Background Breast cancer is the most commonly diagnosed cancer in Europe and worldwide.
With a continuously increasing incidence, it is estimated that by 2040, the breast cancer
burden will increase to more than three million new cases per year worldwide, with more
than one million breast cancer-related deaths per year (50% increase).
The prognosis of breast cancer is steadily improving due to the early detection of
primary cancer through screening programs and revolutionising treatment development.
Despite this, approximately one-third of patients diagnosed with primary breast cancer
will develop metastatic disease. In the metastatic setting, therapy improvements have
made breast cancer a chronic disease with declining mortality rates, and several
effective treatment lines are available for metastatic breast cancer patients today and
in the future. This favourable situation requires accurate methods to assess response to
treatment to achieve the most effective treatment planning.
FDG-PET/CT is increasingly used in cancer staging. Several studies have shown improved
sensitivity of FDG-PET/CT compared with conventional imaging for diagnosing metastatic
breast cancer in retrospective and smaller prospective studies. We expect FDG-PET/CT to
detect disease progression earlier than CT in patients treated for metastatic breast
cancer, enabling earlier start of second-line therapies. This has the potential to
increase the beneficial effect of second-line therapies at the individual level and
result in a delayed need for third-line therapies, prolonged overall survival, and
improved quality of life compared with patients monitored with conventional CT.
Currently, no specific recommendations are provided for a diagnostic modality to monitor
treatment response in patients with metastatic breast cancer. European clinical practice
guidelines (ESMO) state that there is no evidence of any staging or monitoring approach
for metastatic breast cancer patients that provides overall survival benefit over another
approach. ESMO suggests that FDG-PET/CT might provide earlier guidance in the monitoring
of bone-only or bone-predominant metastasis, but it is emphasised that prospective trials
are needed to study the impact of this on treatment decisions and overall survival. This
is the evidence that MONITOR-RCT will deliver.
Study objectives The primary objective of the MONITOR-RCT is to demonstrate that in
patients with metastatic breast cancer, response monitoring based on FDG-PET/CT is
superior to response monitoring based on CT with respect to overall survival. The
objective will be based on applying standardized response evaluation criteria, using an
appropriate adaptation of the PERCIST criteria for FDG-PET/CT and the RECIST1.1 criteria
for CT.
Secondary objectives of the MONITOR-RCT are to demonstrate superiority with respect to
the quality of life and exposure to oncologic treatment and to investigate the
cost-effectiveness.
Consequently, the primary endpoint of the study is overall survival. Secondary endpoints
are quality of life, exposure to oncologic treatment, and cost-effectiveness.
Study design The MONITOR-RCT study will be an international multicenter study. The design
will be a parallel group comparative randomized trial comparing an experimental
monitoring strategy based on FDG-PET/CT with a standard monitoring strategy based on CT.
Eight hospital sites in Denmark, two in Italy, and one in Germany will participate in
patient recruitment and the conduction of the study.
Inclusion criteria
Criteria for inclusion will be:
Women and men aged ≥18 years Diagnosis of distant relapsed metastatic breast cancer
(biopsy-verified) or de novo breast cancer. In patients with distant relapsed metastatic
breast cancer, biopsy verification from a distant metastasis is required. In patients
with de novo metastatic breast cancer, biopsy verification of primary tumor and
diagnostic imaging with distant metastasis with a typical pattern of metastatic breast
cancer is required.
Considered eligible for first-line systemic treatment Considered eligible for continuous
treatment monitoring by scans. Signed informed consent Participants must have the ability
to read and understand the following languages based on their country of participation:
in Denmark, patients must be able to read and understand Danish; in Italy, they must be
able to read and understand Italian or English; and in Germany, they must be able to read
and understand German or English.
Exclusion criteria
Criteria for exclusion will be:
Pregnant or lactating women Ongoing oncological treatment for another cancer Exclusively
brain metastasis Allergy to FDG
Target population Participating patients should have newly diagnosed metastatic breast
cancer and be considered eligible for initiating first-line medicinal treatment and
subsequent regular response monitoring.
This is the patient population for whom a benefit from FDG-PET/CT-based response
monitoring is expected. They are very similar to the criteria defining the populations
investigated in Vogsen et al. (2023) and Naghavi-Behzad et al. (2022).
Quality of life questionnaires Quality of life questionnaires will be completed at home
every three months during the first year and every six months later.
Two questionnaires will be used:
EQ-5D-5L FACT-B In addition, patients can report complaints related to the conduct of
scans in a final open question at the end of the questionnaires.
Interventions The intervention of interest is the use of FDG-PET/CT for response
monitoring compared with CT for response monitoring. The use of CT as a monitoring
modality represents the usual care in patients with metastatic breast cancer.
FDG-PET/CT scans will be evaluated using the standardized response evaluation criteria
for patients with metastatic breast cancer (PREMIO criteria), whereas the CT scan will be
evaluated using the RECIST 1.1 criteria. Both criteria aim at classifying the patient as
having complete (metabolic) response (CR/CMR), partial (metabolic) response (PR/PMR),
stable (metabolic) disease (SD/SMD), equivocal metabolic disease (EMD) or progressive
(metabolic) disease (PD).
The PREMIO set of response evaluation criteria is an adaptation of PERCIST (for
monitoring patients with metastatic breast cancer. The PREMIO criteria are defined based
on data from the MESTAR study, Vogsen et al. (2023), introducing the nadir scan for
comparison in cases where the disease has regressed compared with the baseline scan.
Clinical decision-making: For patients in the intervention group, clinical
decision-making will be supported by FDG-PET/CT and PREMIO, while the conventional group
will be supported by the CE-CT and RECIST 1.1. The decision-making will be in both groups
following the current standard according to the local practice and following
international guidelines. The decision-making may include a request for further imaging
procedures. Parameters such as toxicity profile and the patient's general condition will
also influence treatment decisions. Major components of patient management and the main
reasons for treatment decisions will be registered throughout the study.
Scan procedure and interpretation: All patients will have baseline scans performed before
treatment and according to the randomization group. Treatment and follow-up scans will be
approximated at regular intervals of 9-12 weeks or according to local guidelines. The
choice of the diagnostic modality does not influence the monitoring intervals or time
points.
Contrast-enhanced CT of at least the thorax and abdomen will be performed using
diagnostic scan quality. Pelvic CT may be added based on clinical need. The scan reports
will be made by specialists in radiology with an assessment according to the RECIST 1.1
criteria. FDG-PET/CT will follow standard guidelines from the European Association of
Nuclear Medicine. FDG-PET/CT scans will be conducted on EARL2 certified PET scanners, and
the quantitative assessment, using the SULpeak value of the hottest metastatic lesion,
will based on the EARL2 reconstruction. The CT performed along with the PET scan will be
of diagnostic quality and will have contrast enhancement, if not contraindicated. The
scans will be assessed by specialists in nuclear medicine according to the suggested
PREMIO criteria.
According to RECIST 1.1 and PREMIO, disease measurability will be evaluated at the
baseline and during follow-up in each study group. In cases of no measurable disease
according to the respective criteria applied, the patient's scans will be assessed
qualitatively with a parallel response categorization. This categorization slightly
differs from the one used in the case of measurable disease, but it still allows for the
distinction of progressive disease from all other states.
CT and FDG-PET/CT scans will be viewed based on the existing standard software. Viewing
of FDG-PET/CT scans will be further supported by software developed as part of the
establishment of the PREMIO criteria. Application of the criteria remains a task for
radiologists or nuclear medicine specialists.
Outcome variables The primary endpoint "Overall survival" will be addressed based on the
primary outcome variable "Time from randomization until death".
The secondary endpoint "Quality of life" will be addressed by two outcome variables. The
first is the overall summary score of the FACT-B, the second the complaints related to
the conduct of scans reported by the patients.
The secondary endpoint "Exposure to oncologic treatment" will be addressed by the
following outcome variables describing different aspects of oncological treatment:
Experience of progression Start of a new treatment line because of progression Time to
first progression Time from first to second progression Time from second to third
progression Experiencing other diagnostic procedures Hospitalization
The secondary endpoint "Cost-effectiveness" will be addressed based on relating the
outcome variables "Overall survival" and "Quality of Life" to the outcome variable
"Costs".
These outcome variables correspond to the expected benefits described above.
Sample size considerations Sample size considerations are based on using a direct
comparison of the survival rates at 42 months. The statistical test finally used will be
more powerful due to summarizing the information from all time points and adjustment for
prognostic covariates.
In the study of Naghavi-Behzad et al. (2022), the survival rate after 42 months was 34%
in the CT group and 51% in the FDG-PET/CT group. Due to the introduction of new, more
effective treatment lines in the last decade, we expect higher survival rates in this
RCT. Sample size calculations are based on the assumption that true survival
probabilities will be 39% and 56%, respectively. Under this assumption, we have to
include overall 420 patients to reach a power of 87% (based on two-sided testing at the
5% level).
According to the timeline of the study, the minimal (planned) follow-up time of the
patients will be 36 months, and the maximal follow-up time will be 54 months. In the
above calculations, a uniform distribution of the follow-up time was assumed.
With respect to the primary outcome (survival), we do not expect drop outs, as we can
rely also on national registries. Hence drop-outs are not accounted for in the sample
size calculation.
Significance level A significance level of 5% (two-sided) will be applied.
Exposure to radiation The radiation dose is an issue of consideration. The average
radiation dose per patient per scan procedure is estimated, in conventional diagnostic
CT, to be 9 mSv and in conventional 18F-FDG-PET/CT to an additional 4 mSv, respectively.