Although elderly patients tend to be underrepresented in clinical trials, they account for a significant proportion of cancer patients1. It is undeniable that aging exponentially increases the risk of cancer. Approximately 60% of new cancer cases are diagnosed in persons over 65 years of age2.

It is a well-known fact that dysphagia is an increasingly serious health problem among our aging population. Age-related changes in the physiology of swallowing and age-related diseases are factors that predispose the elderly to dysphagia. Although there is a dearth of precise data on the prevalence of dysphagia, the most conservative estimations suggest that the condition affects up to 15% of elderly persons3.

However, cancer patients are not prone to dysphagia only on account of their age. There are also a series of tumors that have been specifically associated with the disorder. In fact, dysphagia is one of the main symptoms of and one of the main obstacles to treatment for several oncological conditions such as head and neck tumors4, esophagus cancer5, thyroid cancer, and lymphoma, among others.

Oral therapy is becoming increasingly common in treating oncological and hematological disorders not least because patients have been shown to prefer that route of administration6. In 2019, 8 of the 12 new antineoplastics approved by the US Food and Drug Administration were oral compounds7. Nonetheless, patients with swallowing difficulties who receive oral chemotherapy may exhibit lack of adherence and require changes or discontinuations in their treatment, which could negatively impact their clinical results8.

Administration of oral drugs to patients with swallowing problems, who may or may not be on enteral nutritional support, represents a challenge for pharmaceutical care. Generally, solid medications must be crushed or opened, and a suspension/solution is prepared to prevent feeding tube blockage. However, such operations are often ill suited to enteric tablets, and sustained and/or controlled-release formulations9. On top of these problems, the label of oral antineoplastics does not usually contain information on the advisability of carrying out such operations. All of this complicates treatment with oral antineoplastics not only in patients with dysphagia, but also in the pediatric population10, who usually require formulations allowing individualized dosing schemes to ensure drug safety and efficacy.

This is an issue of unquestionable clinical significance as it relates to the effectiveness and/or safety of antineoplastic treatment. Taking into consideration the large number of consultations made to hospital pharmacies about this subject, this review article seeks to compile the literature available with a view to the development of a series of guidelines that may facilitate administration of oral antineoplastics in patients with swallowing disorders.

In September 2019 a review was carried out of all the oral antineoplastic drugs approved by the European Medicines Agency (EMA), as published on the Agency's website. Subsequently, a list was drawn up of the oral antineoplastics available in Spain. The list was distributed among a group of hospital pharmacists (two specialists and a resident), each being assigned a set of drugs. Between September 2019 and June 2020, the group members compiled all the information available on the drugs assigned to them. Firstly, they reviewed the labels of the different medications to find out whether such labels contained any information regarding the possibility of crushing, opening and/or dispersing them in fluids or food.

In those cases where this information was not available, or where the products’ label recommended not to split, open, crush or chew the medication, recourse was made to Pubmed, where the following keywords were searched: “name of the active ingredient”, “oral antineoplastics “, “oral chemotherapy”, “deglutition disorders”, “drug compounding”, “extemporaneous”, “crush*”, “gastrointestinal intubation” and “nasogastric tube”. The titles and abstracts of the different publications were reviewed to select those that contained relevant information (case reports on the administration of medication to patients with dysphagia, whether or not on nutritional support; pharmacokinetic studies; studies on the stability of liquid formulations; and any study on extemporaneous liquid dosage forms). The review was completed with searches in other sources such as Micromedex (dosing/administration section); Uptodate (patient information and dosing/administration sections); the Cancer Care Ontario website (drug formulary section); pharmaceutical newsletters and medication fact sheets, such as the ones produced by the Spanish Society of Hospital Pharmacist (SEFH)’s oncological pharmacy (GEDEFO) and pediatric pharmacy (GEFP) groups; guidelines on the administration of drugs through feeding tubes; and other (tertiary) sources of information.

Lastly, and only in the case of drugs where no information was available, contact was established with the pharmaceutical companies that manufacture them, via email or telephone, to gather the required data.

Each group member reviewed and analyzed the literature they had selected on each of the drugs assigned to them. Finally, an independent physician and a fourth pharmacist reviewed the whole work carried out.

A total of 64 oral antineoplastic drugs were reviewed, which are commonly dispensed by Spanish hospital pharmacy departments. Significant information was obtained on 48 of them, of which 44 (69% of the drugs studied) were eligible for administration to patients with a deglutition disorder.

Only one of the drugs (trametinib), available only as a foreign medication, was marketed as an oral liquid formulation. The most commonly used compounding method was dispersion of the solid therapeutic agent in an aqueous solution, with water, simple syrup, Ora-Plus®, and Ora-Sweet® being typically used as solvents. In three cases, a recommendation to dissolve the drug in oil was found; on other occasions drugs were dispersed in apple compote or orange juice. Crushing of the solid form was only recommended for ten medications, and the use of an intravenous formulation as a basis to prepare the oral liquid form was recommended for three drugs.

Certain drugs were associated with more than one compounding method. In these cases, the selected method was always the one supported by the largest body of evidence. When the level of evidence was the same, the method of choice was selected based on criteria related to the complexity or the stability of the formulation.

All the information obtained is summarized in table 1, where the first column contains all the drugs investigated. Each product is described by the name of its active ingredient, its brand name (in brackets) and, when applicable, its generic formulation. The second column describes how antineoplastics may be modified for feeding tube administration, and the third column contains remarks related to the types of containers to be used to store the medication, the most suitable preservation conditions, stability, etc. When no information is provided regarding the period of stability or the expiry of a certain preparation, administration should be initiated immediately following formulation (within one hour).

The presence of dysphagia, compounded by the unavailability of oral liquid antineoplastic formulations, brings to the forefront the need to seek extemporaneous methods to prepare and administer oral antineoplastics in patients with deglutition disorders. The problem is that, in the majority of cases, the manufacturers of these products do not provide information on how to modify them for feeding tube administration, which makes it necessary to search the literature for answers.

Some clinical studies have been published on the subject, as well as stability analyzes and pharmacokinetic reports, but few of them provide information on the way in which the drug is to be modified. Oral liquid preparations of antineoplastic drugs based on stability data are unusual, most of them being extemporaneous formulations for immediate administration13,15. A review on the preparation and administration of oral antineoplastics by the enteral route was recently published in the United States. However, this review includes several drugs that are not available in Spain and makes no mention of the antineoplastics most frequently used in our clinical practice13.

Modification of dosage forms to adapt them for administration to patients with dysphagia could result in changes in the drugs’ bioavailability profile, with a potential decrease in their therapeutic effect59. As shown in table 1, in some cases it is necessary to change the formulation or take into consideration a series of factors to ensure the quality of the treatment administered to the patient. For that reason, the lack of information and the insufficient training in the preparation and administration of medications to patients with dysphagia often compromises the safety and effectiveness of treatment. Indeed, it is not unusual for formulations not amenable to manipulation to be modified, often without due consideration of criteria such as compatibility with other drugs or nutritional products, or with the vehicle they are diluted in60–62.

In patients with swallowing difficulties, whether or not on an enteral feeding tube, recourse to preparation and administration methods often not contemplated in the drugs’ labels may be warranted provided that such methods are supported by studies dealing specifically with the medication in question. In cases where there is no information on the subject, a case-by-case analysis is required that takes into consideration the risk/benefit balance and the available therapeutic alternatives.

It should be underscored that manipulation of oral antineoplastics must be carried out in accordance with the available guidelines on the handling of hazardous drugs56–58. Moreover, that administering drugs through feeding tubes requires observance of a series of general recommendations such as not mixing the drug in question with other medications or with enteral nutritional support products; and washing the tube with 15 ml of water before and after administration13.

The main limitation of this review is the scarce information found about the manipulation of antineoplastic drugs, both in the products’ labels and in other sources reviewed. Furthermore, the evidence that does exist is of low quality. For that reason, it is essential to conduct further research in this field, leading to stability and pharmacokinetic studies that allow a more informed administration of oral antineoplastics in patients with swallowing disorders.

No funding.

No conflict of interest.

The authors would like to thank the Department of Pharmacy of Torrecardenas University Hospital (Almería, Spain).