 2011).

The sequential order of antineoplastic drugs can also involve unsanctioned use. One is altering sequential drug delivery, and another is no prior treatment in clinical drug priorities. The former example, such as the sequential use of cisplatin followed by ifosfamide, may exacerbate the myelosuppression, neurotoxicity, and nephrotoxicity of ifosfamide. However, research has shown that the concurrent administration of ifosfamide and cisplatin in chemotherapy for ovarian cancer patients can synergistically enhance efficacy (Vanhoefer et al., 2000). In addition, with the latter, for example, there is no prior therapy required for nivolumab. However, a study has shown that nivolumab plus ipilimumab is associated with better survival than chemotherapy-advanced NSCLC patients with varying levels of PD-L1 expression who have not received chemotherapy before (Hellmann et al., 2019).

The use of approved anticancer agents beyond their sanctioned clinical purpose could be divided into two sectors: i) additional diagnostic use. For example, carboplatin is mainly used in chemotherapy for ovarian cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous cell cancer, esophageal cancer, seminoma, bladder cancer, and mesothelioma, but it can also be used in skin tests to diagnose whether patients are allergic to carboplatin. The incidence of anaphylactic reactions was 27% for more than seven courses of carboplatin. For more than eight courses of treatment, the cumulative incidence of anaphylactic reactions was 44%. The highest number of carboplatin-induced anaphylactic reactions occurred during the 8th or 9th treatment cycle (Markman et al., 2003). A longer interval between chemotherapy cycles increases the risk of developing carboplatin allergic reactions (Tham et al., 2015). Therefore, it is advised to perform a skin test before the 6th cycle of carboplatin chemotherapy to ascertain the potential risk of a carboplatin allergy (Sliesoraitis and Chikhale, 2005), and ii) added preventive use. Dexrazoxane is used to prevent heart toxicity caused by anthracycline (Saleh et al., 2021), while the leaflet states it is not recommended for patients who have just started using it.

It is generally considered unreasonable to use medications in contraindicated conditions as it may pose risks to a patient’s health. However, there are exceptions, such as the use of doxorubicin and cyclophosphamide in pregnant women, which are typically prohibited. Yet, anthracycline-based chemotherapy regimens have been utilized in pregnant patients with mid/late-stage breast cancer [chemotherapeutic regimens such as fluorouracil, doxorubicin, and cyclophosphamide (FAC regimen)] (Germann et al., 2004; Amant et al., 2012; Loibl et al., 2012; Peccatori et al., 2013). The decision to use medications in contraindicated conditions was based on a prospective single-group study that included 87 patients receiving fluorouracil, doxorubicin, and cyclophosphamide combination chemotherapy during mid/late-stage pregnancy, without any occurrences of stillbirth, spontaneous abortion, or perinatal death. Moreover, the majority of these children did not experience any severe neonatal complications (Murthy et al., 2014).