Radiotherapy Quality Assurance (RTQA) in clinical trials

Radiotherapy Quality Assurance (RTQA) is an important topic in oncology clinical trials. This article makes a review of scientific literature and international recommendations in this field and briefly describes solutions provided by AQUILAB to improve the quality in RT oncology trials.

Radiotherapy in Cancer treatment

In 2018, there were over 18 million new cases of cancer worldwide. Predictions show that this number will unfortunately continue to increase to reach 27.5 million cases in 2040 ⁱ.

Treatments for cancer include surgery, chemotherapy and radiation therapy. Radiotherapy remains the main treatment, used for more than 50% of patients.

On the other hand, according to the study “Characteristics of radiotherapy trials compared with other oncological clinical trials in the past 10 years” ⁱⁱ published in 2018, radiotherapy trials only represent 5.3% of oncology trials over the period 2006- 2016. This is partly explained by the difficulty in funding these studies, even ithough they are necessary to evaluate new radiotherapy techniques.

However, according to “Overview of ongoing clinical trials investigating combined radiotherapy and immunotherapy” ⁱⁱⁱ published in 2018, the number of clinical trials investigating radiation therapy and immunotherapy (iRT) has drastically increased in the last decade, and this trend should continue in the following years.

Finally, amongst all the oncology studies published in ClinicalTrial.gov, almost 25% include radiation therapy at one part of the treatment. ClinicalTrial.gov lists only 70% of all studies but this proportion seems realistic.

The key numbers:

Radiation therapy is used in the treatment of more than 50% of patients.

Radiotherapy studies only represent 5.3% of oncology trials.

Radiation therapy is used in approximately 25% of oncology clinical trials.

Radiotherapy today

Radiotherapy has undergone major evolutions in recent years, with technological developments to better target the tumor, better follow movements during treatment and better adapt this treatment to each patient, with machines that mainly integrate on-board imaging to ensure that the delivered treatment is in accordance with matches the planned treatment.

However, Radiotherapy remains a complicated and multistep process with :

• Imaging step: to define where to treat, with an increasing use of multimodal imaging

• Planning step: to define how to treat the tumor while avoiding Organs at Risks (OARs)

• Treatment step: To deliver what has been planned during all sessions

This complexity of radiotherapy workflow will be more difficult to harmonize in all the investigating centers of the clinical studies. Main problems to be solved are:

• Compliance with contouring recommendations: are the tumor and organs at risk defined and contoured in the same way in all centers

• Compliance with dosimetric constraints: do all the centers treat according to the same protocol with the same dosimetric constraints.

Without harmonization and standardization of radiotherapy treatments, the clinical results cannot be properly evaluated and analyzed. This is also one of the main objectives of ICRU report 83 published in 2013 ^iv.

Impacts of protocol deviations in clinical trials

In 2013, the study “Radiotherapy Protocol Deviations and Clinical Outcomes: A Meta-analysis of Cooperative Group Clinical Trials” ^v showed the impact of protocol deviations on the quality and clinical outcome. This analysis was done on 8 studies carried out by recognized cooperative groups. In this publication, deviations from the protocol were observed in 8 to 71% of cases (median 32%). These RT protocol deviations showed a significant impact on patient outcomes but RT quality may also influence the interpretability of study results.

In particular, the study “Critical Impact of Radiotherapy Protocol Compliance and Quality in the Treatment of Advanced Head and Neck Cancer: Results From TROG 02.02“ ^vi, published in 2010, evaluates the impact of the quality of the RT treatment on outcome in a large phase III Head & Neck trial. This study already included a first quality control process with a centralized review of treatment plans. After this initial QA process, a second review was done on all plans, classifying 612 patients as “protocol compliant”, and 208 patients as “noncompliant”. In these “noncompliant” plans, a final review was done to separate them into two groups: one in which the deviations were predicted to have a major adverse impact on Tumor Control Probability and one that might be considered compatible with a reasonable standard of care.

The results showed very different survival and recurrence curves between the groups. The patients classified as major TCP impact have a survival curve significantly different from the others.

It was also noted that the response to the study would have been different if we compared the results between patients who received “Good radiotherapy” and those who had “Bad radiotherapy”.

The impact of poor radiotherapy can greatly exceed the anticipated benefit of concurrent chemotherapy

The main need that was expressed in this study was to have real-time quality control and therefore, that it had to be done prospectively, before patient treatment.

Other papers show the same need to have RT QA in clinical trials. In a recent study, “Quality of radiotherapy reporting in randomized controlled trials of prostate cancer” ^vii, reviewing 59 prostate clinical trials from 1987 to 2016, the authors analyzed if the investigators reported 10 specific quality criteria in the trial reports. The study was considered “good” if 7 criteria were met. Only 40% of the trials reported seven criteria or more adequately.

In another Head & Neck study in 2019, “The impact of clinical trial quality assurance on outcome in head and neck radiotherapy treatment“ ^viii, the authors defined RTQA score based on review of target volume and organs at risks contouring associated with dose coverage of targets. This study also showed that poor RTQA scores are correlated with patient local control.

Based on these different studies, we can see how the quality assurance of Radiotherapy (RTQA) is necessary in oncology clinical trials.

Of course, this quality control has a cost, mainly a human cost to review the patient plans, but it proves necessary for the quality of the treatments and the relevance of the results obtained in the studies ^ix. As such, many journals no longer accept manuscripts if the methodology for quality control of radiotherapy is not fully described and documented.

“Although the incorporation of an RT-QA program may be a costly initial component of clinical trials, in the long term we cannot afford to run trials dependent on high-quality RT without it.“

Source: McDowell L., IJROBP, 2018

The RT QA solutions are well known

Many recommendations have been published, such as those of AAPM ^x or from the “Global Harmonization Group” ^xi, which brings together Scientific Societies and cooperative groups. This last group recommends:

• The implementation of Dummy Runs (Benchmark cases), i.e. contouring exercises, dosimetry planning, or even registration on a clinical case in order to ensure that each investigating center has properly integrated the entire study treatment.

• Once the center has been “approved”, based on the Dummy Runs, they recommend a centralized review of RT plans before treatment of the patients

AQUILAB solutions for RT QA clinical trials

AQUILAB has been involved for many years in improving the quality and harmonization of radiotherapy in clinical trials. Our expertise and technological solutions allow a simplified implementation of quality assurance protocols.

In particular, our Share Place solution is a web platform that allows:

• To manage the participants of the clinical trial. There is an investigator area, a promoter area and an expert area. These three spaces are distinct but in connection with each other in order to coordinate the workflow between the different participants.

• To collect, anonymize structure and centralize all DICOM and DICOM RT data (images, structures, plans and doses) necessary QA.

• To analyze images, contours and plans coming from all TPS using the review tools of our ARTIVIEW solution.

According to the study protocol, each project can be customized in order to ensure appropriate monitoring of inclusions while ensuring the security of the information exchanged.

You can find a demonstration of the Share Place platform during the second part of our webinar on centralized quality control of radiotherapy in clinical studies.