TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma

The incidence of cutaneous malignant melanoma (CMM) increases rapidly in many countries. In Sweden there was a 35% increase in incidence between 2013 and 2018, from 3400 to 4600 cases [1]. According to the 2016 annual report from the Swedish Cancer Society, the number of cases are expected to multiply during the next decades [2]. Hence, the number of patients requiring follow-up after surgery for CMM will steadily grow in the future.

The reasons for follow-up include:

The potential value of follow-up programs after radical surgery for CMM has been a matter of debate for many years, and with little scientific evidence in support. A Dutch trial, randomizing stage IB-IIC patients between conventional and stage-adjusted follow-up by physical examinations in the standard arm according to Dutch guidelines and less frequent physical examinations in the experimental arm. Patient-reported outcome measures (PROMs) were completed at 0, 1 and 3 years after diagnosis. Primary outcome was patients´ well-being and secondary outcomes were recurrences and melanoma-related deaths. One hundred and eighty patients were included and the results were published this year. Analysis three years after diagnosis showed no difference in RFS (recurrence-free survival) or DFS (disease-free survival) [3]. Other studies, published a decade ago, have reported relatively low predictive value of the elevated tumor marker, S100B protein in plasma to detect relapse [4, 5].

An important question is whether imaging should be a part of the follow-up program for patients who have undergone surgery for high-risk CMM. Some studies have investigated the value of follow-up including imaging in this patient group. The MSLT-2 study, in a large number of patients (n = 1934), showed in 2017 that repeated controls by ultrasound could replace lymph node dissection in case of a positive sentinel node biopsy (SNB) [6]. However, until now, no randomized study investigating the benefit of whole-body imaging has been conducted. In 2017 the results of an American retrospective study were presented and included 247 CMM patients, 27% followed with clinical examinations only and the remaining 73% underwent a combination of clinical examinations and imaging. The mode of imaging was heterogenous and was limited to chest X-ray for stage IIA/IIB patients. Eighty-seven percent of stage IIC/III patients underwent at least two series of whole body PET/CT or whole body CT plus MRI of the brain. The recurrence rate for stage IIC/III was 23% at a median follow-up time of 31 months. Fifty percent of recurrences in this group were detected by imaging in asymptomatic patients [7].

In a retrospective study of 173 CMM patients from three centers in the UK, CT or FDG-PET/CT plus MRI of the brain were performed according to a UK consensus stipulating repeated imaging up to five years for high-risk patients. Forty-seven per cent had relapsed at a median follow-up time of 23 months, the majority of which (66%) was detected by imaging. Median time to recurrence was ten months. Forty-five per cent of relapsing patients underwent surgery and median OS for this subgroup has not been reached. Median OS for patients who received systemic therapy was 13 months [8]. An Australian study, published in the same year (2018), had a similar approach which but resulted in fewer detected relapses than in the previous study. In a PET database, 170 stage III melanoma patients were identified who regularly had undergone routine FDG-PET/CT +/−MRI of the brain. Melanoma relapse was detected in 38% and mainly (69%) in asymptomatic patients. No relapses were identified by clinical examination without first being reported by patients. Fifty-two percent of relapsing patients underwent surgery. Median follow-up time was 47 months [9].

In addition, a few prospective non-randomized studies have also been conducted. In a Spanish study, published in 2016, almost half of 115 recorded relapses in 290 patients were detected by imaging [10]. In a large German study on patients with all stages of CMM (n = 2008), a follow-up program including frequent imaging examinations was prospectively applied. The authors presented the results in 2008 and concluded that the relapses mainly occurred during the first years after radical surgery and earlier in stage III disease compared to stages I-II [11].

The findings in these studies suggest that if a follow-up program is introduced, it should be more intense during or limited to the first years after diagnosis. The observation that more than half of new primary CMMs are detected during the first two years following surgery further indicates that follow-up, if applied, should focus on this time period [11‐13]. In a recent Australian cohort study, also with prospective approach, stage III CMM patients (n = 154) underwent either CT or FDG-PET/CT at baseline and at least twice annually thereafter. Median follow-up time was 85 months and distant metastasis was identified in 13%. However, 124 out of 1022 examinations were false-positive or showed incidental findings, resulting in unnecessary invasive procedures in 15 patients. The authors concluded in their publication last year that false-positive results and incidental findings occurred in at least half of all patients with substantial additional demands on healthcare resources [14]. This study underlines the costs as a major drawback of intense follow-up programs with imaging. In the choice of imaging, FDG-PET/CT is more expensive than CT, and not as widely available, but covers the whole body and offers slightly better sensitivity than CT. Another difference between the two methods is that a CT scan has a higher predictive value than a PET/CT scan in identifying metastases to the liver and lung. For detection of brain metastases, MRI is better than CT, even though the difference is small when contrast-enhanced high resolution CT protocol is applied as in our study. MRI is associated with long scan times, contraindications (the presence of metal implants) and is more costly and less available than CT [15]. Another negative effect of routine imaging (except for MRI) is the irradiation exposure to the patient, which should not be neglected even though the doses are clearly lower with modern scanners [16].

In recent years, new treatment options have become available for metastatic CMM; immunotherapy and targeted therapy. The introduction of novel drugs emphasizes the need to develop optimal follow-up programs for early detection of recurrent disease, since early onset of treatment seems to improve outcome [17, 18].

According to the Swedish national guidelines [19], blood tests or imaging are not parts of the follow-up schedule for CMM. The current recommendation is clinical examinations only for three years for stage IB-III, except in patients with a positive SNB when lymph node dissection is not performed. These patients for three years regularly undergo ultrasound of the positive regional lymph node region [6]. Despite lack of evidence, there is an international tendency for more frequent imaging, such as in the Nordic countries, except Sweden, where FDG-PET/CT is performed regularly up to five years [20, 21].

In summary, there is lack of evidence regarding the potential benefits of follow-up schedules, and even less so concerning the choice of methods, or schedule intensity to apply. The aim of this paper is to present the study design of the randomized TRIM study, evaluating the effects of adding whole-body imaging and laboratory tests to clinical examinations according to Swedish national guidelines.

The incidence of CMM is rapidly increasing in many countries and hence the number of patients who will be subject to follow-up is growing. Follow-up programs usually aim to support and educate the patients and to improve outcome by earlier detection of recurrent disease, both locoregional and distant. Early detection of recurrence is proposed to be beneficial by increasing the chance of radical resection or enabling an early onset of systemic treatment. Due to lack of reliable data it is, however, unclear if scheduled follow-up visits lead to earlier detection of localized disease. One exception is when regional ultrasound is performed in patients with a positive SNB, but no benefit in survival was demonstrated [6]. In fact, the patients usually detect their relapses themselves despite regular controls [29].

In earlier studies the majority of relapses occurred during the first years after primary surgery, indicating that follow-up is most appropriate in the first few years after diagnosis. However, little is known about the potential OS benefit in finding recurrent metastatic disease early, not the least in the modern era with potent systemic melanoma treatments available. As a consequence, there are great variations between national guidelines regarding the recommendations for follow-up after surgery for high-risk CMM. An increasing number of countries have implemented whole-body FDG/PET-CT or CT at various frequencies and duration, as part of their routine follow-up programs in spite of lack of evidence from randomized studies. Intense follow-up programs require resources which are expensive and might negatively affect the patients´ HRQoL.

The importance of not introducing a more intense follow-up program based on mere assumptions of benefit is underlined by the results of the COLOFOL study. In this study, additional CT examinations after curative surgery for colorectal cancer did not result in a significant reduction in 5-year overall mortality or colorectal cancer–specific mortality [30].

In conclusion, the impacts of high-volume follow-up programs including imaging after radical surgery for CMM on OS are not sufficiently studied to create evidence-based guidelines. Despite this, the Current Oncological Practice (COP) is moving towards high intensity follow-up programs while a Minimal Acceptable Practice (MAP) might be just as good. It is therefore of uttermost importance to perform a large controlled trial, randomizing patients to control programs with or without imaging. The TRIM study aims to include at least 1300 patients and is the first randomized trial to investigate the potential benefit of imaging assessments as part of the follow-up program after radical surgery of CMM and to explore their impact on the patients´ HRQoL. A first HRQoL data analysis is planned when 100 patients in each study arm have completed baseline and first year HRQoL assessments which is expected in early spring 2021. The results of the TRIM study will most likely impact future guidelines for follow-up of high-risk CMM patients.