Understanding Research Studies on Canine Hepatocellular Carcinoma

Types of Studies You May See

Research papers may use terms such as case report, case series, cohort study, randomized controlled trial, retrospective study, and prospective study when describing research. Being familiar with these terms can help you better understand how a study was designed and how its data was collected.

Understanding Randomized Controlled Trials

Randomized controlled trials (RCTs) are among the strongest forms of primary research for evaluating the effectiveness of treatments and other interventions.^{Sargeant et al., 2023}

In randomized controlled trials:

• Dogs are selected for participation in the study.^{Merck, Epidemiology}
• The selected dogs are randomly assigned to one of two groups: a study group or a control group.^{Merck, Epidemiology}
• The study group receives the intervention being evaluated.^{Merck, Epidemiology}
• The control group does not receive the intervention being evaluated.^{Merck, Epidemiology}
• Blinding (or masking) may be used so that certain people involved in the study do not know which dogs are assigned to which group, helping reduce potential bias.^{Merck, Epidemiology}

Conducting large randomized controlled trials in veterinary medicine can be challenging because of the logistical, financial, and time demands involved. However, evidence from smaller randomized controlled trials can still be valuable, especially when results from similar studies contribute to a broader body of research.^{Weese et al.}

Limitations of Small Sample Sizes

Sample size refers to the number of dogs included in a study. Many studies involving canine HCC include a relatively small number of dogs.

Smaller sample sizes may:

• limit a study’s ability to detect differences in the effects of an intervention.^{Tan et al.}
• make it more difficult to determine whether a small association or no association is present.^{O'Connor et al., 2016}
• result in greater uncertainty around study findings.^{O'Connor et al., 2016}
• lead to more extreme results.^{Jeffery et al.}

Small studies can still provide valuable data.^{Weese et al.} But when reading a small study, it is important to keep the limitations of its sample size in mind.

What “Median Survival Time” Means

A commonly reported statistic in veterinary oncology studies is median survival time.

Median survival time refers to the point at which half of the dogs in the study have died and half remain alive.^{Merck, Survival Analysis}

It is important to understand that:

• median survival time is not the same as average (mean) survival time^Intile
• it does not predict how long an individual dog will live^{Pieper Veterinary}
• survival outcomes can vary widely from one dog to another^{Pieper Veterinary}

Median survival time should be understood in the context of the group of dogs included in a specific study instead of as an expectation for an individual dog.

Putting Survival Times Into Context

Survival times in research studies are measured from a defined starting point. This may be the time of diagnosis, study enrollment, the start of treatment, or another relevant event (such as the date of biopsy). This starting point is sometimes referred to as “time zero.”^{Delgado et al.}

Using a defined starting point provides a consistent way to measure outcomes within a study, but it does not necessarily mean that all dogs were at the same stage of disease when measurement began.

For example, one dog may undergo biopsy early in the course of the disease when the tumor is smaller or more localized, while another may be diagnosed later when the disease is more advanced. Even though both dogs are measured from the time of biopsy, their disease may have been at very different stages at that point.

Because of this, survival times can sometimes appear longer simply because measurement started earlier in the disease process. This is known as lead-time bias, where earlier detection can make measured survival appear longer even when the course of the disease has not changed.^{NCI, Lead Time Bias}

It's important to keep in mind differences in the starting points used to measure survival and where dogs were in the course of their disease when measurement began, as these differences can make direct comparisons of survival times between individual dogs or across different studies difficult.

Putting Treatment Outcomes Into Context

Dogs included in a study, or in different treatment groups within a study, may vary in important ways, such as:

• tumor size and extent within the liver
• whether the tumor is surgically resectable
• overall health and presence of other medical conditions
• age and general condition at the time of diagnosis

These differences are worth keeping in mind when comparing outcomes between groups.

One consideration is confounding (literally, "confusion of effects"). When another factor is associated with both the exposure (for example, treatment) and the outcome being studied, the observed relationship between the exposure and outcome cannot necessarily be interpreted as causal.^{O'Connor et al.}

Another consideration is cointerventions. Dogs within the same study may also receive additional treatments or procedures (cointerventions), such as tumor debulking. Differences in cointerventions between groups can introduce bias into study results.^{Moutzouri et al.} When multiple interventions could contribute to an outcome, it may be difficult to determine how much of that outcome is associated with the treatment being studied.

When reading about survival times or treatment outcomes, the characteristics of the dogs included in the study, the characteristics of their tumors, and the treatments or procedures they received can all provide important context. Findings reported in one group of dogs with HCC may not necessarily apply in the same way to every dog with HCC.

Association/Correlation vs. Causation

An association or correlation means that two things are associated or occur together. Causation means that one thing directly causes another.^{NIH, Association, Causation}

For example, a study might find that dogs who underwent surgery had longer survival times. This shows an association between surgery and survival, but it does not by itself establish that surgery caused the difference. Dogs that undergo surgery may differ from other dogs in important ways – such as tumor location, stage of disease, or overall health – that may also be related to survival.

An observed association does not necessarily mean that one factor caused the outcome.

Randomized controlled trials can provide stronger evidence about whether an intervention causes an outcome because randomization can reduce selection bias and help make treatment groups more comparable with respect to factors that could affect prognosis.^{Moher et al.}

As mentioned earlier, these types of studies can be challenging to conduct in veterinary medicine.

What to Keep in Mind When Reading a Study

When reading a study about canine HCC, looking at the details can help put the results into context. Some factors and questions to consider include:

Putting Research Into Perspective

Research on canine HCC has limitations, but the available studies still provide valuable information that can help improve our understanding of the disease.

Approaching research with a thoughtful and informed perspective can help you better understand what study findings may – and may not – mean for your dog.

Decisions about your dog’s care should be made together with your veterinary team, who can help interpret research in the context of your dog’s specific situation.