The last few decades have seen Hodgkin lymphoma (HL), which had been a frequently fatal malignancy, become a disease which is often curable using modern frontline and salvage therapies. Despite the successes noted in the treatment of HL, the therapies utilized have many toxicities associated with them. Consequently, researchers have sought a means to guide therapy and differentiate those patients for whom more vigorous chemotherapy is necessary from those who may only require limited treatment.
One imaging modality which has been employed in the treatment of patients with HL is FDG-PET (2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography). In this technique, more metabolically active malignant cells uptake a radiolabeled fluoroglucose analog which is then visualized using PET.
In a recent article, Steven Bair, MD, in the Lymphoma Program at Abramson Cancer Center, University of Pennsylvania, described the incorporation of FDG-PET into response-adapted treatment strategies for patients with HL (PET Clin 2019;14:353-368). “This imaging modality has provided clinicians with a powerful tool to more accurately assess the burden of residual disease and to prognosticate,” he noted.
Hodgkin Lymphoma Therapies
One of the most frequently used frontline treatments is the ABVD regimen that consists of doxorubicin, bleomycin, vinblastine, and dacarbazine. This regimen is often given in combination with radiotherapy and can produce long-term complete remission rates of up to 80 percent.
Another highly effective HL treatment frequently utilized outside of the U.S. is the eBEACOPP regimen that consists of escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. When treated with this regimen, patients with early-stage HL frequently attain 5-year progression-free survival (PFS) rates greater than 90 percent.
For those with advanced HL, slightly worse outcomes are obtained, with 5-year PFS values ranging from 70 to 90 percent, depending on the patient subpopulation and specific treatment regimen studied. Although this regimen tends to display higher anti-lymphoma activities than that of ABVD, it also tends to have greater toxicities associated with administration.
When asked about the toxicities associated with the different treatments for HL, Bair noted, “Traditionally, patients treated with combined modality therapy (i.e., chemotherapy and radiation) had a higher risk of secondary malignancies, such as breast, lung, and gastrointestinal cancers, which were mostly attributed to local effect of radiation on the tissues within the treatment field. More aggressive chemotherapy regimens are associated with a higher risk of myelodysplasia and treatment-related leukemia. In addition, higher rates of early coronary artery disease, pulmonary dysfunction, and infertility have been described.
“As treatments have evolved, especially with respect to radiation planning and administration, the rates of some of these toxicities have declined,” he stated. “However, it remains important to minimize these toxicities whenever possible without sacrificing the curative potential of available treatments.”
Why Use FDG-PET for HL?
“Over the course of several decades,” Bair stated, “HL has been transformed from an often fatal disease to one that is cured in the vast majority of patients. However, the therapies used to treat HL are not benign and may carry long-term toxicity, such as the risk of secondary malignancies, infertility, and cardiopulmonary toxicity. For this reason, there has been a strong effort to understand which patients could be cured with less-aggressive therapy (i.e., by omitting radiotherapy or exposing to lower cumulative doses of chemotherapy). Conversely, the ability to intensify treatment early on in those patients who are most likely to relapse might further increase the rate of cure.”
The first studies that evaluated the use of FDG-PET in patients with lymphoma were performed in the early 1990s. Since then, several studies have been performed that suggest FDG-PET could have utility for monitoring treatment response and that, if performed early enough during therapy (i.e., interim PET), may have prognostic utility.
“In a particularly relevant study,” Bair stated, “Galamini, et al, found that interim FDG-PET performed after 2-3 cycles of therapy has been found to discriminate reasonably well between patients who are likely to experience durable remissions and those that are more likely to relapse (i.e., interim PET-negative and PET-positive, respectively), and in fact, outperforms more traditional prognostic systems such as the International Prognostic Score (IPS) (J Clin Oncol 2007;25(24):3746-3752).”
When discussing the strengths of FDG-PET, Bair commented, “Conventional CT scans did not provide the ability to differentiate between metabolically active and residual fibrotic tissue. The incorporation of FDG-PET into the standard treatment response assessment for patients with HL has provided a greater degree of anatomic and prognostic information than was previously possible.
“The development and incorporation of response-adapted treatment approaches into the standard of care for patients with HL has facilitated more of a personalized approach to therapy,” he observed.
A Predictive Tool
Regarding the utility of FDG-PET as a means for predicting patient outcomes, Bair commented, “As early as 2005, studies began to demonstrate the substantial predictive utility of interim FDG-PET in HL. One of the first prospective studies to document the predictive utility of interim FDG-PET was the previously mentioned study by Galamini and colleagues in 2007, which reported on outcomes in patients primarily with advanced stage HL.
“They found 2-year PFS rates of 95 percent and 13 percent in patients with interim PET-negative and PET-positive disease, respectively, after 2 cycles of therapy. In fact, FDG-PET even demonstrated superiority over the conventional IPS in predicting progression-free survival.”
Challenges in FDG-PET Use
“The use of FDG-PET is not without its challenges,” Bair noted, “especially in the context of response-adapted treatment. Clinicians who regularly use FDG-PET in the evaluation of patients with HL know that FDG uptake due to inflammation, infection, or other process can commonly produce false-positive results, thereby complicating interpretation. In addition, HL is unique among other types of lymphoma because the malignant Hodgkin-Reed-Sternberg cells usually comprise only 1-2 percent of the tumor.”
Further highlighting the difficulties with this modality, Bair noted, “One recent systematic review by Adams and colleagues reported that, among lesions found to be FDG-avid on interim or end-of-treatment scans and subsequently biopsied, only about 50 percent were confirmed to have active malignancy (Eur J Haematol 2016;97(9):491-498). Conversely, a negative interim FDG-PET doesn't perfectly predict cure—5-10 percent of patients with early-stage HL and 10-20 percent of patients with advanced stage disease and a negative interim PET scan will go on to relapse.
“Incorporating the use of additional biomarkers into response assessment and risk stratification will likely result in greater predictive accuracy, thereby overcoming or minimizing some of these limitations.”
Immunotherapies & FDG-PET
“HL is known to be a disease associated with immune dysregulation and immunotherapy has already been demonstrated to play an important role in the treatment of this disease,” Bair stated.
Two prominent immunotherapies for the treatment of classical HL (cHL) are the checkpoint inhibitors nivolumab and pembrolizumab. In May 2016, nivolumab was granted accelerated approval by the FDA for the treatment of patients with cHL who have relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin therapy. For pembrolizumab, the FDA granted accelerated approval in March 2017 for the treatment of adult and pediatric patients with refractory cHL, or those who experienced relapse after three or more previous lines of therapy.
“The incorporation of immune therapies such as PD-1 inhibitors into the treatment of HL introduces additional complexity into the interpretation of FDG-PET treatment response,” Bair commented. “These therapies are associated with well-known radiographic phenomena: delayed response and pseudo-progression.
“The Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC), which have recently been developed by Cheson and colleagues, provide some guidance in differentiating pseudo-progression from true progression (Blood 2016;128(21):2489-2496); however, additional prospective validation will be important,” he noted.
When queried about the future prospects of FDG-PET for guiding HL therapy, Bair replied, “Certainly for the foreseeable future, FDG-PET will remain an important tool in the assessment of treatment response and risk prediction in patients with HL. The anatomic, functional, and prognostic information provided by FDG-PET cannot be captured with any other currently available modality and for this reason, it will remain an essential tool in the near future.
“As previously mentioned, FDG-PET is limited in terms of resolution (resulting in false-negative results), as well as specificity (resulting in false-positive results, for example, in the setting of benign inflammation or infection). Therefore, the most important advance in the coming years will be to combine the results of FDG-PET imaging with additional clinical data, such as circulating tumor DNA levels, to provide a more robust understanding of disease burden, treatment response, and prognosis in each individual patient.”
Regarding other potentially useful applications of FDG-PET, Bair stated, “Additional approaches to characterizing disease burden and response with this modality have been developed; one such method is total metabolic tumor volume. These methods might provide additional prognostic information for patients and clinicians, and some studies have suggested that total metabolic tumor volume might outperform more conventional staging systems (i.e., IPS) in predicting outcomes. However, further validation is required before this parameter can be incorporated into routine clinical practice.”
Richard Simoneaux is a contributing writer.
The Use of FDG-PET as a Diagnostic in Malignancies
Recently, Oncology Times had a conversation with Gary Ulaner, MD, PhD, FACNM, from the Department of Radiology at Memorial Sloan Kettering Cancer Center, about the FDG-PET (2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography) imaging modality.
In principle, how does this imaging modality work?
“In this method, the imaging agent is the 18F-labeled glucose analog, 2-deoxy-2-(18F)fluoro-D-glucose. This molecule is taken up into cells in a manner analogous to glucose. Once taken up into cells, the FDG is phosphorylated and trapped in the cell, as the 2-fluoro group prevents further metabolic processing. Then, the 18F undergoes radioactive decay (its half-life is approximately 110 minutes), giving off a positron, and in doing so is converted to [18O]-labeled glucose, a non-radioactive compound. The emitted positron, after going a short distance in the body, will encounter an electron, resulting in annihilation of both the positron and electron and simultaneous emission of two 511 keV gamma photons moving in opposite directions. These are the entities that are then measured by the detector, and then, based on their direction, computer software is then able to determine the photons' point of origin.”
Why is this modality applicable for oncology?
“In patients with cancer, generally speaking, malignant cells tend to have greater energy needs because of enhanced metabolism, and as a result, these active cells may have greater glucose uptake. For example, intermediate- to high-grade lymphomas with high metabolic activity or solid tumors with high concentrations of malignant cells with high FDG-avidity are good candidates for assessment using this technique. However, it is important to note that some malignancies are not easily visualized using this methodology. For example, many low-grade hematologic malignancies, such as chronic lymphocytic leukemia/small lymphocytic lymphoma, may not be well-detected with FDG-PET.”
What are some of the pitfalls of FDG-PET?
“The two main concerns for FDG-PET visualization are the occurrence of false-positives and false-negatives. Most mistakes that occur in cancer patients are false-positives, which can result from inflammation, chemotherapy, radiotherapy, or other iatrogenic causes. As for false-negatives, those can occur in those malignancies which lack FDG-avidity.”
What means do you have at your disposal to sort out these false-positives and false-negatives from the correct proper results?
“FDG PET is now almost always performed as a combined PET/CT or PET/MR exam. The CT or MR findings are very helpful for determining which FDG-avid findings are benign and for identifying non-FDG avid malignancy. In addition, a patient's medical history may also guide interpretation. For example, after certain medications and therapies, FDG-avid iatrogenic findings should be expected. Experience and medical knowledge help reach the best interpretations of imaging findings.”