Early interval and serial positron emission tomography‐computed tomography (PET‐CT) after an indeterminate response defined by a PET scored 4 on the Deauville scale in lymphoma

Field: Medicine (Health Sciences)

Indeterminate 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) responses at the ‘end of treatment’ (EOT) for lymphomas such as high-grade non-Hodgkin lymphoma (NHL) and classic Hodgkin lymphoma (HL) that are treated with curative intent can pose a challenge. Although a further biopsy following treatment to confirm persistent disease is the gold standard prior to salvage treatment, clinical decisions are often based on the EOT PET-CT scan showing a Deauville score (DS) of 4 or 5 using the six-point scoring system.1, 2 Biopsies may not be feasible or risk complications hence potentially overtreating patients who have a false-positive EOT PET-CT.3, 4 We assessed the value of early interval PET-CTs in patients with an indeterminate EOT study (DS4) as a surrogate for histological confirmation or refutation of refractory disease where confirmation biopsy was not feasible. We undertook a retrospective study to investigate the hypothesis that early interval PET-CTs can improve the specificity of indeterminate EOT PET-CT scans by decreasing the rate of ‘false positives’. Patients with high-grade NHL or HL who had an indeterminate EOT PET-CT (performed four weeks after treatment completion) and a follow-up ‘early interval’ PET-CT at 30–60 days following the EOT PET-CT were identified from January 2004 to December 2017. Indeterminate PET-CTs were those initially reported with equivocal changes and then independently reviewed and allocated a DS4, defined as uptake at an initial site that is ‘moderately’ increased compared to the liver at any site (‘moderately’ defined as not two times more than liver). Findings on the early interval study radiological report and any subsequent serial PET-CTs were noted, with retrospective DS added for correlation with the report findings. Chemotherapy regime with histological subtype and patients' one-year outcomes were noted. Thirty patients were identified with an indeterminate (DS4) EOT PET-CT and a subsequent early interval PET-CT study; their demographics are shown in Table I. Chemotherapy regimes used with histological subtype are demonstrated in Table II. All major radiological characteristics including the site of disease and presence of symptoms are tabulated in Table III. Graph 1 demonstrates the total number of scans per patient and Graph 2 highlights the DS for each scan per individual patient. At the early interval scan, radiological reports demonstrated that 19 (63%) of the patients achieved complete metabolic response (CMR), seven (23%) had progressive disease and four (13%) had a further indeterminate study (Tables IV and V). Maintained remission: 16 Death: 3 Remission: 2 Unknown: 2 Remission: 4 Progression: 3 Of the 19 patients who had achieved CMR on the early interval PET-CT, 16 patients were still in remission at one year. Three patients subsequently relapsed 1–6 months following the interval PET-CT; all died within one year due to relapsed disease. The four patients with a second indeterminate result on the early interval PET-CT proceeded to have a median of 2 (range 0–4) further PET-CT scans. Three of the four patients had HL; one had a subsequent biopsy which confirmed disease and so proceeded to have salvage chemotherapy. The second patient had consolidation radiotherapy to the sites of indeterminate disease. The third patient had three subsequent PET-CTs that showed increasing standardised uptake value (SUV), increasingly suspicious for disease progression; however the patient declined further treatment and thus was monitored with further serial PET-CTs, with the fourth study (nine months following the EOT PET-CT) showing stable changes and the fifth and sixth studies showed CMR resulting in no further therapy with clinical surveillance only. The one patient with DLBCL had a third PET-CT which showed CMR and hence continued with clinical surveillance. All seven patients with radiological evidence of progressive disease on the early interval PET-CT had further treatment. Four patients achieved remission by one year with salvage chemotherapy/radiotherapy. Of the seven patients, one died due to lymphoma and one due to lung adenocarcinoma at one year. The Lugano response assessment criteria advocate EOT PET-CT at 8–12 weeks post treatment to avoid false positives; however they still occur, and if not amenable to biopsy may lead to overtreatment.5 Early interval scans can be used as a surrogate for histological confirmation or refutation of refractory disease in indeterminate EOT cases where suspicion of a false positive is higher than clearly persistent disease. This study revealed that in 63% of such cases an early interval PET-CT demonstrated CMR (Fig 1) which was maintained in the majority, providing early prognostication with reassurance, reducing anxiety and avoiding the need for biopsy and hence overtreatment. Studies specifically in primary mediastinal B-cell lymphoma (PMBCL) have demonstrated EOT PET-CT to have low positive predictive values at 17%, with a significant number of DS4 patients reflecting false-positive PET-CTs with patients achieving long-term remissions without needing further treatment.6 Recognition that EOT PET-CT DS 4 may be false positive is also important in clinical trial design: the ECHELON-1 trial in AS (Advanced Stage) HL utilised modified progression-free survival (modified progression defined as DS 3, 4 or 5, followed by subsequent anticancer therapy) as a primary end-point (without histological confirmation), a proportion of these patients were likely to have been false positive on PET-CT assessment.7 Several patients in the remission group had multiple PET-CTs with a high DS 4 despite a radiological report and clinical symptoms supporting remission (Graph 2). This highlights the potential inaccurate use of DS and that it should not be used ‘in isolation’ for clinical decision making, correlation with clinical/treatment parameters and patient review at multidisciplinary meetings contributing to optimal outcomes.3 Those patients who continue to have indeterminate PET-CTs may benefit from histological confirmation, Picardi et al. performed biopsies on EOT PET-CT-positive patients in AS HL, finding malignancy in only 12·5% of DS 4 patients, suggesting biopsy should be performed;8 however the suspicious site may not be amenable to biopsy. The numbers in this study were too small to assess the effectiveness of serial PET-CTs and SUVs in monitoring patients with potentially refractory disease. This is warranted with a larger patient cohort; however it did confirm that some patients can be safely monitored with serial PET-CTs rather than further potentially unnecessary treatment. This was demonstrated in the context of PMBCL, where serial PET-CT improved the reliability of discriminating residual disease from post-treatment inflammation,9 and in a limited study of classic Hodgkin lymphoma.10 Serial PET-CT is also advocated by the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) classification in the context of possible pseudoprogression with immunomodulatory therapies, with three new Indeterminate Response categories recognising that PET-CT positivity does not necessarily indicate progressive disease.11 Also notably, a proportion of cases interpreted as DS4 reflect a DS of ‘X’ (‘activity which may not reflect active lymphoma’) — this DS is underrecognised in clinical and scientific practice.2, 6, 9 Only a minority (23%) of patients in this study, had an indeterminate scan that on subsequent radiology suggested that this was indeed with hindsight a ‘true positive’ and represented refractory disease. However their outcomes did not appear worse than those described in the published literature due to the potential delay in starting salvage chemotherapy. Treatment decisions post EOT scan are the major challenge of response assessment. Early interval and serial PET-CTs may aid clinical management. They could prevent the need for difficult biopsies or provide reassurance if there is concern that a biopsy does not demonstrate disease, hence potentially representing a “geographical miss”. The concept of using early interval scans in indeterminate cases as a surrogate for histological confirmation or negation of persistent disease should be considered. Serial PET-CTs should be investigated systematically in different NHL and HL histological subtypes (akin to initial studies in PMBCL and the LYRIC classification) as a method for monitoring patients who continue to have an indeterminate early interval PET-CT study, potentially predicting remission or active lymphoma. The authors acknowledge the National Health Service funding to the National Institute for Health Research Biomedical Research Centre (London, UK). RK designed and performed the research study, analysed the data and wrote the letter for submission. NH was involved in data analysis. KM performed detailed statistical analysis on the data. AA, EA, IC and DC were involved in the clinical decision-making process and contributed essential knowledge in patient management in order to write this study. SI and DE aided in the study design, data collection and writing of the letter. BS aided in designing the research study, data collection, analysis and wrote the letter and cover letter for submission.