Page 17 - ARNM-3-2

Advances in Radiotherapy
& Nuclear Medicine Role of PET/CT in exploring tumor heterogeneity

above; however, they are still under investigation, and their outcomes. Heterogeneity can be spatial (as described
role in tumor heterogeneity remains undefined. above) or temporal, which develops over time. Since the
development of heterogeneity is a dynamic process and
7. Clinical applications of PET/CT in tumor may develop temporally, serial PET/CT scans during the
heterogeneity treatment process may provide diagnostic insights. As the

7.1. Diagnosis and initial staging and treatment disease progresses, the treatment-resistant clones of cancer
planning cells continue growing, leading to disease progression;
consequently necessitating a change in therapy regime.
Diagnosing and staging cancer can be complex and For example, breast cancer patients display significant
challenging due to the considerable biological, cellular, and intratumoral and interpatient heterogeneity due to the
tissue variation within tumors. This diversity occurs not presence of various molecular subtypes. The tumor cells
only between cancer cells in an individual patient but also and their metastases express dynamic changes in their
between tumors in different patients. Such heterogeneity molecular subtypes over time, which affects treatment
complicates choosing appropriate treatment plans, as response to neoadjuvant therapy. These variations can be
certain therapies may not be effective against different identified on PET/CT scans, thereby providing critical
clones of cancer cells. The use of multiple PET radiotracers insights into patient management. 53
offers a solution by enabling visualization of the various Spatiotemporal heterogeneity is often seen in
parts of tumor cells and their microenvironments. In gastrointestinal tumors, as cells change their characteristics
addition, PET scans provide full-body, non-invasive during metastases to different anatomical sites over
imaging in a solitary session, which is highly beneficial time. The RECIST and PERCIST guidelines designed to
for detecting tumor heterogeneity. F-FDG PET scans can assess response on radiological and PET imaging are not
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diagnose heterogeneity by analyzing non-homogenous suitable for assessing response with targeted drugs, as the
tracer distribution in the tumor sites with areas of high 52
and low uptake. Similarly, applying multiple PET tracers response is lesion- or organ-specific. Zhou et al., in their
can help identify tumor diversity, as different lesions study on colorectal tumors, reported a better response in
hepatic metastases compared to lungs and lymph nodes
may absorb various tracers differently, depending on the when treated with targeted therapies. In another study
underlying biology of the tumor cells.
by Schmid et al. on lung cancer patients treated with
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Various quantitative parameters (e.g., SUV, TLG, and immunotherapy, an organ-specific response was observed,
MTV) further assist in diagnosing heterogeneity and with better response in lymph nodes compared to liver,
assessing disease prognosis. Tracer uptake patterns may bone, and adrenal glands. Heterogeneity is associated with
reveal the presence of different cancer cell clones, each prognosis, overall progression-free survival, and overall
with varying levels of aggressiveness, which can influence survival, thus it is related to drug efficacy. Therefore, better
the overall prognosis of the patient. In addition, due to strategies for diagnosis and response assessment to address
significant heterogeneity, the same treatment regime may heterogeneity are needed for cancer management.
not be equally effective on different clones of cancer cells
and can lead to treatment failure or resistance. It has been 7.3. Tumor heterogeneity as a cause of mixed
reported that low-grade tumors exhibit lower SUV values response in patients on systemic therapies
on F-FDG PET scans, while higher-grade tumors have Tumor heterogeneity frequently leads to difficulties
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high SUV values. In addition, some lesions with low FDG in treatment and poor outcomes. In numerous cases,
51
uptake may exhibit high uptake when imaged with different follow-up PET/CT scans after systemic therapy reveal a
tracers. Research conducted by Marusyk et al. and Zhou mixed response, where both responding and progressing
9
et al. has demonstrated that the integration of several cells (i.e., resistant to treatment) coexist inside the patient.
52
tracers, including F-FDG and Ga-FAPI, enhances the This combined response reflects the heterogeneous
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visualization of tumor heterogeneity, uncovering metabolic characteristics of different tumor lesions. This heterogeneity
and stromal variations that influence diagnostic and staging is either present from the beginning or develops temporally
precision. 9,13,51,52 Therefore, combining multiple tracers during treatment, where some cancer cells become
in PET scans provides a more comprehensive view of all resistant to treatment. During therapy, the treatment-
lesions and enhances the detection of tumor heterogeneity. sensitive subclones of heterogenous tumors respond,
while the resistant subclones continue growing and form
7.2. Monitoring treatment response tumors, leading to the detection of a mixed response on
Heterogeneity in cancer leads to significant challenges PET/CT scans. In a study on lung cancer, Zhong et al.
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in treatment response and its assessment and influences highlighted the high incidence of mixed response in lung

Volume 3 Issue 2 (2025) 9 doi: 10.36922/ARNM025040005