Novelties from the Joint EANM/SNMMI/ANZSNM Guidelines on Immunotherapy

Abstract

In the past decade, the implementation of immunotherapy with checkpoint inhibitors has determined a major change in the management of oncological patients. The challenges associated to the new therapeutic regimen have promoted adapted criteria for response assessment to interpret imaging findings and atypical patterns of response. Parallel to the new morphological criteria, also ¹⁸fluoro-deoxyglucose positron emission/computed tomography imaging has required novel approaches and specific guidelines on how to perform, interpret, and report the scan in patients with solid tumors under immune checkpoint inhibitors therapy. A summary of the novelties related to the new joint international European Association of Nuclear Medicine (EANM)/Society of Nuclear Medicine and Molecular Imaging (SNMMI)/Australian and New Zealand Society of Nuclear Medicine (ANZSNM) guidelines on immunotherapy is provided herein to elucidate most critical aspects in image interpretation.

Introduction

In the past decade, a large number of publications, predominantly single-centered, have investigated ¹⁸fluoro-deoxyglucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) in cancer patients undergoing treatment with immune checkpoint inhibitors.^1,2 The challenges associated to this new therapeutic regimen have promoted adapted criteria for response assessment to interpret imaging findings and atypical patterns of response (Fig. 1). Parallel to the new criteria applied for morphological imaging (i.e., modified Response Evaluation Criteria in Solid Tumors for immune-based therapeutics [iRECIST], immune-modified Response Evaluation Criteria in Solid Tumors [imRECIST]),^3,4 also [¹⁸F]FDG PET/CT imaging has required novel approaches and specific guidelines on how to perform, interpret, and report the scan in patients with solid tumors undergoing immune checkpoint inhibitors therapy.

FIG. 1.

Illustration of four specific patterns of response to immunotherapy: (A) pseudoprogression, or a transitory “progression” followed by response. (B) Hyperprogression, or augmented progression profile leading to a doubling of tumor burden and/or a twofold increase in tumor growth rate. (C) dissociated response, or a decrease or stabilization in some tumor sites with a concomitant increase in other sites, often referred to as mixed response. (D) Durable response, or progressive reduction in size and/or number of tumor lesions. Modified from Lopci et al¹ under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Earlier this year, the “Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [¹⁸F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0” have been published.¹ The steering committee of the aforementioned guidelines included international experts from all over the world, aiming to shed light on the appropriate indications and recommendations on [¹⁸F]FDG PET/CT use in the era of immunotherapy, with a special focus on response assessment in solid tumors.

Based on these criteria, three different time points are reported as indicated.

TIME POINT 1: Baseline Evaluation Before Treatment Start

PET/CT is regarded as mandatory in all [¹⁸F]FDG avid tumors before treatment start with immunotherapeutic regimens. The scan serves as a staging/restaging tool, depending on the line of treatment, and defines a time zero (T0) assessment useful for subsequent monitoring.

NOTE : Along classical measurements related to most intense sites of [¹⁸F]FDG uptake, also volumetric analyses are regarded as useful (e.g., MTV, metabolic tumor volume) and their computation recommended at baseline.

TIME POINT 2: Assessment During the Course of the Treatment

The first response assessment with [¹⁸F]FDG PET/CT is recommended 8–12 weeks after treatment start (i.e., 3–4 cycles). Given the prevailing use in this context of morphological evaluation with CT, PET/CT should be performed routinely in case of discordant findings and in nonresponding patients, to complement the information obtained from CT. Earlier or later assessment is recommended in case of clinical deterioration and/or suspicious progression on contrast-enhanced CT.¹

The guideline highlights the use of appropriate reporting of metabolic response to treatment (Fig. 2), by providing as optional the available response criteria in solid tumors (i.e., European Organisation for Research and Treatment of Cancer [EORTC] and PET Response Criteria in Solid Tumors [PERCIST]), as well as the new immunotherapy-adapted metabolic criteria (i.e., PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy [PECRIT], PET Response Evaluation Criteria for Immunotherapy [PERCIMT], immune PET Response Criteria in Solid Tumors (iPERCIST), and immunotherapy-modified PERCIST [imPERCIST]).^5

–10

FIG. 2.

Interpretation of [¹⁸F]FDG PET/CT findings in a patient with metastatic melanoma treated with nivolumab. From baseline images (A) to first response evaluation (B) the patient showed a significant metabolic response in the original pathological lymph nodes located in the left iliac and para-aortic region, along the appearance of new hypermetabolic nodes in the right inguinal region (full circle). Herein, according to immunotherapy-adapted PET criteria, that is, PERCIMT and imPERCIST,^8,10 the patient was considered as SMD and PMR, respectively, whereas based on iPERCIST,⁹ it was defined as iuPMD (immune unconfirmed PMD). On subsequent evaluation, the lesion was considered as pseudoprogression (C), whereas the remaining areas of nodal involvement showed an additional metabolic response. In the meantime, multiple hypermetabolic adenopathies in the lung hilum and mediastinum were detected (dotted circles), considered consistent with sarcomatoid-like reaction. In fact, this finding resulted persistent in almost all subsequent evaluations and showed no significant changes related to the treatment with checkpoint inhibitors (B–E). Subsequent [¹⁸F]FDG PET/CT scanning (D) revealed a complete response of original sites of disease, whereas new lesions were detected in the left external and common iliac region (full circles). Only one lesion showed a functional diameter > 1.5 cm, consistent with a SMD according to PERCIMT criteria. On counterpart, almost all conventional and immunotherapy-adapted PET criteria (i.e., EORTC, PERCIST, and imPERCIST) proved a PMD.^5,6,10 Once again, iPERCIST would result as iuPMD.⁹ After treatment continuation, the new imaging evaluation (E) showed the complete disappearance of all previously outlined malignant lesions. [¹⁸F]FDG, ¹⁸fluoro-deoxyglucose; EORTC, European Organisation for Research and Treatment of Cancer; PERCIMT, PET Response Evaluation Criteria for Immunotherapy; iPERCIST, immune PET Response Criteria in Solid Tumors; imPERCIST, immunotherapy-modified PERCIST; PERCIST, PET Response Criteria in Solid Tumors; PET/CT, positron emission tomography/computed tomography.

NOTE : Some immunotherapy-adapted metabolic response criteria (i.e., PERCIMT and imPERCIST) have shown some superiority, particularly in SD patients on CT,¹¹ although none of the new criteria has been proved to be superior in survival prediction, given the lack of multicenter randomized clinical trials focused on imaging data.

TIME POINT 3: Assessment Before Immunotherapy Discontinuation or Treatment Stop

Patients receiving maintenance therapy or undergoing long-term treatment with checkpoint inhibitors would benefit from metabolic assessment of response with [¹⁸F]FDG PET/CT, particularly in partial responders or stable disease on CT.^12,13

NOTE : In case of temporary interruption, before treatment rechallenge, [¹⁸F]FDG PET/CT should be repeated to restage the disease and obtain some new T0 data useful for subsequent monitoring.

The joint European Association of Nuclear Medicine (EANM)/Society of Nuclear Medicine and Molecular Imaging (SNMMI)/Australian and New Zealand Society of Nuclear Medicine (ANZSNM) guidelines/procedure standards support the general recommendations provided by previous EANM guidelines,¹⁴ and SNMMI procedure standards for tumor imaging,¹⁵ as well as the RSNA QIBA FDG/CT guidance.^16,17 In this context, given the importance of reproducible and repeatable data on [¹⁸F]FDG PET/CT imaging, international harmonizing standards, such as those based on the EANM/EARL program,¹⁸ should be granted. This is especially true when considering semiquantitative parameters for response assessment.

Additional information for image interpretation and reporting are provided through a detailed checklist (Table 1), which should serve as guidance for [¹⁸F]FDG PET/CT imaging during immunotherapy with checkpoint inhibitors. Special attention is given with this regard to the signs of the immune activation, that is, spleen-to-liver ratio, and the occurrence of the immune-related adverse events (irAEs), which should be promptly reported, whereas more severe toxicities should be directly communicated to the referring physician or to the appropriate health care provider.

Table 1.

Recommended Checklist for the Assessment of Patients with Solid Tumors Undergoing Immunotherapy with Checkpoint Inhibitors

Checklist
Clinical history	Type of immunomodulatory treatment ICI: e.g., anti-CTLA-4, anti-PD-1/PD-L1, or combination Intratumoral immunotherapies Cell-based immunotherapies
	Detailed information on therapy Number of cycles and date of the last injection If intratumoral administration, define the site of injection Prior lines of treatment; if combination treatment, report the type of treatment or, in case of radiation, the site of irradiation
	Clinical symptoms Report symptoms suggesting immune-related adverse events
	Interfering drugs For diabetic patients, check whether drugs likely to mimic colitis (biguanides) have been given Previous or ongoing use of corticosteroids and antibiotics should be noted
Therapy response	Response assessment Define response of target lesion(s); assess nontarget lesion(s) behavior; Use recommended conventional (i.e., EORTC or PERCIST) or immunotherapy-adapted response criteria (i.e., PECRIT, PERCIMT, iPERCIST, imPERCIST)^5 –10
	In case of new lesion(s) appearance Define the number of new anatomical sites and the number of new lesions Could new lesions be explained by other processes such as sarcoidosis or other irAES? If new nodal sites occur: Are they located in the drainage area of the main tumor? Is the distribution suggestive of sarcoid-like lymphadenopathy? If there is doubt whether there is progression or pseudoprogression, a confirmatory follow-up [¹⁸F]FDG PET/CT study >4 weeks later, in the setting of clinical stability, or biopsy should be recommended
	Volumetric assessment If possible, include MTV/TLG at baseline and subsequent studies
Signs of immune-activation	Immune organs Report spleen-to-liver ratio Increased bone marrow activity and inversion of spleen-to-liver [¹⁸F]FDG uptake ratio may support systemic immune response; If available comparison with baseline study, it is critical to monitor the metabolic activity within the organs
Immune-related adverse events	Reporting irAEs Different ICIs have differing side-effect profiles (e.g., colitis is more common in anti CTLA-4 and pneumonitis more common in anti-PD-1/PD-L1) Sarcoidosis can have variable presentations and can involve lymph nodes and other organs Preferably, the brain should be included, [¹⁸F]FDG uptake in the pituitary gland should be checked and compared it with the baseline study When immune-related adverse events are shown on [¹⁸F]FDG PET/CT check patient's recovery on subsequent studies

Modified from Lopci et al¹ under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

[¹⁸F]FDG, ¹⁸fluoro-deoxyglucose; EORTC, European Organisation for Research and Treatment of Cancer; PECRIT, PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy; PERCIMT, PET Response Evaluation Criteria for Immunotherapy; iPERCIST, immune PET Response Criteria in Solid Tumors; imPERCIST, immunotherapy-modified PERCIST; PERCIST, PET Response Criteria in Solid Tumors; PET/CT, positron emission tomography/computed tomography.

While representing up-to-date recommendations on [¹⁸F]FDG PET/CT use during immunomodulatory treatments, these guidelines are not carved in stone. Response assessment and patient management during immunotherapy remains a dynamic research field, which continuously provides new evidence and applications. Therefore, the aforementioned guidelines should serve as a starting point to clarify the role of PET/CT in this clinical scenario, which has to be furthermore validated. Particularly with respect to the use of the new radiopharmaceuticals developed for immune-PET imaging.

As for many other clinical indications in nuclear medicine, a multidisciplinary approach is important to optimally manage unexpected events and imaging challenges. In view of the complexity of new therapies and often unique patterns of response or irAEs on [¹⁸F]FDG PET/CT, it is vital that prospective clinical research and trials are conducted to establish evidence for appropriate use that can be utilized by nuclear medicine specialists and clinicians treating and managing these patients.

Footnotes

Acknowledgments

The authors would like to thank all original contributors of the joint EANM/SNMMI/ANZSNM guidelines¹ for their precious collaboration: Nicolas Aide, Rodney J. Hicks, Antonia Dimitrakopoulou-Strauss, Laurent Dercle, Amir Iravani, Romain D. Seban, Christos Sachpekidis, Olivier Humbert, Olivier Gheysens, Andor W.J.M. Glaudemans, Wolfgang Weber, Richard Wahl, Andrew M. Scott, and Neeta Pandit-Taskar.

Disclosure Statement

E.L. reports receiving grants from Fondazione AIRC (Associazione Italiana per la Ricerca sul Cancro) and from the Italian Ministry of Health, and faculty remuneration from ESMIT (European School of Multimodality Imaging and Therapy) and MI&T congressi. A.C. reports previous fellowships from Fondazione AIRC. L.F. declares no conflict of interest.

Funding Information

No funding was received for this article.

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