In oncology, we often encounter situations where the event rate is quite low and de-escalation trials are planned to reduce toxicity and potentially improve QoL. In cancer sites with a large patient population, non-inferiority trials using traditional frequentist approaches are possible. However when the cancer is not so common this becomes a problem. My question is how to design these trials safely.
A practical example.
We know that in patients with carcinoma cervix who are node negative (ie. the cancer has not metastasized to pelvic nodes), the risk of recurrence in the pelvic nodes is quite low (3 - 5%). Most of the toxicity that the patients encounter during treatment (like nausea, vomiting, diarrhea etc) are related to the volume of bowel and bone marrow exposed to radiation. We have high quality data from several randomized trials as well as prospective studies, that reducing the dose to these areas can result in meaninful reductions in toxicities and improvement in patient’s quality of life. Not only does acute toxicity reduce but late toxicity also reduces.
Traditionally we have been prescribing a pelvic radiotherapy dose of 45 Gy in 25 fractions over 5 weeks to these patients (Gy is the unit of dose and fractions is number over which the total dose is divided). Given the low event rates it is tempting to design trials where dose de-escalation will be considered.
A standard frequentist design non-inferiority trial would involve in excess of 2500 patients (depending on the non-inferiority margin). This is obviously inefficient and difficult to conduct.
What is currently done
A good example of a similiar trial design is the UPGRADE-RT Trial (Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma | BMC Cancer | Full Text). The study protocol has the following details for sample size calculation:
- Primary endpoint : Reduction in toxicity - ‘normalcy of diet’ at 1 year after treatment, measured using the performance status scale for patients with head and neck cancer (PSS-HN) -
This study was designed to detect a 10-point difference on the PSS-HN ‘normalcy of diet’ score at 12 months after radiation therapy with a power of 90% at a two-sided significance level of 0.05. An average ‘normalcy of diet’ score of 70 is expected after standard treatment. To achieve this significance level with an unequal randomization ratio (2:1), a total of 300 patients needs to be included.
- Secondary Endpoint : actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment.
The current rate of recurrence in electively irradiated lymph nodes was estimated to be 5% at 2 years after treatment . An equal rate of recurrence is expected in the intervention arm, despite elective dose de-escalation. A recurrence rate of ≥10% will be considered clinically relevant and unacceptable. This difference can be detected with the number of patients planned for the primary outcome of the study and a one-sided α = 0.10.
As can be seen above the results of such trials are difficult to actually implement in practice as they allow the experimental arm (dose reduction) to have a nodal failure rate that is double that of the control arm. Practically, most oncologists will not accept this high failure rate. However practically in most studies, the actual absolute difference in the recurrence rates between arms is around 1- 3%.
What needs to come out from the study is how probable that we will see a failure rate in excess of say 5% given the result of the trial. I would like to know if it is possible to design trials that allow us to make this conclusion ? Maybe using Bayesian trial designs ? Note that recurrence is actually a time to event endpoint in these studies and not a binomial endpoint.
An even better endpoint may be a composite endpoint where estimate the probability that the patient will be alive, disease free and toxicity free at say 2 - 3 years. How much worse can we expect the dose de-escalated arm to be.