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Metastatic Melanoma and Follow-Up MRI Scans
Metastatic melanoma is an aggressive tumor, which may spread to organs either by local invasion, or lymphatic or hematogenous dissemination. Central Nervous System (CNS), especially the brain, account for up to 50% of metastasis. Skin, lymph nodes, lung, and liver are other commonly involved organs, but melanoma can metastasize to any organ in the body. Metastatic melanoma has a poor prognosis, with a median survival rate of only 6 to 9 months and a 5-year survival rate <6%.Small volume, asymptomatic brain metastases are most common in metastatic melanoma. Therefore, brain imaging techniques such as magnetic resonance imaging (MRI) are crucial in making the diagnosis, determining the best course of treatment, monitoring response to therapy, and to predict prognosis.
In the last decade, the diagnosis and management landscape of metastatic melanoma evolved quickly. Thanks to molecularly targeted therapy, immunotherapy (immune checkpoint inhibitors such as BRAF/MEK, high-dose IL-2, cancer vaccination, and adoptive T-cell transfer) and combining approaches. In a recent review, Shalini Makawita, MD, of MD Anderson Cancer Center in Houston said, patients with melanoma and brain metastases should get combination immunotherapy unless there’s a compelling reason to avoid it.
Since the information on MRI’s effectiveness in detecting melanoma brain metastases and the frequency of screening or follow-up scans is limited, the authors sought to determine them.
Materials & Methods
This was a single-center retrospective study carried out at the Department of Medical Oncology of the University Medical Center Groningen (UMCG), the Netherlands. Electronic retrieval of patient data was approved by the institutional review board.
Patient records between June 2015 and January 2018, were obtained from the UMCG database. Two cohorts were defined to evaluate the impact of screening and follow-up MRI scans.
- Cohort 1: Metastatic melanoma patients without brain metastases at the time of diagnosis. Cohort 1 was used to evaluate the impact of 6-monthly screening MRI scans.
- Cohort 2: Patients diagnosed with melanoma brain metastases between June 2015 and January 2018. Cohort 2 was used to evaluate the impact of 3- monthly follow-up MRI scans of melanoma brain metastases.
Patients of Cohort 1 could also be included in Cohort 2 if they developed brain metastases during follow-up. Exclusion criteria included: patients with follow-up at other hospitals, patients who died from other invasive malignancies, and patients with ocular melanoma
Management of patients with melanoma in the UMCG
As per UMCG’s standard diagnostic work-up, all patients diagnosed with metastatic melanoma received a brain MRI. To screen asymptomatic brain metastases, a 6-monthly brain MRI was suggested for patients without brain metastases. If brain metastases were diagnosed, 3-monthly follow-up MRI scans were advised to assess treatment response. Contrast CT, contrast-enhanced computed tomography (CECT), was performed on patients with contraindication for MRI scans. Regular CT scans at 3-month intervals were also performed to evaluate extracranial diseases.
Extraction of patient and tumor data
Patient and tumor-related characteristics (age, gender, BRAF- mutational status, LDH levels at the time of diagnosis of metastatic melanoma and brain metastases), and the presence of neurological symptoms were extracted. All anti-tumor treatments received and changes in treatment plan (i.e., commencing, ceasing, shortening of scanning window, or providing additional treatments) after MRI scans were also documented.
Evaluation of the impact of screening and follow-up MRI scans
For Cohort 1, the first 2 years after the initial metastatic melanoma diagnosis were retrospectively examined ; the number of screening MRI scans and indications were recorded along with the total number of brain metastases diagnosed at the asymptomatic stage. Neurological symptoms before or within 1 week after the diagnosis of brain metastases were also documented. Furthermore, changes in treatment plan after brain metastases diagnosis were registered.
Similarly, for Cohort 2, the number of changes in treatment plan after follow-up MRI scans was evaluated to assess the impact of 3-monthly follow-up MRI scans. First, all MRIs performed within the first year after brain metastases diagnosis, and their indications were identified. Subsequently, the MRI outcomes were classified as progressive, stable disease, partial or complete response. In mixed responses, the radiologist report, clinical notes, and MRI images were used to classify the scan outcome. Cases with differing interpretations were discussed until consensus was reached. Lastly, the changes in the treatment plan after follow-up MRI scans were identified, and the influence of the MRI scans was classified. For patients treated with BRAF/MEK inhibitors or immune checkpoint inhibitors, the number of treatment plan changes after follow-up MRI scans was examined.
Statistical analyses were performed using SPSS 24.0. Mean and standard deviation or median and range were used to describe continuous variables. Kolmogorov– Smirnov tests, histograms, and Q– Q plots were used to analyze the patient data distribution. For categorical variables, frequencies and percentages were also presented.
Patient and tumor characteristics
A total of 212 patients with metastatic melanoma were identified and divided into 2 Cohorts. The median age of Cohort 1 (n = 116; 52% female; 48% male) at the time of metastatic melanoma diagnosis was 66 years (range: 21–86). About 55% (n = 64) of the patients had a BRAF-mutation. The median time between metastatic melanoma diagnosis and brain metastases diagnosis or last follow-up (death or end of study follow-up) was 13.1 months (range: 0–24). The median age of Cohort 2 (n = 96; 43% male; 57% female) at the time of diagnosis of brain metastases was 63 years (range:35-90). About 69% (n = 66) of patients had a BRAF-mutation. The median time between brain metastases diagnosis and last follow-up was 7.7 months (range: 0-12).
Impact of screening MRI scans
A total of 238 MRI scans were performed in the first 2 years after a metastatic melanoma diagnosis. Of these, 101 were baseline MRIs. In 15 cases, baseline MRI was omitted (6 poor performance cases; 2 refused further treatment; 1 claustrophobic case; and 6 with unknown reasons). Of the 102 screening MRI scans out of 238 total scans, 36% were advised to perform 6-monthly screening MRI scans. In 48% (n = 56) no screening MRIs were performed; 30 patients died or were diagnosed with brain metastases within 6months of metastatic melanoma diagnosis; 2 avoided screening due to claustrophobia; 3 refused further treatment; 21 had no specific reasons. 25 additional scans were performed due to neurological symptoms. The remaining 11 were for the follow-up of skull metastases (n = 3), extra response assessment (n = 4), and hypophysitis evaluation (n = 4).
Of the 116 patients of Cohort 1, 28 (24%) developed brain metastases within the first 2 years after metastatic melanoma diagnosis. In the 60 patients who had undergone at least one screening MRI scan, 17 (28%) developed brain metastases (11 with no symptoms and 6 with neurological symptoms). Due to asymptomatic brain metastases treatment plan of 8 patients was changed; these changes included additional SRT (n = 4), change in systemic treatment (n = 1), and shortening of scan window to less than 3 months (n = 3).
In the 56 patients with no screening MRIs, 11 developed brain metastases, and 8 out of 11 were symptomatic. In the remaining 3 patients, brain metastases were diagnosed due to a suspicious brain lesion on PET imaging (n = 1) and additional baseline MRI scans before first-line treatment (n = 2).
follow-up MRI scan
352 MRI scans were performed in Cohort 2 (n = 96), including 107 baseline MRI scans, 168 follow-up MRI scans, 38 for localized treatments, and 22 due to the occurrence of neurological symptoms. The remaining 17 MRI scans were performed for other indications; additional response assessment (n = 16) and the evaluation of an abscess after craniotomy (n = 1). A 3-monthly follow-up MRI was performed in 68% of patients.
Changes in treatment strategy
Changes in treatment strategy were observed in 75 out of 168 follow-up MRI scans (67 were due to scanning outcome; 6 due to extracranial progression; 2 due to treatment-related toxicity). In 42 cases, the change in treatment was due to progressive disease and included changes in systemic treatment (n = 20), the introduction of localized treatment (n = 9), shortening of scanning window (n = 7), and cessation of anti-tumor treatment (n = 6). Changes after MRI scans showing stable disease (n = 9) were mainly shortening of scan intervals due to mixed treatment responses (n = 4). Of the 23 changes observed after MRI scans showing a partial response, 12 had a change in systemic treatment. The change in systemic treatment included a change from BRAF/MEK inhibitors to immune checkpoint inhibitors (10/12).
Impact of follow-up MRI scans in time on treatment
Out of 66 brain metastases cases with a BRAF-mutation, BRAF/MEK inhibitors were prescribed to 54 patients. 1 symptomatic patient received BRAF/MEK inhibitors for a few days while awaiting mutation analysis, which was eventually BRAF wild type. Of the patients treated with BRAF/MEK inhibitors, 9 had a durable response (≥6 months). Within the first 6, treatment changes were observed in 32 out of 56 follow-up MRI scans (57%). Of the 32 MRI scans performed after a change in treatment, 13 showed progression, 15 partial responses, 1 complete response, and 3 stable disease. 7 MRI scans were performed in patients responding to BRAF/MEK inhibitors for at least 6 months. The treatment strategy changed after 3 scans and all of them showed progressive disease.
Among the 56 patients administered with immune checkpoint inhibitors, 19 patients showed durable responses. Within the first 6 months, treatment changes were observed in 15 out of 47 follow-up MRI scans. Of these 15 follow-up scans, 11 showed progression, 3 stable disease, and 1 partial response. In patients administered with immune checkpoint inhibitors, the number of follow-up scans resulting in a change in treatment plan decreased over time. By the end of the first year after brain metastases diagnosis, treatment changes were observed after 3 out of 21 follow-up MRI scans. All 3 scans showed a partial intracranial response, and the treatment changed due to oligo extracranial progression (n = 2) and treatment toxicity (n = 1).
In this retrospective study, about one-third of the patients diagnosed with metastatic melanoma, without brain metastases at diagnosis, developed brain metastases within 2 years after diagnosis. This demonstrates the importance of regular MRI screening in metastatic melanoma patients. Treatment plan changes were suggested for about 45% of the 3-monthly follow-up MRI scans. However, in patients with durable response to immune checkpoint inhibitors, change in treatment was less frequent.
In patients who had at least one screening MRI scan, the majority of brain metastases were diagnosed asymptomatically through screening MRI. On the other hand, in patients who lacked screening MRI, the majority of brain metastases were diagnosed symptomatically. Furthermore, over half of the patients without screening MRI either died or were diagnosed with brain metastases within 6 months of metastatic melanoma diagnosis. In some patients, oncologists omitted screening MRI for unknown reasons and these data must be interpreted with caution.
The results of the current study can also be used as a guide to design and optimize scanning intervals in patients. Potential determinants for optimal screening interval include melanoma location and type, metastatic sites, BRAF- and NRAS-mutational status, and LDH-levels at diagnosis. In addition, extra- and intra-cranial treatment responses and onset of neurological symptoms should also be considered before considering brain imaging techniques.
The results of this study also demonstrated that follow-up MRI scan outcomes often change the treatment strategy, especially in patients treated with BRAF/MEK inhibitors. This was in contrast to the decrease in the number of treatment changes after follow-up scans in patients who received immune checkpoint inhibitors. It was also observed that the changes in treatment strategy within the first 6 months on immune checkpoint inhibitors were mostly seen in scans showing progression.
The findings of this study demonstrate the need for screening MRI scans for early detection of brain metastases in patients with metastatic melanoma. Furthermore, it provides an overview of how regular follow-up MRI scans helps in determining the treatment strategy. Further investigations are required to validate the impact and cost-effectiveness of brain scanning and treatment changes.
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