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DOI: 10.1111/bjh.12601
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Citation for published version (APA): Barrington, S. F., & Mikhaeel, N. G. (2014). When should FDG-PET be used in the modern management of lymphoma? British Journal of Haematology, 164(3), 315-328. https://doi.org/10.1111/bjh.12601
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Download date: 03. Oct. 2021 British Journal of Haematology
When should FDG -PET be used in the modern management of lymphoma?
Journal:For British Peer Journal of Haematology Review Manuscript ID: BJH-2013-01212.R1
Manuscript Type: State of the Art Review
Date Submitted by the Author: n/a
Complete List of Authors: Barrington, Sally; PET Imaging Centre, Division of Imaging and Biomedical Engineering, King's College London Mikhaeel, N; Guys' and St Thomas' NHS Foundation Trust, Department of Clinical Oncology
LYMPHOMAS, IMAGING, HODGKINS LYMPHOMA, NON-HODGKIN-S Key Words: LYMPHOMA, CLINICAL TRIALS
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Barrington&Mikhaeel 1 2 3 4 5 6 7 When should PET be used in the modern management of 8 9 lymphoma? 10 11 12 1 2 13 SF Barrington and NG Mikhaeel 14 15 16 17 18 For Peer Review 19 1 PET Imaging Centre at St Thomas’ Hospital, Division of Imaging and 20 21 Biomechanical Engineering, King’s College, London 22 23 2 24 Department of Clinical Oncology, Guy’s & St Thomas’ Foundation Trust, London 25 26 27 28 Running title: PET CT in the management of lymphoma 29 30 31 32 33 Corresponding Author: 34 35 Sally Barrington 36 37 PET Imaging Centre 38 39 Westminster Bridge Road 40 41 London SE1 7EH 42 43 44 0044 207 188 4988 45 46 [email protected] 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1
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Barrington&Mikhaeel 1 2 3 Summary 4 5 6 Positron Emission Tomography (PET) is a functional imaging technique which 7 8 9 combined with CT (PET CT) is increasingly used in lymphoma. Most subtypes 10 11 accumulate Fluorodeoxyglucose (FDG) and its increased sensitivity, especially for 12 13 extranodal disease, compared to CT makes PET CT an attractive staging tool. 14 15 ‘Interim’ PET CT can be used to assess early response and end of treatment PET 16 17 CT to assess remission. Clinical trials are currently seeking to establish whether the 18 For Peer Review 19 20 predictive value of PET CT can be successfully used to guide individual treatment to 21 22 reduce toxicity and/or to improve outcomes. Standardised methods for performing 23 24 and reporting PET have been developed in the context of trials. The role of PET in 25 26 transplantation selection is evolving as PET appears to be more accurate and 27 28 29 prognostic than CT. The role of FDG PET CT throughout the management course in 30 31 patients with lymphoma is explored in this review and the potential role for FLT to 32 33 image proliferation. (146 words) 34 35 36 37 38 39 Keywords: Positron Emission Tomography, Hodgkin Lymphoma, 40 41 42 Non-Hodgkin Lymphoma, Clinical Trials, Imaging. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2
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Barrington&Mikhaeel 1 2 3 What is PET? 4 5 6 Positron Emission Tomography (PET) is a technique which images physiological 7 8 processes in vivo by detecting radioactive emissions from Positron Emitting 9 10 radioisotopes or ‘tracers’ injected into a patient. The most commonly used tracer is 11 12 13 18F Fluorodeoxyglucose (FDG) which is a glucose analogue that reflects glucose 14 15 metabolism. In cancer cells, there is increased uptake of FDG due to enhanced 16 17 glucose transport, turnover and trapping. Other processes with increased glycolysis, 18 For Peer Review 19 such as infection and inflammation also have increased FDG uptake, but often to a 20 21 22 lesser degree than malignancy. 23 24 25 Modern PET cameras are now combined with a CT scanner, enabling functional and 26 27 anatomical information to be obtained during the same imaging session. CT and 28 29 PET can be viewed separately, side by side or ‘fused’ with the PET scan overlaid on 30 31 the CT in colour. 32 33 34 PET scans are usually reported using visual assessment. The intensity and 35 36 37 locations of FDG avid disease are reported and distinguished from areas with high 38 39 physiological uptake, such as the brain and the urinary system, where FDG is 40 41 excreted. Scans are usually displayed according to the standardised uptake value 42 43 (SUV) which is the activity of the tracer, corrected for patient weight and the 44 45 administered radioactivity (Figure 1). The use of a fixed display, with images scaled 46 47 48 to a common SUV level aids consistency of reporting, allowing uptake within the 49 50 same patient to be assessed at during different time points during treatment and 51 52 reducing the effect of patient weight on the level of tracer uptake. Using a fixed 53 54 display, SUV measures may be used to compare regions of interest, most commonly 55 56 57 the ‘maximum’ (SUVmax) is used to describe the intensity of uptake at disease sites. 58 59 60 3
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Barrington&Mikhaeel 1 2 3 The CT is used to localise the PET abnormalities and any additional findings on CT 4 5 reported. 6 7 8 The CT may be acquired at full dose with intravenous and/or bowel contrast, as 9 10 would commonly be performed during a stand alone CT but the scan has to be 11 12 13 acquired during normal breathing rather than full inspiration, to fuse with the PET 14 15 which is acquired in steps over 15 25 minutes rather than during a single breath 16 17 hold. Alternatively the CT may be acquired at lower dose, which is more common 18 For Peer Review 19 practice. Then the CT is used a) to measure how Xrays are attenuated in the patient 20 21 22 and apply a correction to the FDG images to give a truer appreciation of the tracer 23 24 distribution and b) to accurately localise sites of FDG uptake. 25 26 27 Which Lymphomas can be imaged with PET ? 28 29 30 Most Lymphomas are FDG avid. In a series of 766 patients imaged with lymphoma, 31 32 100% of Hodgkin lymphoma (HL), 97% of Diffuse Large B cell Lymphoma (DLBCL) 33 34 and 95% of Follicular Lymphomas (FL) were FDG avid (Weiler Sagie et al., 2010). 35 36 37 Less common aggressive subtypes were also reported to be universally FDG avid 38 39 including Burkitt lymphoma, Mantle Cell lymphoma and aggressive T cell 40 41 lymphomas. More variable avidity has been reported for small lymphocytic 42 43 lymphoma (50 83%), extranodal marginal zone lymphoma (54 67%), and 44 45 lymphomas that involve the skin (Elstrom et al., 2003; Tsukamoto et al., 2007; 46 47 48 Weiler Sagie et al., 2010). 49 50 51 Aggressive lymphomas tend to have higher uptake than indolent lymphomas. In a 52 53 study of 97 patients with NHL, although there was some overlap amongst patients 54 55 with indolent and aggressive disease in the low SUV range, all patients with indolent 56 57 lymphoma had SUVmax <13 (Schoder et al., 2005). Using an SUVmax ≥ 10 58 59 60 4
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Barrington&Mikhaeel 1 2 3 distinguished aggressive from indolent disease with 81% specificity and 71% 4 5 sensitivity. SUVmax also correlates with proliferation, measured by the Ki 67 index in 6 7 lymph node and extranodal biopsies obtained from patients with indolent and 8 9 10 aggressive lymphomas (Watanabe et al., 2010). 11 12 13 This suggests that FDG PET may be used in patients with suspected transformation 14 15 to direct biopsy. 16 17 18 What is the addedFor value of Peer PET for staging? Review 19 20 21 PET is more sensitive and specific for nodal and extranodal disease than CT 22 23 (Schaefer et al., 2004) because abnormal FDG uptake may be observed in normal 24 25 sized lymph nodes and uptake may be seen without changes in organ architecture, 26 27 28 for example focal uptake may be present in a spleen with normal appearance and 29 30 size on CT (Figure 2). Equally, slightly enlarged nodes may be reactive and will not 31 32 accumulate FDG. Upstaging occurs more commonly than downstaging, although 33 34 both occur and this influences management in a proportion of patients. Extranodal 35 36 37 disease is more often identified with PET than CT within the bone and bone marrow 38 39 (Figure 3), liver and spleen (Raanani et al., 2006) but also occasionally in the 40 41 peritoneum. Small lung nodules may not be resolved by PET but these are usually 42 43 visible on the accompanying CT. Cutaneous lesions tend to be less FDG avid than 44 45 extracutaneous disease and it has been suggested that PET may have a role to 46 47 48 detect extracutaneous disease in patients with Mycosis Fungoides, which confers a 49 50 worse prognosis (Feeney et al., 2010; Otero et al., 2009). The brain is an area of 51 52 high FDG avidity which in other diseases limits the ability to detect metastatic 53 54 disease (Larcos & Maisey, 1996) but intracerebral lymphoma is highly FDG avid and 55 56 57 PET has been used to distinguish toxoplasmosis from intracerebral lymphoma in HIV 58 59 60 5
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Barrington&Mikhaeel 1 2 3 patients (O'Doherty et al., 1997). Nonetheless, leptomeningeal disease which is 4 5 diffuse and may be low volume is difficult to assess with PET and MR is the 6 7 investigation of choice for initial assessment of CNS lymphoma. 8 9 10 The availability of a baseline scan improves the accuracy of subsequent response 11 12 13 assessment (S. Barrington et al., 2011; Meignan et al., 2009; Quarles van Ufford et 14 15 al., 2010). Baseline PET is also important for the accurate planning of radiotherapy 16 17 treatment, especially with the use of newer techniques treating smaller volumes that 18 For Peer Review 19 traditional involved field radiotherapy (IFRT). It is recommended that the use of 20 21 22 ‘involved site’ radiotherapy (Specht et al., 2013) and ‘involved node’ radiotherapy 23 24 (INRT) (Girinsky et al., 2007) should ideally be based on staging PET CT rather than 25 26 CT alone. 27 28 29 The frequency of management change resulting from using PET CT for staging 30 31 differs between patient series from approximately 10 50%, but on average is 32 33 34 around 15% (M. Hutchings et al., 2006; Naumann et al., 2004; Partridge et al., 2000; 35 36 Pelosi et al., 2008; Raanani et al., 2006; Wirth et al., 2008). Patients with apparently 37 38 limited stage on CT with Follicular Lymphoma are a group where PET may have an 39 40 important impact because up to 60% (Karam et al., 2006; Luminari et al., 2013; Wirth 41 42 et al., 2008) of patients will have more advanced disease demonstrated using PET, 43 44 45 which is not curable with radiotherapy and systemic treatment would be preferred. 46 47 48 The presence of uni or multi focal disease in the bone marrow on PET CT is more 49 50 sensitive for the detection of bone marrow involvement than bone marrow biopsy in 51 52 HL and aggressive NHL. Diffuse homogenous uptake may be seen with reactive 53 54 hyperplasia in the marrow, especially in HL and does not necessarily indicate 55 56 57 marrow involvement. In a study in 454 patients with HL, no patients with stage I or II 58 59 60 6
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Barrington&Mikhaeel 1 2 3 disease on PET CT were upstaged by bone marrow biopsy. Of the whole group, 82 4 5 patients had marrow involvement by PET, 27 by biopsy. Of these 27 patients, 22 6 7 had extranodal disease anyway on PET, the remaining five patients were upstaged 8 9 10 from stage 3 to 4 by biopsy but this did not change the treatment plan. Thus the 11 12 biopsy did not alter management in a single patient (T. C. El Galaly et al., 2012) 13 14 suggesting that staging PET may be used in preference to biopsy to assess bone 15 16 marrow involvement in HL. In this study, only the presence of focal uptake was 17 18 For Peer Review 19 considered to represent disease involvement. 20 21 22 In aggressive NHL, small volume disease, typically ≤ 10% marrow involvement or 23 24 coexistent low grade lymphoma may be missed by PET but this is unlikely to affect 25 26 prognosis or treatment (Campbell et al., 2006). In a recent study of 130 patients with 27 28 DLBCL, 33 patients had marrow involvement on PET, 14 on biopsy (Khan et al., 29 30 2013). No case was classified as stage 4 based on biopsy alone. Patients with PET 31 32 33 and biopsy evidence of marrow involvement had worse prognosis than the rest of the 34 35 study population but these patients frequently had adverse factors predictive of high 36 37 risk disease. 2 patients with marrow involvement on biopsy had normal marrow 38 39 appearances on PET with <10% of the marrow involved. This also suggests a 40 41 42 restricted role for bone marrow biopsy in DLBCL patients staged by PET CT. 43 44 45 PET CT is less sensitive than bone marrow biopsy for marrow involvement in 46 47 indolent lymphomas, which is frequently diffuse, can be small volume and has low 48 49 grade FDG uptake. The sensitivity was reported as only 46% in indolent lymphomas 50 51 in a recent meta analysis and BMB is indicated in preference to PET (Chen et al., 52 53 54 2011). BMB with detailed histological examination including immunohistochemistry 55 56 and testing for clonality remains the gold standard in indolent lymphomas. 57 58 59 60 7
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Barrington&Mikhaeel 1 2 3 4 5 6 7 8 9 Is contrast enhanced CT necessary in addition to PET (CT) ? 10 11 12 PET CT is now considered to be routine for staging patients with HL and aggressive 13 14 NHL in many centres worldwide. What is less clear is whether a full dose contrast 15 16 17 enhanced CT (ceCT) is required in addition to the low dose (ldCT) that is usually 18 For Peer Review 19 performed as part of the PET CT examination. Several publications have compared 20 21 the use of ceCT versus ldCT as part of the PET CT scan for staging/restaging 22 23 lymphoma patients. All found that PET CT with ldCT demonstrated more lesions 24 25 than ceCT alone (Elstrom et al., 2008; Raanani et al., 2006; Schaefer et al., 2004). 26 27 28 The use of ceCT rather than ldCT as part of the PET CT examination did not affect 29 30 stage nor alter management in three series (Elstrom et al., 2008; Gollub et al., 2007; 31 32 Pinilla et al., 2011) but in one series, the use of ceCT altered stage in 8/68 patients 33 34 with NHL and 4/35 patients with HL, which affected management in 9 patients 35 36 37 (Raanani et al., 2006). The detail on how management was affected was not 38 39 reported, but in two further publications (Pinilla et al., 2011), the use of ceCT was felt 40 41 to improve the detection of disease in the small bowel in two patients and 42 43 additionally the pancreas (in one of these patients), but affected management in one 44 45 patient only (Schaefer et al., 2004) . This suggests that ce CT used in place of ldCT 46 47 48 in the PET CT examination does not often impact on lymphoma management. 49 50 51 Pragmatically, many patients will have a ceCT scan performed prior to PET CT, in 52 53 which case a ldCT will suffice for PET CT. If PET CT is performed first, then ceCT 54 55 may be preferred in patients likely to undergo radiotherapy treatment, preferably in 56 57 the anticipated treatment position. In patients on trials, where nodal or extranodal 58 59 60 8
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Barrington&Mikhaeel 1 2 3 size measurements are required, ceCT is also necessary and would be more 4 5 convenient if performed as a single test at the same scanning visit where possible. 6 7 For other patients, whether the additional radiation incurred with a ceCT is justified 8 9 10 should be considered when choosing the optimal examination. Advantages reported 11 12 for ceCT were due to the use of contrast material rather than the increased X ray 13 14 dose and there may be a role for regional low dose CT with contrast after PET CT. If 15 16 the ceCT is performed at staging and there is no additional benefit, subsequent 17 18 For Peer Review 19 examinations should be performed at lower dose. 20 21 22 What is the role of PET in early response assessment? 23 24 25 Metabolic changes precede changes in tumour size, which enables response to be 26 27 assessed earlier in the course of treatment with PET than CT. Rapid reduction in 28 29 FDG uptake during chemotherapy is associated with a good prognosis in patients 30 31 with HL and persistent FDG uptake with a poor prognosis in advanced HL patients. 32 33 34 The group at Guy’s and St Thomas’ first reported in 2005 on a retrospective analysis 35 36 of 85 patients with HL that PFS and OS were significantly different according to 37 38 whether the PET scan performed after 2 or 3 cycles of chemotherapy was reported 39 40 as ‘negative’, had ‘minimal residual uptake’ (MRU) or was reported as 41 42 ‘positive’(Hutchings et al., 2005). Patients with a negative scan or MRU had 5y PFS 43 44 45 rates of 92% compared with 39% for patients with a positive scan. This was followed 46 47 by five further reports after 2 cycles of chemotherapy in HL, involving 1066 patients 48 49 treated with ABVD (Biggi et al., 2013; Cerci, Pracchia, et al., 2010; Andrea Gallamini 50 51 et al., 2007; M.; Hutchings et al., 2006; P. L. Zinzani et al., 2012), three of which 52 53 54 were prospective (Cerci, Pracchia, et al., 2010; Andrea Gallamini et al., 2007; M.; 55 56 Hutchings et al., 2006). These studies also reported 2y or longer PFS rates of 90 57 58 96% for patients with early complete metabolic response (CMR) and PFS rates of 59 60 9
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Barrington&Mikhaeel 1 2 3 0%, 13%, 28%, 28%, 53% respectively for patients with positive scans, with poorer 4 5 outcomes for patients with advanced disease (Andrea Gallamini et al., 2007; M.; 6 7 Hutchings et al., 2006). PET was a better predictor of outcome than the IPS (Andrea 8 9 10 Gallamini et al., 2007). A further study reporting outcomes in 96 patients with early 11 12 stage non bulky HL (Barnes et al., 2011) found no difference in PFS according to 13 14 early or ‘interim’ PET although the PET carried out at the end of treatment was 15 16 predictive of outcome, probably due to the very good prognosis of this patient group 17 18 For Peer Review 19 and the effect of RT use. Overall, RT was given to 56% of patients in this study and 20 21 there was a higher tendency to giving radiotherapy to patients with positive iPET 22 23 (88%) than patients with negative iPET (54%). A report in 69 patients treated with 24 25 BEACOPP reported a 4y PFS of 98 % for patients with a negative iPET versus 78% 26 27 for patients with a positive iPET (p=0.016)(Markova et al., 2012). The ability of iPET 28 29 30 to predict prognosis early in treatment is clearly influenced by the timing of the scan 31 32 in relation to chemotherapy, the stage of disease and the treatment regimen. At 33 34 present, iPET at 2 3 cycles has been shown to be predictive of outcome in advanced 35 36 stage, ABVD treated patients but extrapolation of these results to BEACOPP treated 37 38 39 patients is not advisable and the role of iPET in early stage patients receiving 40 41 combined modality treatment is not yet clear. 42 43 44 These studies highlighted the potential to use PET to tailor treatment for the 45 46 individual according to their response during chemotherapy. The good prognosis 47 48 associated with a negative iPET has led to the question of whether short course 49 50 51 chemotherapy without radiotherapy is an option for patients with early stage 52 53 favourable HL who have a negative iPET scan during ABVD treatment rather than 54 55 combined modality treatment. 56 57 58 59 60 10
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Barrington&Mikhaeel 1 2 3 The UK National Cancer Research Institute study group recently presented the first 4 5 results of the RAPID trial involving 602 patients with HL who had a PET scan 6 7 performed after 3 cycles of ABVD (Radford et al., 2012). The study included non 8 9 10 bulky stage I & IIA disease and was designed to exclude a difference of ≥7% 11 12 between RT and no RT. Patients with a CMR on PET (defined as score 1 & 2 only 13 14 using a 5 point scale) were randomised to receive IFRT or no further treatment, 15 16 whilst patients with a positive scan (score 3 5) received one further cycle of ABVD 17 18 For Peer Review 19 and 30Gy IFRT. 3y PFS in 420 randomised patients with PET negative scans was 20 21 93.8% in the group receiving RT and 90.7% in the group receiving no further 22 23 treatment, (risk difference 2.9%, 95%CI 10.7 to 1.4%: the lower CI marginally 24 25 exceeded the maximum allowable difference of 7% for non inferiority). 3 year OS 26 27 was 97.0% in the RT group versus 99.5% in patients with no further treatment. PFS 28 29 30 and OS in the PET positive group was 85.9 % and 93.9% respectively with a median 31 32 follow up of 46 months. These preliminary data suggest that patients with iPET score 33 34 1 or 2 after 3 cycles of ABVD have excellent prognosis with 3 ABVD alone but longer 35 36 follow up will be required to assess the trade off between disease control and risks of 37 38 39 late treatment effects in this patient group. This is especially relevant in patients for 40 41 whom the risks associated with RT may be lower, eg patients >35 years and when 42 43 irradiation of female breast tissue and/or the heart is not required. 44 45 46 The H10 study from the EORTC is ongoing and was designed with randomisation to 47 48 experimental or standard arms. The standard arm received 3 or 4 cycles of ABVD 49 50 51 according to whether disease was classified as favourable (F) or unfavourable (U) 52 53 followed by INRT 30Gy + 6Gy boost to sites of residual lesions. The experimental 54 55 arm adopted a PET based strategy and consisted of 2 cycles of ABVD followed by 56 57 PET. If PET showed CMR, patients received 3 (F) or 4 (U) additional cycles of 58 59 60 11
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Barrington&Mikhaeel 1 2 3 ABVD and no RT. If PET was positive, patients received 2 cycles of escBEACOPP. 4 5 The first planned interim analysis of 1137 patients was recently presented (Andre et 6 7 al., 2012). In the favourable group, a total of 10 events occurred; 1 in the standard 8 9 10 arm, 9 in the experimental arm (1y PFS 100% and 94.9% for standard and 11 12 experimental arms respectively, HR 9.36 (CI : 2.45 – 35.73). In the unfavourable 13 14 group, a total of 23 events occurred; 7 in the standard arm, 16 in the experimental 15 16 arm (1y PFS 97.3% and 94.7% for standard and experimental arms, HR = 2.42 (CI: 17 18 For Peer Review 19 1.5 4.36). The Trial Steering Committee declared futility according to previously set 20 21 rules and considered that the risk of early relapse in non irradiated patients with 22 23 stage I II cHL was significantly higher than standard combined modality treated 24 25 patients even in the selected group with early PET negativity. Consequently the no 26 27 RT arm was closed down and the study continued, with all patients receiving INRT, 28 29 30 to investigate the secondary aim to determine the effect of escalation of therapy for 31 32 patients with PET positive scans. 33 34 35 Both H10 and RAPID investigated the role of PET in applying a “response adapted 36 37 strategy” for early stage cHL but came to apparently opposite conclusions with 38 39 regards to the possibility of omitting RT in PET negative patients. Final results with 40 41 42 longer follow up of both studies will be required before firm conclusions can be made 43 44 on this promising therapeutic strategy. 45 46 47 Two further ongoing studies from the German Hodgkin Study Group are also 48 49 examining a response guided approach in early stage disease, (HD16,HD17) with 50 51 ABVD treatment for favourable disease (http://www.clinicaltrials.gov/ NCT00736320 ) 52 53 54 or a combination of ABVD and escBEACOPP for unfavourable disease 55 56 (http://www.clinicaltrials.gov/ NCT01356680 ). Both include a randomisation to a 57 58 standard arm of combined modality treatment and an experimental arm where RT is 59 60 12
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Barrington&Mikhaeel 1 2 3 given to iPET positive patients and omitted for iPET negative patients. These 4 5 studies are aiming to recruit 1100 patients each. 6 7 8 In advanced HL, trials are also testing whether it is safe to de escalate treatment in 9 10 good responders on interim PET as well as whether treatment outcomes can be 11 12 13 improved in poorer responders. For patients receiving ABVD chemotherapy, de 14 15 escalation strategies on the basis of a negative interim PET include randomisation to 16 17 ABVD vs AVD (RATHL study http://www.clinicaltrials.gov/ct2/show/NCT00678327 ), 18 For Peer Review 19 and IFRT vs no IFRT after completion of ABVD for patients with bulky disease 20 21 22 (HD0801) http://www.clinicaltrials.gov/ct2 /NCT00784537 . Escalation strategies on 23 24 the basis of a positive interim PET include switching to BEACOPP (RATHL, HD0607 25 26 http://www.clinicaltrials.gov/ct2/show/NCT00795613 , Rambam Health Care/RHC 27 28 http://www.clinicaltrials.gov/ct2/show/NCT00392314 , SWOGS0816 29 30 http://www.clinicaltrials.gov/ct2/show/NCT00822120 ) or high dose chemotherapy 31 32 33 and autologous stem cell transplant (ASCT) (HD0801). For patients receiving 34 35 escBEACOPP chemotherapy, de escalation strategies include randomisation to 36 37 escBEACOPP vs ABVD (AHL 11 study 38 39 http://clinicaltrials.gov/ct2/show/NCT01358747 ) randomisation to escBEACOPP 4 40 41 42 cycles vs 8 cycles (HD18 http://www.clinicaltrials.gov/ct2/show/NCT00515554 ) and 43 44 switching to ABVD (RHC). Escalation strategies include randomisation to 45 46 escBEACOPP vs escBEACOPP and rituximab (HD18). 47 48 49 In aggressive NHL including Diffuse Large B cell Lymphoma (DLBCL), rapid 50 51 reduction in FDG uptake during chemotherapy is associated with good prognosis 52 53 54 (Figure 4). In studies involving 924 patients treated with CHOP or ACVBP ± 55 56 rituximab, 2 5y PFS/EFS rates have been reported ranging between 73 86% for 57 58 patients with CMR (Cashen et al., 2011; Haioun et al., 2005; Micallef et al., 2011; 59 60 13
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Barrington&Mikhaeel 1 2 3 Mikhaeel et al., 2005; Safar et al., 2012; Spaepen et al., 2002; D. H. Yang et al., 4 5 2011; Yoo et al., 2011; P. L. Zinzani et al., 2011). Studies from 2005 and earlier 6 7 reported poorer outcomes for patients with PET ‘positive’ scans with 2 5yPFS/EFS 8 9 10 rates of 0 43% (Figure 5). Two recent studies also reported poor outcomes with 3 11 12 5y PFS rates of 18 29% (D. H. Yang et al., 2011; P. L. Zinzani et al., 2011) but four 13 14 other studies reported more favourable outcomes for patients with PET positive 15 16 interim scans (Cashen et al., 2011; Micallef et al., 2011; Safar et al., 2012; Yoo et al., 17 18 For Peer Review 19 2011) with 2 3y PFS rates of 47 – 66%. Possible reasons for this may be the 20 21 improved prognosis in this disease with the addition of rituximab to standard 22 23 treatment and inflammatory induced uptake associated with the use of 24 25 immunotherapy. In a disease where salvage treatment has become less effective 26 27 since the introduction of rituximab, it is disappointing that early response assessment 28 29 30 with PET appears to be less predictive of primary treatment failure than initially 31 32 thought. 33 34 35 Methods to improve the predictive value of early PET include the use of quantitative 36 37 approaches, such as measuring the reduction of the maximum SUV in the ‘hottest’ 38 39 lesion before and during treatment referred to as ‘∆SUV’ (Emmanuel Itti et al., 2009; 40 41 42 Lin et al., 2007). Using receiver operating curves to define the best threshold to 43 44 discriminate between good and poor treatment response groups, the French GELA 45 46 group have published data to suggest that ‘ ∆SUV’ predicts outcome better than 47 48 49 visual assessment in DLBCL (Casasnovas et al., 2011; Emmanuel Itti et al., 2009; E. 50 51 Itti et al., 2013; Lin et al., 2007). The optimal cut off varies according to when the 52 53 PET scan is performed during treatment, as FDG uptake declines during 54 55 chemotherapy, so a higher threshold is used at 4 cycles than 2 cycles (Emmanuel Itti 56 57 58 et al., 2009). The ∆SUV is being used as a response measure in the PETAL study 59 60 14
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Barrington&Mikhaeel 1 2 3 (Duhrsen et al., 2009), with poor responders identified according to a ∆SUV ≥ 66% in 4 5 the experimental arm randomised to receive escalated treatment with a B ALL 6 7 8 regimen in place of R CHOP and good responders with ∆SUV <66% in the 9 10 experimental arm receiving a total of 6 cycles of R CHOP instead of the standard 11 12 arm 8 cycles. Using the 66% cut off, one retrospective study reported that ∆SUV 13 14 15 was predictive of response in DLBCL (Safar et al., 2012) but another was unable to 16 17 demonstrate an association of ∆SUV with PFS (Pregno et al., 2012). Other 18 For Peer Review 19 published studies have reported that ∆SUV is predictive of response but using 20 21 22 different cut offs for the ∆SUV of 76% and 92% respectively (Fuertes et al., 2013; D. 23 24 H. Yang et al., 2013). The application of ∆SUV clearly requires further study and is 25 26 dependent on proper standardisation of PET methods, including PET acquisition, 27 28 cross calibration of cameras and appropriate maintenance and quality control of 29 30 31 imaging equipment prior to widespread use. Guidelines have been published 32 33 regarding the best methods to perform PET for multicentre trials which are also 34 35 recommended for best clinical practice and make such quantitative applications a 36 37 realistic goal for future clinical use (Boellaard et al., 2010). 38 39 40 In Follicular Lymphoma with high tumour burden, interim PET is predictive of 41 42 43 response to initial therapy, but the end of treatment scan appears to be a better 44 45 predictor (Dupuis et al., 2012), perhaps because the response to chemotherapy is 46 47 slower than in HL and DLBCL. 48 49 50 Currently there is insufficient evidence to change standard treatment based on the 51 52 results of an interim PET CT scan. Nonetheless an interim scan may be helpful to 53 54 55 confirm that patients are responding to treatment and exclude progression of 56 57 disease. PET CT could replace CT in the interim setting if a mid treatment scan is 58 59 60 15
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Barrington&Mikhaeel 1 2 3 indicated. The results of the PET CT scan should always be interpreted in the 4 5 context of the clinical situation and anticipated prognosis of disease, ideally in a 6 7 multidisciplinary setting. If an interim scan shows a complete metabolic response, 8 9 10 then there is no need to perform a treatment at the end of therapy if the clinical 11 12 course is uncomplicated (M.; Hutchings et al., 2006; Strobel et al., 2007). In a study 13 14 in 38 patients with HL and 30 with NHL, all patients with a complete response on 15 16 interim PET had complete response on the end of treatment scan (Strobel et al., 17 18 For Peer Review 19 2007). 20 21 22 What is the role of PET in end-of-treatment remission assessment? 23 24 25 There is a high predictive value for remission assessment using FDG PET. In HL 26 27 the NPV for ≥ 2 yPFS is 94 100% for patients treated with ABVD (Barnes et al., 28 29 2011; Cerci, Trindade, et al., 2010; Spaepen et al., 2001) with PPV of 91 92% 30 31 (Cerci, Trindade, et al., 2010; Spaepen et al., 2001) for all stages but 46% in early 32 33 34 stage non bulky disease, again reflecting the good prognosis of patients in this group 35 36 (Barnes et al., 2011). 37 38 39 In aggressive NHL including DLBCL, the NPV for end of treatment PET is also high, 40 41 reported at 90 100% (Micallef et al., 2011; Pregno et al., 2012; Spaepen et al., 2001) 42 43 but the PPV is lower and more variable, reported at 50 82% (Micallef et al., 2011; 44 45 Pregno et al., 2012; Spaepen et al., 2001). The lower PPV is due to the non specific 46 47 48 nature of FDG as a tracer which is taken up in inflammation, such as may be seen 49 50 following chemotherapy and radiotherapy treatment. For this reason, it is 51 52 recommended that minimum periods between the end of treatment and scanning be 53 54 left; at least 10 days for chemotherapy, at least 2 weeks after GCSF treatment and 3 55 56 57 months after radiotherapy (Boellaard et al., 2010). Biopsy confirmation of residual 58 59 60 16
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Barrington&Mikhaeel 1 2 3 disease is advisable before giving second line treatment in both HL and aggressive 4 5 NHL or if the clinical suspicion of residual disease is low, an interval scan may be 6 7 preferred. 8 9 10 The improved remission assessment by PET led to its incorporation in the IWG 11 12 13 criteria in 2007. In these criteria residual masses with negative FDG uptake were 14 15 included in the Complete Response Category (Cheson et al., 2007). In a previous 16 17 study in NHL this led to better discrimination of response categories and the removal 18 For Peer Review 19 of the category of CR ‘unconfirmed’ as patients were either reclassified as CR or PR 20 21 22 according to FDG uptake (Juweid et al., 2005). Nowadays an end of treatment scan 23 24 is usually performed in both HL and DLBCL to confirm remission (Figure 6) or to 25 26 direct biopsy in the case of residual FDG uptake if further treatment is being 27 28 considered (Figure 7). 29 30 31 FDG PET may have a role in selecting patients with advanced HL who will benefit 32 33 34 from the addition of consolidation RT after a full course of chemotherapy. In patients 35 36 treated with escBEACOPP in the HD 15 study from the GHSG, 739 patients with 37 38 residual masses >2.5cm were treated with radiotherapy according to the results of 39 40 an end of treatment PET scan (Engert et al., 2012). 191 patients with PET positive 41 42 residual masses received radiotherapy. Patients with negative residual masses 43 44 45 were not treated with RT and had the same PFS as patients with complete 46 47 radiological response and this strategy reduced the use of radiotherapy in advanced 48 49 stage HL from 70% in HD12 to 11% in HD15. Radiotherapy is therefore not required 50 51 in advanced stage HL patients treated with BEACOPP who achieve complete 52 53 54 metabolic response after chemotherapy even in the presence of a residual mass. 55 56 However it is important to note that these results may not apply to ABVD treated 57 58 patients or patients with early stage bulky disease where similar evidence is lacking. 59 60 17
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Barrington&Mikhaeel 1 2 3 In high tumor burden FL, two studies involving 122 and 116 patients respectively 4 5 have recently reported inferior outcomes for patients according to PET CT status at 6 7 the end of treatment with rituximab and chemotherapy (Dupuis et al., 2012; Trotman 8 9 10 et al., 2011). PFS rates of 33% and 51% for patients with residual uptake were 11 12 reported compared to 71% and 87% for patients with CMR. OS rates were 78% and 13 14 88% for patients with residual uptake compared to 96% and 100% for patients with 15 16 CMR. In the prospective study (Dupuis et al., 2012), the assessment of response at 17 18 For Peer Review 19 end treatment was predictive of response whereas the interim scan was not and this 20 21 may reflect a slower metabolic response in this disease compared to HL and DLBCL. 22 23 Maintenance rituximab was not given in one study (Dupuis et al., 2012) and in the 24 25 other too few patients were included who had received maintenance rituximab to 26 27 demonstrate a difference in PFS in patients according to maintenance therapy 28 29 30 (Trotman et al., 2011). Whilst the role of PET in patients who receive maintenance 31 32 rituximab may require further clarification, both studies found that response 33 34 assessment with PET provided significant information with regard to prognosis 35 36 where CT did not. In the prospective study, where a priori criteria were defined for 37 38 39 PET reporting, a visual graded response assessment using the Deauville criteria 40 41 were superior to 2007 IWG criteria (Dupuis et al., 2012). These data suggest that 42 43 evaluating patients for trials with novel agents after initial treatment is best 44 45 undertaken with PET CT. 46 47 48 What is meant by a PET negative or positive scan? 49 50 51 PET scans are often referred to as ‘negative’ or ‘positive’ but FDG uptake represents 52 53 54 a continuum, and the likelihood of malignancy in a lesion increases with the intensity 55 56 of FDG uptake. The Guy’s and St Thomas’ group reported PET scans using 3 57 58 categories as ‘negative’ with ‘minimal residual uptake’ (MRU) or ‘positive’ (Hutchings 59 60 18
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Barrington&Mikhaeel 1 2 3 et al., 2005; Mikhaeel et al., 2005) and reported that the interpretation of MRU 4 5 differed according to subtype and stage. For example, the PFS of patients with HL 6 7 and aggressive NHL but limited stage at interim was the same or similar for patients 8 9 10 with MRU as patients with negative scans, likely due to the effectiveness of 11 12 treatment in these patients (Hutchings et al., 2005; Mikhaeel et al., 2005). 13 14 Conversely MRU in aggressive NHL and advanced stage was predictive of poor 15 16 prognosis (Mikhaeel et al., 2005). How FDG uptake is interpreted may also be time 17 18 For Peer Review 19 dependent. The IHP criteria which were recommended for end of treatment 20 21 assessment, chose to use the mediastinum to define a ‘negative’ scan in lesions 22 23 2cm or larger but to use the adjacent background in smaller lesions (Juweid et al., 24 25 2007). However uptake higher than this, especially during the course of treatment is 26 27 also associated with good prognosis in some patients (Andrea Gallamini et al., 28 29 30 2007). The need for criteria that could be adapted to the clinical context and take 31 32 account of timing in relation to chemotherapy led to the development of a five point 33 34 scale that might better reflect differing degrees of FDG uptake. This scale was 35 36 recommended for use of reporting PET at the first international workshop on PET 37 38 39 and lymphoma held in Deauville and is often referred to as the ‘Deauville 40 41 criteria’(Meignan et al., 2009) (Table 1). The five point scale has good interobserver 42 43 agreement (Sally F. Barrington et al., 2010; Biggi et al., 2013; Dupuis et al., 2012; 44 45 Furth et al., 2011; Le Roux et al., 2011) and appears to improve the PPV whilst 46 47 maintaining the high NPV compared with IHP criteria (Dupuis et al., 2012; Le Roux 48 49 50 et al., 2011; D. H. Yang et al., 2011) if higher thresholds than the mediastinum are 51 52 used to differentiate good from less good response, especially in the interim setting. 53 54 The five point scale is in use in several response adapted trials (RAPID, RATHL, 55 56 HD0607,NCI, http://clinicaltrials.gov/ct2/ NCT00822120, IELSG37, 57 58 59 60 19
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Barrington&Mikhaeel 1 2 3 http://clinicaltrials.gov/ct2 /NCT01599559) with the advantage that the threshold of 4 5 FDG uptake chosen may be higher for a trial involving escalation (to avoid risk of 6 7 over treatment) than a trial investigating de escalation (to avoid under treatment). 8 9 10 Score 1,2,3 were used in the UK led RATHL study to define a negative scan with 11 12 patients with positive scans escalated to BEACOPP from ABVD. Score 1, 2 was 13 14 however used to define a negative scan in the UK RAPID study where patients with 15 16 early stage non bulky disease and a negative scan were randomised to RT or no 17 18 For Peer Review 19 further treatment after 3 cycles of ABVD treatment. The use of the five point scale 20 21 relies on consistency in scanning conditions for serial scans and attention to patient 22 23 preparation, scan acquisition and the quality control of imaging equipment as well as 24 25 reporting methods is crucial (Boellaard et al., 2010). 26 27 28 What confounding factors may affect the use of FDG PET in lymphoma 29 30 management? 31 32 33 34 FDG uptake is not specific for malignancy and uptake of the tracer occurs in 35 36 inflammatory cells and infection which also have increased glucose metabolism. 37 38 Indeed it has been suggested that one of the reasons why FDG is a good imaging 39 40 biomarker in HL is its ability to detect inflammatory cells in the tumour 41 42 microenvironment (A Gallamini, 2010). Clinicians need to be aware of potential 43 44 45 confounding causes of increased FDG uptake which are well described (S. F. 46 47 Barrington & O'Doherty, 2003; Cook et al., 2004) including intercurrent infection, 48 49 inflammatory responses to treatment, synchronous malignancy and physiological 50 51 variants such as thymic hyperplasia which may confound response assessment. It is 52 53 54 especially important to question findings that are at variance with the clinical picture 55 56 or where there is a ‘mixed response’ with apparent improvement in response in 57 58 some areas of disease, but persistent FDG uptake or new lesions with increased 59 60 20
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Barrington&Mikhaeel 1 2 3 FDG uptake in others. These situations are best discussed in a multidisciplinary 4 5 team setting. 6 7 8 What is the role in relapse and pre transplant assessment of PET? 9 10 11 PET can be used for restaging of patients at relapse as it is used in staging of de 12 13 14 novo lymphomas (Elstrom et al., 2008; Janikova et al., 2008; Schaefer et al., 2004). 15 16 For patients undergoing autologous stem cell transplant (ASCT) for relapsed or 17 18 refractory disease,For a PET scan Peer performed afterReview salvage treatment has prognostic 19 20 value with patients with a positive scan 3 7 times more likely to relapse or progress 21 22 than patients with a negative scan. Series are mostly retrospective and used a 23 24 25 variety of different salvage regimens (Terasawa et al., 2010), but all appear to 26 27 support a role for PET in pre transplant assessment with ASCT with PFS rates of 23 28 29 41% reported for patients with residual uptake and 71 82% for CMR patients 30 31 (Devillier et al., 2012; Mocikova et al., 2011; Moskowitz et al., 2012; Smeltzer et al., 32 33 34 2011; Sucak et al., 2011). It remains controversial whether to offer transplantation to 35 36 patients with less than CMR, with some series reporting successful outcomes in up 37 38 to 40% of PET positive patients or to offer extended salvage therapy on the basis of 39 40 a positive scan (Moskowitz et al., 2012). Perhaps the most important role for PET 41 42 might be to act as a surrogate/early end point in testing novel agents such as SGN 43 44 45 35 (Hutchings, 2011). Post transplant assessment with PET has been reported as 46 47 being predictive of PFS/OS in a small study with 43 patients with HL (Sucak et al., 48 49 2011) but not in another study of 68 patients with HL and NHL (Palmer et al., 2011). 50 51 Prior to reduced intensity conditioning allogeneic transplant, one study in a mixed 52 53 54 population of 80 patients (Dodero et al., 2010) reported that PET status was 55 56 predictive of PFS and OS, whilst another in mixed population of 80 patients did not 57 58 (Lambert et al., 2010). The authors of the latter study reported that PET detected 59 60 21
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Barrington&Mikhaeel 1 2 3 relapse post allogeneic transplant earlier than CT and might be a useful tool during 4 5 surveillance to select patients for donor lymphocyte infusion (DLI) and reported low 6 7 incidence of graft versus host disease in patients who were PET +ve treated with 8 9 10 DLI. 11 12 13 Is there a role for PET in surveillance of patients ? 14 15 16 Relapses are more likely to be detected in symptomatic patients than with 17 18 surveillance imagingFor (Goldschmidt Peer et al., 2011) Review especially for aggressive NHL. 19 20 Surveillance scanning with PET however has been reported to detect unsuspected 21 22 relapses in up to 10% of patients with HL and aggressive NHL in one series of 421 23 24 25 patients routinely scanned at 6,12,18,24 months then annually (Pier Luigi Zinzani et 26 27 al., 2007). However lead time bias is a problem in studies of patients undergoing 28 29 surveillance imaging with earlier detection of disease leading to false impressions of 30 31 longer survival time. As yet no data exist that demonstrates that earlier detection of 32 33 34 disease improves outcomes for patients. Balanced against the desirability to detect 35 36 early relapse, are the high rate of false positive rates reported with PET CT scans. 37 38 PPVs for PET CT of only 21% and 23% were reported in two series of 52 patients 39 40 with aggressive NHL in first CR and 192 patients with HL respectively (Tarec El 41 42 Galaly et al., 2011; Lee et al., 2010) leading to unnecessary biopsies and patient 43 44 45 anxiety. The cost to detect a single event was estimated at US$100 000 in the latter 46 47 study (Lee et al., 2010). CT was similarly associated with a low PPV of 29% but 48 49 considerably lower financial cost. The associated radiation burden also has to be 50 51 taken into consideration. Currently there is no clear evidence to support surveillance 52 53 54 imaging with PET CT. However, it may be justified in very selected cases with high 55 56 risk of relapse (T El Galaly et al., 2013). 57 58 59 60 22
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Barrington&Mikhaeel 1 2 3 4 5 6 7 8 9 What is the Radiation dose typically associated with PET-CT? 10 11 12 The effective dose (ED) associated with a half body PET scan is around 8mSv if the 13 14 FDG activity administered is 400MBq, which is the diagnostic reference level used in 15 16 17 the UK ("Administration of Radioactive Substances Advisory Committee Notes for 18 For Peer Review 19 Guidance," 2006,revised 2011). With recent advances with 3D imaging, time of flight 20 21 and better image reconstruction algorithms, lower activities could be used or instead 22 23 the activity may be kept the same, if faster imaging times are preferred. With the 24 25 most up to date cameras, the effective dose could be reduced to 4 5 mSv (Boellaard 26 27 28 et al., 2010) without a loss in image quality. If a low dose CT scan is used for 29 30 localisation and attenuation correction, as part of PET CT, with the parameters 31 32 currently in use in our institution, the effective dose is 9mSv, but with more modern 33 34 CT cameras would be approximately 7mSv, giving rise to a combined ED for PET 35 36 37 CT typically of 11 17mSv. This equates to 5 8 years of natural background radiation, 38 39 which is 2.2mSv in the UK. The National Reference Dose Level for a full dose 40 41 contrast enhanced CT of the chest abdomen and pelvis of 940 mGycm (Shrimpton et 42 43 al., 2005) corresponds to an Effective Dose of approximately 16 mSv ("The 2007 44 45 Recommendations of the International Commission on Radiological Protection," 46 47 48 2007) which is comparable to a PET CT examination. 49 50 51 What about the use of PET-CT for T-cell Lymphomas? 52 53 54 Most reports related to staging and response assessment have included patients 55 56 with B cell malignancy although some reports in patients with aggressive NHL have 57 58 59 60 23
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Barrington&Mikhaeel 1 2 3 included a few patients with T cell lymphomas. As a separate entity however, there 4 5 are limited data on the use of FDG in patients with T cell and NK cell lymphomas. 6 7 Most are FDG avid, with higher uptake in more aggressive subtypes but significantly 8 9 10 lower uptake in cutaneous disease (Feeney et al., 2010; P. L. Zinzani, 2011). 11 12 Patients with Mycosis Fungoides have higher FDG uptake in the presence of large 13 14 cell transformation and it has been suggested that suspected transformation may be 15 16 an indication for PET CT, analogous to its use in FL (Feeney et al., 2010). Higher 17 18 For Peer Review 19 uptake is also seen in systemic manifestations of cutaneous lymphomas and a role 20 21 in the detection of visceral involvement has been suggested as this alters 22 23 management (Otero et al., 2009). Although PET also detects more lesions than CT 24 25 in nodal and leukaemic variants of T cell lymphomas, this rarely affects management 26 27 (Casulo et al., 2013). Interim assessment with FDG was reported to be predictive of 28 29 30 PFS, but not OS, in one study of 50 patients with peripheral T cell lymphomas 31 32 (Casulo et al., 2013), but not in another study involving 54 patients (Cahu et al., 33 34 2011); in the latter study the post therapy scan also was not predictive of outcome. It 35 36 is important not to extrapolate data relating to B cell lymphomas to patients with T 37 38 39 cell lymphomas. As yet,there is no clearly defined role for FDG PET in this disease 40 41 group with the possible exceptions of excluding visceral involvement with MF and 42 43 suspected transformation. Because the numbers of patients are small, prospective 44 45 multicentre trials are required. A UK study opened in 2012 investigating the 46 47 response rate of CHOP versus gemcitabine, methylprednisolone and cisplatin and is 48 49 50 prospectively measuring the complete metabolic response rate in patients with 51 52 untreated T cell lymphoma (http://www.clinicaltrials.gov/ct2/NCT01719835). 53 54 55 What other tracers are on the horizon for lymphoma? 56 57 58 59 60 24
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Barrington&Mikhaeel 1 2 3 There is growing interest in other tracers that might be more specific for malignancy 4 5 than FDG and which will detect early changes in tumour behaviour in response to 6 7 treatment. The use of 18F – Fluoro L Thymidine (FLT) has been explored in murine 8 9 10 models of DLBCL (Graf et al., 2012), Mantle Cell Lymphoma (MCL)(Brepoels et al., 11 12 2009) Burkitts Lymphoma (BL)(Saint Hubert et al., 2012) and FL (Buck et al., 2007). 13 14 FLT follows the salvage pathway for DNA synthesis like thymidine and is 15 16 phosphorylated by thymidine kinase 1 (TK1) in the cytosol and trapped 17 18 For Peer Review 19 intracellularly. TK1 is found in proliferating cells but not resting cells and activity 20 21 increases just before and during the S Phase of the cell cycle when DNA synthesis 22 23 occurs . FLT is thus a marker of proliferation. 24 25 26 In murine models, doxorubicin (Graf et al., 2012) and cyclophosphamide (Brepoels 27 28 et al., 2009; Buck et al., 2007) induced falls in FLT as early as 48hours after 29 30 treatment, associated with reduction in Ki67. In one study the fall in FLT was dose 31 32 33 dependent (Graf et al., 2012) and in vitro cell lines, DNA flow cytometry revealed 34 35 dose dependent reductions in the S phase and increased G2 arrest with doxorubicin 36 37 (Graf et al., 2012). FLT uptake remained steady thereafter. In contrast FDG uptake 38 39 initially fell, but was then followed by a temporary rise (Graf et al., 2012) with 40 41 42 doxorubicin and cyclophosphamide at 4 7 days (Brepoels et al., 2009) accompanied 43 44 by an influx of inflammatory cells, then a fall followed by a further rise at day 12 14 45 46 due to tumour regrowth. This suggested that FLT might be less affected by the 47 48 inflammatory response than FDG, although uptake of FLT has been reported in 49 50 51 granulomatous conditions (Zhao et al., 2008) and reactive lymph nodes (Troost et 52 53 al., 2007). In a BL model (Saint Hubert et al., 2012), FDG fell rapidly with 54 55 cyclophosphamide, with a marked increase in apoptosis measured with TUNEL, then 56 57 levels reached a plateau at day 7 9 with increased inflammatory cells observed, but 58 59 60 25
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Barrington&Mikhaeel 1 2 3 no later rise in FDG levels was seen. FLT fell less markedly and later after treatment 4 5 than FDG, with a small reduction in Ki67 observed. Delayed response with FLT was 6 7 attributed to increased DNA repair and a rise in TK1 in response to 8 9 10 cyclophosphamide induced DNA crosslinks early after administration (Saint Hubert 11 12 et al., 2012) and the authors suggested contrary to their earlier work using a MCL 13 14 model, that in BL, FDG might be a better tracer to assess response than FLT. With 15 16 Temsirolimus, an mTOR inhibitor, rapid and marked reductions in both FLT and FDG 17 18 For Peer Review 19 were reported (Brepoels et al., 2009; Saint Hubert et al., 2012)with a rise in FDG at 20 21 day 4 in one study but not the other and slow rises in both tracers towards day 14 22 23 with tumour regrowth. In the MCL model a temporary rise in FLT occurred at day 7, 24 25 accompanied by a rise in cyclin D1 levels. Cyclin D1 induces cell cycle transition 26 27 from the G1 to the S phase and is one of the targets controlled by mTOR, which 28 29 30 regulates cellular proliferation and is over expressed in MCL due to the translocation 31 32 t(11;14). This suggests that at day 7, the tumour had overcome the effects of the 33 34 mTOR inhibitor. To better understand when to assess response relies on 35 36 understanding the complex interactions between the tracer behaviour and the 37 38 39 tumour biology and mechanisms of drug action(s). 40 41 42 In a study of 22 patients with high grade NHL (Herrmann et al., 2007), reductions in 43 44 FLT were reported at day 2 and day 7 after treatment with CHOP but not with single 45 46 agent rituximab. The only patient who progressed on treatment demonstrated high 47 48 persistent FLT uptake and there were significant differences in patients who 49 50 51 achieved CR compared to PR. There were insufficient non responding patients to 52 53 determine any effect on responders vs. non responders. FLT has high uptake in 54 55 bone marrow and liver and may be more limited to assess disease at these sites. 56 57 58 59 60 26
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Barrington&Mikhaeel 1 2 3 Uptake with FLT is lower than FDG at baseline in lymphoma (Brepoels et al., 2009) 4 5 however baseline mean FLT has been reported to be significantly lower in patients 6 7 with aggressive NHL in one study who achieved CR (n=55) compared to patients 8 9 10 with no CR (n=7) and to correlate with the IPI (Herrmann et al., 2011). In 48 11 12 lymphoma patients with residual masses post chemotherapy, 31 of whom had 13 14 radiotherapy, FDG was a better predictor of overall survival than FLT, although 15 16 patients who were FDG positive and FLT positive had a worse outcome than those 17 18 For Peer Review 19 that were FDG positive and FLT negative (Kasper et al., 2007). Perhaps 20 21 proliferation effects in lymphoma are less important at this time point and interest will 22 23 continue to focus on early response assessment with FLT. 24 25 26 Conclusion 27 28 29 The indications and benefits of using PET CT in the modern management of 30 31 lymphoma are summarised in Table 2. 32 33 34 PET CT is routinely used in the staging of patients with HL and DLBCL and early 35 36 37 stage FL because it alters stage in a proportion of patients, but also because a 38 39 baseline scan is required for accurate subsequent response assessment. In FL and 40 41 MF, PET CT may be used to direct biopsy in suspected transformation. There is 42 43 strong evidence to support a role for interim assessment with PET CT in HL. In 44 45 DLBCL, iPET has a high negative predictive value but the positive predictive value is 46 47 48 lower in patients receiving R chemotherapy. The role of response adapted treatment 49 50 in both these diseases is being explored in multicentre international trials. 51 52 Preliminary reports from RAPID and H10 studies are emerging on the role of iPET in 53 54 selecting patients who may not need RT in early stage cHL but final reports of these 55 56 57 studies are awaited with interest. Post treatment assessment with PET CT is more 58 59 60 27
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Barrington&Mikhaeel 1 2 3 accurate than CT for HL, DLBCL and FL. Complete metabolic response is highly 4 5 indicative of remission and HL patients treated with BEACOPP with PET negative 6 7 residual masses do not require radiotherapy. Residual uptake following ABVD or R 8 9 10 chemotherapy requires biopsy or interval scanning. PET CT prior to ASCT is a 11 12 strong predictor of outcome and may have a role in the evaluation of novel agents in 13 14 this setting. Data relating to the use of FDG in T cell lymphomas is limited and 15 16 further studies are required. In cutaneous T cell lymphoma, PET does not have a 17 18 For Peer Review 19 routine role in staging or response assessment with the exception of the detection of 20 21 visceral involvement in MF. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 28
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Barrington&Mikhaeel 1 2 3 4 5 Figures 6 7 8 Figure 1 Coronal slices with low dose CT, PET and fused images are shown of a 9 10 patient with HL. Note the PET and fused images are displayed to a maximum SUV 11 12 13 of 10. This is the fixed scale used for reporting at our Centre. 14 15 16 Figure 2 Coronal slices (low dose CT, PET and fused images) show focal uptake in 17 18 the spleen (arrowed)For which isPeer not enlarged Reviewand has normal appearances on CT. 19 20 21 Figure 3 Sagittal slices (low dose CT, PET and fused images) are shown of a patient 22 23 with DLBCL and marrow involvement, pre (A) and post treatment (B). Note how 24 25 some vertebrae eg T12 with increased uptake become photopaenic with ablation of 26 27 28 marrow, whilst other vertebrae with normal uptake at baseline have increased uptake 29 30 relative to baseline due to the effects of chemotherapy. The images demonstrate a 31 32 ‘mirror’ effect. 33 34 35 Figure 4 Coronal slices (low dose CT, PET and fused images) are shown of a 36 37 patient with DLBCL with extensive nodal and pleural disease at staging (A) but with a 38 39 complete metabolic response after 2 cycles of R CHOP with a residual pleural 40 41 42 effusion (B). 43 44 45 Figure 5 Coronal slices (low dose CT, PET and fused images) are shown of a 46 47 patient with DLBCL with disease in the left axilla (A) which persists during treatment 48 49 with 2 cycles of R CHOP (B). 50 51 52 Figure 6 Axial slices (low dose CT, PET and fused images) are shown of a patient 53 54 with HL with high grade uptake in a mediastinal mass pre treatment (A) and a 55 56 57 complete metabolic response post treatment (B). 58 59 60 29
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Barrington&Mikhaeel 1 2 3 Figure 7 Axial slices (low dose CT, PET and fused images) are shown of a patient 4 5 with HL with high grade uptake in a mediastinal mass pre treatment (A) with a small 6 7 focus of residual uptake post treatment (B) concerning for treatment failure, requiring 8 9 10 biopsy. 11 12 13 Figure 8 Coronal slices (low dose CT, PET and fused images) are shown of a patient 14 15 with sarcoid like reaction with a typical distribution of FDG uptake in nodes in the 16 17 mediastinum and within the lung. 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 30
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1 2 Barrington&Mikhaeel 3 4 5 Table 1 – The Five point scale (5PS/Deauville criteria) 6 7 8 The 5PS scores the most intense residual uptake in a site of initial disease as: 9 10 1. no uptake 11 12 2. uptake ≤ mediastinum ** 13 For Peer Review 14 3. uptake > mediastinum but ≤ liver 15 16 17 4. uptake moderately higher than liver 18 19 5. uptake markedly higher than liver and/or new lesions 20 21 X new areas of uptake unlikely to be related to lymphoma 22 23 24 **NOTE if MBP ≥ liver activity, the uptake within lesions should be compared with liver (uptake 25 lesion < liver is score 2; lesion = liver is score 3) 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 31 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 32 of 115
1 2 Barrington&Mikhaeel 3 4 5 6 7 8 Table 2 Indications and Benefits for using PET CT in Lymphomas 9 10 11 12 Indication/s Benefit/s 13 For Peer Review 14 PRE TREATMENT 15 16 Staging of patients with FDG avid Lymphomas Increased staging accuracy 17 18 19 Improved treatment selection 20 21 Improved accuracy of response assessment 22 23 To direct biopsy in suspected transformation of FL Improved disease characterisation and treatment selection 24 25 Assessment of bone marrow involvement in HL and DLBCL Improved accuracy than biopsy 26 27 28 Avoidance of morbidity associated with BMB 29 30 Radiotherapy planning for patients with HL and DLBCL More refined definition of radiotherapy volume + less irradiation 31 32 of normal tissue. 33 34 Essential for techniques less than IFRT 35 36 37 DURING TREATMENT 38 39 Mid treatment imaging to monitor response in HL and DLBCL More accurate monitoring of response than mid treatment CT 40 41 42 32 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 33 of 115 British Journal of Haematology
1 2 Barrington&Mikhaeel 3 4 5 (and earlier assessment) 6 7 8 No evidence to modify treatment as yet, but useful to detect poor 9 10 or no response early 11 12 POST TREATMENT 13 For Peer Review 14 End of treatment assessment in HL DLBCL and FL (unless More accurate assessment of remission than CT especially in 15 16 17 patients have had mid treatment imaging showing complete cases of CRu or PR 18 19 metabolic response) to confirm disease remission or to direct Part of IWG criteria 20 21 biopsy if residual disease is suspected Possible role to select patients for consolidation RT (e.g. 22 23 advanced stage cHL after BEACOPP) 24 25 26 RELAPSE 27 28 Pre transplant assessment in patients undergoing ASCT with HL More accurate and prognostic than CT 29 30 or DLBCL 31 32 33 34 35 36 37 38 39 40 41 42 33 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 34 of 115
Barrington&Mikhaeel 1 2 3 References 4 5 6 7 The 2007 Recommendations of the International Commission on Radiological 8 9 10 Protection. (2007). Annals of the International Commission on Radiological 11 12 Protection, 37 (2 4). 13 14 . Administration of Radioactive Substances Advisory Committee Notes for Guidance. 15 16 (2006,revised 2011). Oxford: Health Protection Agency. 17 18 For Peer Review 19 Andre, M. P., Reman, O., Federico, M., Girinski, T., Brice, P., Brusamolino, E., 20 21 Ferme, C., vander Maazen, R., Bellei, M., Sebban, C., Morschhauser, F., 22 23 Lugtenburg, E., Stamatoulas, A., Fortpied, C., Meignan, M., Versari, A., 24 25 Hutchings, M., & Raemaekers, J. (2012). Interim Analysis of the Randomized 26 27 Eortc/Lysa/Fil Intergroup H10 Trial On Early PET Scan Driven Treatment 28 29 30 Adaptation in Stage I/II Hodgkin Lymphoma. Blood,ASH Annual Meeting 31 32 Abstracts 120 , 549. 33 34 Barnes, J. A., LaCasce, A. S., Zukotynski, K., Israel, D., Feng, Y., Neuberg, D., 35 36 Toomey, C. E., Hochberg, E. P., Canellos, G. P., & Abramson, J. S. (2011). 37 38 39 End of treatment but not interim PET scan predicts outcome in nonbulky 40 41 limited stage Hodgkin's lymphoma. Annals of Oncology, 22 (4), 910 915. doi: 42 43 10.1093/annonc/mdq549 44 45 Barrington, S., MacKewn, J. E., Schleyer, P., Marsden, P. K., Mikhaeel, N. G., Qian, 46 47 W., Mouncey, P., Patrick, P., Popova, B., Johnson, P., Radford, J., & 48 49 50 O'Doherty, M. J. (2011). Establishment of a UK wide network to facilitate the 51 52 acquisition of quality assured FDG PET data for clinical trials in lymphoma. 53 54 Annals of Oncology, 22 (3), 739 745. doi: 10.1093/annonc/mdq428 55 56 57 58 59 60 34
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Barrington&Mikhaeel 1 2 3 diffuse large B cell lymphoma. Blood, 118 (1), 37 43. doi: 10.1182/blood 2010 4 5 12 327767 6 7 Cashen, A. F., Dehdashti, F., Luo, J., Homb, A., Siegel, B. A., & Bartlett, N. L. 8 9 10 (2011). (18)F FDG PET/CT for Early Response Assessment in Diffuse Large 11 12 B Cell Lymphoma: Poor Predictive Value of International Harmonization 13 14 Project Interpretation. Journal of Nuclear Medicine, 52 (3), 386 392. doi: 15 16 10.2967/jnumed.110.082586 17 18 For Peer Review 19 Casulo, C., Schoder, H., Feeney, J., Lim, R., Maragulia, J., Zelenetz, A. D., & 20 21 Horwitz, S. (2013). FDG PET in the Staging and Prognosis of T cell 22 23 Lymphoma. [Journal article]. Leukemia & lymphoma (in press) . 24 25 Cerci, J. J., Pracchia, L. F., Linardi, C. C. G., Pitella, F. A., Delbeke, D., Izaki, M., 26 27 Trindade, E., Soares Junior, J., Buccheri, V., & Meneghetti, J. C. (2010). 28 29 30 (18)F FDG PET After 2 Cycles of ABVD Predicts Event Free Survival in Early 31 32 and Advanced Hodgkin Lymphoma. Journal of Nuclear Medicine, 51 (9), 1337 33 34 1343. doi: 10.2967/jnumed.109.073197 35 36 Cerci, J. J., Trindade, E., Pracchia, L. F., Pitella, F. A., Linardi, C. C., Soares, J., Jr., 37 38 39 Delbeke, D., Topfer, L. A., Buccheri, V., & Meneghetti, J. C. (2010). Cost 40 41 effectiveness of positron emission tomography in patients with Hodgkin's 42 43 lymphoma in unconfirmed complete remission or partial remission after first 44 45 line therapy. [Research Support, Non U.S. Gov't]. J Clin Oncol, 28 (8), 1415 46 47 1421. 48 49 50 Chen, Y. K., Yeh, C. L., Tsui, C. C., Liang, J. A., Chen, J. H., & Kao, C. H. (2011). F 51 52 18 FDG PET for evaluation of bone marrow involvement in non Hodgkin 53 54 lymphoma: a meta analysis. [Meta Analysis 55 56 Research Support, Non U.S. Gov't]. Clinical Nuclear Medicine, 36 (7), 553 559. 57 58 59 60 37
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Barrington&Mikhaeel 1 2 3 Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. 4 5 J., Coiffier, B., Fisher, R. I., Hagenbeek, A., Zucca, E., Rosen, S. T., 6 7 Stroobants, S., Lister, T. A., Hoppe, R. T., Dreyling, M., Tobinai, K., Vose, J. 8 9 10 M., Connors, J. M., Federico, M., & Diehl, V. (2007). Revised response criteria 11 12 for malignant lymphoma. Journal of Clinical Oncology, 25 (5), 579 586. doi: 13 14 10.1200/jco.2006.09.2403 15 16 Cook, G. J., Wegner, E. A., & Fogelman, I. (2004). Pitfalls and artifacts in 18FDG 17 18 For Peer Review 19 PET and PET/CT oncologic imaging. [Research Support, Non U.S. Gov't 20 21 Review]. Seminars in Nuclear Medicine, 34 (2), 122 133. 22 23 Devillier, R., Coso, D., Castagna, L., Brenot Rossi, I., Anastasia, A., Chiti, A., Ivanov, 24 25 V., Schiano, J. M., Santoro, A., Chabannon, C., Balzarotti, M., Blaise, D., & 26 27 Bouabdallah, R. (2012). Positron emission tomography response at the time 28 29 30 of autologous stem cell transplantation predicts outcome of patients with 31 32 relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage 33 34 therapy. Haematologica, 97 (7), 1073 1079. 35 36 Dodero, A., Crocchiolo, R., Patriarca, F., Miceli, R., Castagna, L., Ciceri, F., 37 38 39 Bramanti, S., Frungillo, N., Milani, R., Crippa, F., Fallanca, F., Englaro, E., & 40 41 Corradini, P. (2010). Pretransplantation 18 F Fluorodeoxyglucose Positron 42 43 Emission Tomography Scan Predicts Outcome in Patients With Recurrent 44 45 Hodgkin Lymphoma or Aggressive Non Hodgkin Lymphoma Undergoing 46 47 Reduced Intensity Conditioning Followed by Allogeneic Stem Cell 48 49 50 Transplantation. Cancer, 116 (21), 5001 5011. doi: 10.1002/cncr.25357 51 52 Duhrsen, U., Huttmann, A., Jockel, K. H., & Muller, S. (2009). Positron emission 53 54 tomography guided therapy of aggressive non Hodgkin lymphomas the 55 56 57 58 59 60 38
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Barrington&Mikhaeel 1 2 3 PETAL trial. Leukemia & lymphoma, 50 (11), 1757 1760. doi: 4 5 10.3109/10428190903308031 6 7 Dupuis, J., Berriolo Riedinger, A., Julian, A., Brice, P., Tychyj Pinel, C., Tilly, H., 8 9 10 Mounier, N., Gallamini, A., Feugier, P., Soubeyran, P., Colombat, P., Laurent, 11 12 G., Berenger, N., Casasnovas, R. O., Vera, P., Paone, G., Xerri, L., Salles, 13 14 G., Haioun, C., Meignan, M., Ghesquieres, H., Cartron, G., Seymour, J. F., 15 16 Delfau Larue, M. H., Offner, F., Soubeyran, P., Perrot, A., Brice, P., 17 18 For Peer Review 19 Bouabdallah, R., Sonet, A., Dupuis, J., Casasnovas, O., Catalano, J. V., 20 21 Delmer, A., Jardin, F., Verney, A., Dartigues, P., Salles, G., Le Gouill, S., De 22 23 Guibert, S., Planche, L., Brice, P., Dupuis, J., Cartron, G., Van Hoof, A., 24 25 Casasnovas, O., Gyan, E., Tilly, H., Fruchart, C., Deconinck, E., Fitoussi, O., 26 27 Gastaud, L., Delwail, V., Gabarre, J., Gressin, R., Blanc, M., Foussard, C., & 28 29 30 Salles, G. (2012). Impact of [18F]Fluorodeoxyglucose Positron Emission 31 32 Tomography Response Evaluation in Patients With High Tumor Burden 33 34 Follicular Lymphoma Treated With Immunochemotherapy: A Prospective 35 36 Study From the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. 37 38 39 [Multicenter Study 40 41 Randomized Controlled Trial 42 43 Research Support, Non U.S. Gov't 44 45 Clinical Trial, Phase III]. J Clin Oncol, 30 (35), 4317 4322. 46 47 El Galaly, T., Mylam, K., Brown, P., Rossing, M., Gang, A., Haglund, A., Arboe, B., 48 49 50 Clausen, M., Jensen, P., Pedersen, M., Bukh, A., Amdi Jensen, B., Poulsen, 51 52 C., D'Amore, F., & Hutchings, M. (2013). Patient Reported Symptoms are still 53 54 the Single Most Important Factor for detecting Lymphoma Relapse 31 (S1), 55 56 Abstract 225. 57 58 59 60 39
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Barrington&Mikhaeel 1 2 3 El Galaly, T., Prakash, V., Christiansen, I., Madsen, J., Johansen, P., Boegsted, M., 4 5 Johnsen, H. E., & Bukh, A. (2011). Efficacy of routine surveillance with 6 7 positron emission tomography/computed tomography in aggressive non 8 9 10 Hodgkin lymphoma in complete remission: status in a single center. Leukemia 11 12 & Lymphoma, 52 (4), 597 603. doi: 10.3109/10428194.2010.547642 13 14 El Galaly, T. C., d'Amore, F., Mylam, K. J., de Nully Brown, P., Bogsted, M., Bukh, 15 16 A., Specht, L., Loft, A., Iyer, V., Hjorthaug, K., Nielsen, A. L., Christiansen, I., 17 18 For Peer Review 19 Madsen, C., Johnsen, H. E., & Hutchings, M. (2012). Routine Bone Marrow 20 21 Biopsy Has Little or No Therapeutic Consequence for Positron Emission 22 23 Tomography/Computed Tomography Staged Treatment Naive Patients With 24 25 Hodgkin Lymphoma. [Journal article]. J Clin Oncol, 30 (36), 4508 4514. 26 27 Elstrom, R., Guan, L., Baker, G., Nakhoda, K., Vergilio, J. A., Zhuang, H., Pitsilos, 28 29 30 S., Bagg, A., Downs, L., Mehrotra, A., Kim, S., Alavi, A., & Schuster, S. J. 31 32 (2003). Utility of FDG PET scanning in lymphoma by WHO classification. 33 34 Blood, 101 (10), 3875 3876. doi: 10.1182/blood 2002 09 2778 35 36 Elstrom, R., Leonard, J. P., Coleman, M., & Brown, R. K. (2008). Combined PET and 37 38 39 low dose, noncontrast CT scanning obviates the need for additional 40 41 diagnostic contrast enhanced CT scans in patients undergoing staging or 42 43 restaging for lymphoma. [Research Support, N.I.H., Extramural]. Annals of 44 45 Oncology, 19 (10), 1770 1773. 46 47 Engert, A., Haverkamp, H., Kobe, C., Markova, J., Renner, C., Ho, A., Zijlstra, J., 48 49 50 Kral, Z., Fuchs, M., Hallek, M., Kanz, L., Dohner, H., Dorken, B., Engel, N., 51 52 Topp, M., Klutmann, S., Amthauer, H., Bockisch, A., Kluge, R., Kratochwil, C., 53 54 Schober, O., Greil, R., Andreesen, R., Kneba, M., Pfreundschuh, M., Stein, 55 56 H., Eich, H. T., Muller, R. P., Dietlein, M., Borchmann, P., & Diehl, V. (2012). 57 58 59 60 40
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Barrington&Mikhaeel 1 2 3 Reduced intensity chemotherapy and PET guided radiotherapy in patients 4 5 with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open 6 7 label, phase 3 non inferiority trial. [Clinical Trial, Phase III 8 9 10 Comparative Study 11 12 Multicenter Study 13 14 Randomized Controlled Trial 15 16 Research Support, Non U.S. Gov't]. Lancet, 379 (9828), 1791 1799. 17 18 For Peer Review 19 Feeney, J., Horwitz, S., Gonen, M., & Schoder, H. (2010). Characterization of T cell 20 21 lymphomas by FDG PET/CT. AJR, 195 (2), 333 340. 22 23 Fuertes, S., Setoain, X., Lopez Guillermo, A., Carrasco, J. L., Rodriguez, S., Rovira, 24 25 J., & Pons, F. (2013). Interim FDG PET/CT as a prognostic factor in diffuse 26 27 large B cell lymphoma. European Journal of Nuclear Medicine and Molecular 28 29 30 Imaging, 40 (4), 496 504. 31 32 Furth, C., Amthauer, H., Hautzel, H., Steffen, I. G., Ruf, J., Schiefer, J., 33 34 Schoenberger, S., Henze, G., Grandt, R., Hundsdoerfer, P., Dietlein, M., & 35 36 Kobe, C. (2011). Evaluation of interim PET response criteria in paediatric 37 38 39 Hodgkin's lymphoma results for dedicated assessment criteria in a blinded 40 41 dual centre read. Annals of Oncology, 22 (5), 1198 1203. doi: 42 43 10.1093/annonc/mdq557 44 45 Gallamini, A. (2010). Positron emission tomography scanning: a new paradigm for 46 47 the management of Hodgkin's lymphoma. [Editorial 48 49 50 Review]. Haematologica, 95 (7), 1046 1048. 51 52 Gallamini, A., Hutchings, M., Rigacci, L., Specht, L., Merli, F., Hansen, M., Patti, C., 53 54 Loft, A., Di Raimondo, F., D'Amore, F., Biggi, A., Vitolo, U., Stelitano, C., 55 56 Sancetta, R., Trentin, L., Luminari, S., Iannitto, E., Viviani, S., Pierri, I., & 57 58 59 60 41
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Barrington&Mikhaeel 1 2 3 Levis, A. (2007). Early interim 2 F 18 Fluoro 2 Deoxy D Glucose positron 4 5 emission tomography is prognostically superior to international prognostic 6 7 score in advanced stage Hodgkin's lymphoma: A report from a joint Italian 8 9 10 Danish study. Journal of Clinical Oncology, 25 (24), 3746 3752. doi: 11 12 10.1200/jco.2007.11.6525 13 14 Girinsky, T., Ghalibafian, M., Bonniaud, G., Bayla, A., Magne, N., Ferreira, I., & 15 16 Lumbroso, J. (2007). Is FDG PET scan in patients with early stage Hodgkin 17 18 For Peer Review 19 lymphoma of any value in the implementation of the involved node 20 21 radiotherapy concept and dose painting? [Research Support, Non U.S. Gov't]. 22 23 Radiotherapy and oncology : journal of the European Society for Therapeutic 24 25 Radiology and Oncology, 85 (2), 178 186. 26 27 Goldschmidt, N., Or, O., Klein, M., Savitsky, B., & Paltiel, O. (2011). The role of 28 29 30 routine imaging procedures in the detection of relapse of patients with 31 32 Hodgkin lymphoma and aggressive non Hodgkin lymphoma. Annals of 33 34 Hematology, 90 (2), 165 171. 35 36 Gollub, M. J., Hong, R., Sarasohn, D. M., & Akhurst, T. (2007). Limitations of CT 37 38 39 during PET/CT. [Comparative Study 40 41 Evaluation Studies]. J Nucl Med, 48 (10), 1583 1591. doi: 42 43 10.2967/jnumed.107.043109 44 45 Graf, N., Herrmann, K., Numberger, B., Zwisler, D., Aichler, M., Feuchtinger, A., 46 47 Schuster, T., Wester, H. J., Senekowitsch Schmidtke, R., Peschel, C., 48 49 50 Schwaiger, M., Keller, U., Dechow, T., & Buck, A. K. (2012). [(18)F]FLT is 51 52 superior to [(18)F]FDG for predicting early response to antiproliferative 53 54 treatment in high grade lymphoma in a dose dependent manner. [Journal 55 56 article]. European Journal of Nuclear Medicine and Molecular Imaging . 57 58 59 60 42
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Barrington&Mikhaeel 1 2 3 Haioun, C., Itti, E., Rahmouni, A., Brice, P., Rain, J. D., Belhadj, K., Gaulard, P., 4 5 Garderet, L., Lepage, E., Reyes, F., & Meignan, M. (2005). F 18 fluoro 2 6 7 deoxy D glucose positron emission tomography (FDG PET) in aggressive 8 9 10 lymphoma: an early prognostic tool for predicting patient outcome. Blood, 11 12 106 (4), 1376 1381. doi: 10.1182/blood 2005 01 0272 13 14 Herrmann, K., Buck, A. K., Schuster, T., Junger, A., Wieder, H. A., Graf, N., 15 16 Ringshausen, I., Rudelius, M., Wester, H. J., Schwaiger, M., Keller, U., & 17 18 For Peer Review 19 Dechow, T. (2011). Predictive value of initial 18F FLT uptake in patients with 20 21 aggressive non Hodgkin lymphoma receiving R CHOP treatment. [Clinical 22 23 Trial 24 25 Research Support, Non U.S. Gov't]. J Nucl Med, 52 (5), 690 696. 26 27 Herrmann, K., Wieder, H. A., Buck, A. K., Schoffel, M., Krause, B. J., Fend, F., 28 29 30 Schuster, T., Meyer zum Buschenfelde, C., Wester, H. J., Duyster, J., 31 32 Peschel, C., Schwaiger, M., & Dechow, T. (2007). Early response assessment 33 34 using 3' deoxy 3' [18F]fluorothymidine positron emission tomography in high 35 36 grade non Hodgkin's lymphoma. Clin Cancer Res, 13 (12), 3552 3558. 37 38 39 Hutchings, M. (2011). Pre transplant positron emission tomography/computed 40 41 tomography (PET/CT) in relapsed Hodgkin lymphoma: time to shift gears for 42 43 PET positive patients? [Comment]. Leukemia & lymphoma, 52 (9), 1615 1616. 44 45 doi: 10.3109/10428194.2011.601477 46 47 Hutchings, M., Loft, A., Hansen, M., Pedersen, L. M., Berthelsen, A. K., Keiding, S., 48 49 50 D'Amore, F., Boesen, A. M., Roemer, L., & Specht, L. (2006). Position 51 52 emission tomography with or without computed tomography in the primary 53 54 staging of Hodgkin's lymphoma. Haematologica-the Hematology Journal, 55 56 91 (4), 482 489. 57 58 59 60 43
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Barrington&Mikhaeel 1 2 3 Hutchings, M., Loft, A., Hansen, M., Pedersen, L. M., Buhl, T., Jurlander, J., Buus, 4 5 S., Keiding, S., D'Amore, F., Boesen, A. M., Berthelsen, A. K., & Specht, L. 6 7 (2006). FDG PET after two cycles of chemotherapy predicts treatment failure 8 9 10 and progression free survival in Hodgkin lymphoma. Blood, 107 (1), 52 59. 11 12 doi: 10.1182/blood 2005 06 2252 13 14 Hutchings, M., Mikhaeel, N. G., Fields, P. A., Nunan, T., & Timothy, A. R. (2005). 15 16 Prognostic value of interim FDG PET after two or three cycles of 17 18 For Peer Review 19 chemotherapy in Hodgkin lymphoma. Annals of Oncology, 16 (7), 1160 1168. 20 21 doi: 10.1093/annonc/mdi200 22 23 Itti, E., Lin, C., Dupuis, J., Paone, G., Capacchione, D., Rahmouni, A., Haioun, C., & 24 25 Meignan, M. (2009). Prognostic Value of Interim (18)F FDG PET in Patients 26 27 with Diffuse Large B Cell Lymphoma: SUV Based Assessment at 4 Cycles of 28 29 30 Chemotherapy. Journal of Nuclear Medicine, 50 (4), 527 533. doi: 31 32 10.2967/jnumed.108.057703 33 34 Itti, E., Meignan, M., Berriolo Riedinger, A., Biggi, A., Cashen, A. F., Vera, P., Tilly, 35 36 H., Siegel, B. A., Gallamini, A., Casasnovas, R. O., & Haioun, C. (2013). An 37 38 39 international confirmatory study of the prognostic value of early PET/CT in 40 41 diffuse large B cell lymphoma: comparison between Deauville criteria and 42 43 DeltaSUVmax. [Journal article]. European Journal of Nuclear Medicine and 44 45 Molecular Imaging . 46 47 Janikova, A., Bolcak, K., Pavlik, T., Mayer, J., & Kral, Z. (2008). Value of 48 49 50 [18F]fluorodeoxyglucose positron emission tomography in the management of 51 52 follicular lymphoma: the end of a dilemma? [Research Support, Non U.S. 53 54 Gov't]. Clinical lymphoma & myeloma, 8 (5), 287 293. 55 56 57 58 59 60 44
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Barrington&Mikhaeel 1 2 3 Juweid, M. E., Stroobants, S., Hoekstra, O. S., Mottaghy, F. M., Dietlein, M., 4 5 Guermazi, A., Wiseman, G. A., Kostakoglu, L., Scheidhauer, K., Buck, A., 6 7 Naumann, R., Spaepen, K., Hicks, R. J., Weber, W. A., Reske, S. N., 8 9 10 Schwaiger, M., Schwartz, L. H., Zijlstra, J. M., Siegel, B. A., Cheson, B. D., & 11 12 Imaging Subcommittee of International Harmonization Project in, L. (2007). 13 14 Use of positron emission tomography for response assessment of lymphoma: 15 16 consensus of the Imaging Subcommittee of International Harmonization 17 18 For Peer Review 19 Project in Lymphoma. [Consensus Development Conference 20 21 Practice Guideline]. J Clin Oncol, 25 (5), 571 578. doi: 10.1200/JCO.2006.08.2305 22 23 Juweid, M. E., Wiseman, G. A., Vose, J. M., Ritchie, J. M., Menda, Y., Wooldridge, J. 24 25 E., Mottaghy, F. M., Rohren, E. M., Blumstein, N. M., Stolpen, A., Link, B. K., 26 27 Reske, S. N., Graham, M. M., & Cheson, B. D. (2005). Response assessment 28 29 30 of aggressive non Hodgkin's lymphoma by integrated International Workshop 31 32 Criteria and fluorine 18 fluorodeoxyglucose positron emission tomography. 33 34 [Comparative Study 35 36 Research Support, N.I.H., Extramural 37 38 39 Research Support, Non U.S. Gov't 40 41 Research Support, U.S. Gov't, P.H.S.]. J Clin Oncol, 23 (21), 4652 4661. doi: 42 43 10.1200/JCO.2005.01.891 44 45 Karam, M., Novak, L., Cyriac, J., Ali, A., Nazeer, T., & Nugent, F. (2006). Role of 46 47 fluorine 18 fluoro deoxyglucose positron emission tomography scan in the 48 49 50 evaluation and follow up of patients with low grade lymphomas. [Comparative 51 52 Study]. Cancer, 107 (1), 175 183. 53 54 Kasper, B., Egerer, G., Gronkowski, M., Haufe, S., Lehnert, T., Eisenhut, M., 55 56 Mechtersheimer, G., Ho, A. D., & Haberkorn, U. (2007). Functional diagnosis 57 58 59 60 45
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Barrington&Mikhaeel 1 2 3 of residual lymphomas after radiochemotherapy with positron emission 4 5 tomography comparing FDG and FLT PET. [Comparative Study 6 7 Research Support, Non U.S. Gov't]. Leukemia & lymphoma, 48 (4), 746 753. 8 9 10 Khan, A. B., Barrington, S. F., Mikhaeel, N. G., Hunt, A. A., Cameron, L., Morris, T., 11 12 & Carr, R. (2013). PET CT staging of DLBCL accurately identifies and 13 14 provides new insight into the clinical significance of bone marrow involvement. 15 16 Blood, 122 (1), 61 67. 17 18 For Peer Review 19 Lambert, J. R., Bomanji, J. B., Peggs, K. S., Thomson, K. J., Chakraverty, R. K., 20 21 Fielding, A. K., Kottaridis, P. D., Roughton, M., Morris, E. C., Goldstone, A. H., 22 23 Linch, D. C., Ell, P. J., & Mackinnon, S. (2010). Prognostic role of PET 24 25 scanning before and after reduced intensity allogeneic stem cell 26 27 transplantation for lymphoma. [Research Support, Non U.S. Gov't]. Blood, 28 29 30 115 (14), 2763 2768. 31 32 Larcos, G., & Maisey, M. N. (1996). FDG PET screening for cerebral metastases in 33 34 patients with suspected malignancy. Nuclear Medicine Communications, 35 36 17 (3), 197 198. 37 38 39 Le Roux, P. Y., Gastinne, T., Le Gouill, S., Nowak, E., Bodet Milin, C., Querellou, S., 40 41 Mahe, B., Dubruille, V., Blin, N., Salaun, P. Y., & Bodere Kraeber, F. (2011). 42 43 Prognostic value of interim FDG PET/CT in Hodgkin's lymphoma patients 44 45 treated with interim response adapted strategy: comparison of International 46 47 Harmonization Project (IHP), Gallamini and London criteria. [Comparative 48 49 50 Study]. Eur J Nucl Med Mol Imaging, 38 (6), 1064 1071. doi: 10.1007/s00259 51 52 011 1741 0 53 54 Lee, A. I., Zuckerman, D. S., Van den Abbeele, A. D., Aquino, S. L., Crowley, D., 55 56 Toomey, C., Lacasce, A. S., Feng, Y., Neuberg, D. S., & Hochberg, E. P. 57 58 59 60 46
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Barrington&Mikhaeel 1 2 3 (2010). Surveillance imaging of Hodgkin lymphoma patients in first remission: 4 5 a clinical and economic analysis. [Evaluation Studies]. Cancer, 116 (16), 3835 6 7 3842. 8 9 10 Lin, C., Itti, E., Haioun, C., Petegnief, Y., Luciani, A., Dupuis, J., Paone, G., Talbot, J. 11 12 N., Rahmouni, A., & Meignan, M. (2007). Early 18F FDG PET for prediction of 13 14 prognosis in patients with diffuse large B cell lymphoma: SUV based 15 16 assessment versus visual analysis. [Research Support, Non U.S. Gov't]. J 17 18 For Peer Review 19 Nucl Med, 48 (10), 1626 1632. doi: 10.2967/jnumed.107.042093 20 21 Luminari, S., Biasoli, I., Arcaini, L., Versari, A., Rusconi, C., Merli, F., Spina, M., 22 23 Ferreri, A. J., Zinzani, P. L., Gallamini, A., Mastronardi, S., Boccomini, C., 24 25 Gaidano, G., D'Arco, A. M., Di Raimondo, F., Carella, A. M., Santoro, A., 26 27 Musto, P., & Federico, M. (2013). The use of FDG PET in the initial staging of 28 29 30 142 patients with follicular lymphoma: a retrospective study from the FOLL05 31 32 randomized trial of the Fondazione Italiana Linfomi. [Journal article]. Annals of 33 34 oncology : official journal of the European Society for Medical Oncology / 35 36 ESMO . 37 38 39 Markova, J., Kahraman, D., Kobe, C., Skopalova, M., Mocikova, H., Klaskova, K., 40 41 Dedeckova, K., Eich, H. T., Boll, B., Dietlein, M., & Kozak, T. (2012). Role of 42 43 [18F] fluoro 2 deoxy D glucose positron emission tomography in early and 44 45 late therapy assessment of patients with advanced Hodgkin lymphoma 46 47 treated with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, 48 49 50 procarbazine and prednisone. Leukemia & lymphoma, 53 (1), 64 70. 51 52 Meignan, M., Gallamini, A., Meignan, M., Gallamini, A., & Haioun, C. (2009). Report 53 54 on the First International Workshop on Interim PET Scan in Lymphoma. 55 56 57 58 59 60 47
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Barrington&Mikhaeel 1 2 3 [Congresses]. Leukemia & lymphoma, 50 (8), 1257 1260. doi: 4 5 10.1080/10428190903040048 6 7 Micallef, I. N., Maurer, M. J., Wiseman, G. A., Nikcevich, D. A., Kurtin, P. J., Cannon, 8 9 10 M. W., Perez, D. G., Soori, G. S., Link, B. K., Habermann, T. M., & Witzig, T. 11 12 E. (2011). Epratuzumab with rituximab, cyclophosphamide, doxorubicin, 13 14 vincristine, and prednisone chemotherapy in patients with previously 15 16 untreated diffuse large B cell lymphoma. [Clinical Trial, Phase II 17 18 For Peer Review 19 Multicenter Study 20 21 Research Support, N.I.H., Extramural 22 23 Research Support, U.S. Gov't, P.H.S.]. Blood, 118 (15), 4053 4061. doi: 24 25 10.1182/blood 2011 02 336990 26 27 Mikhaeel, N. G., Hutchings, M., Fields, P. A., O'Doherty, M. J., & Timothy, A. R. 28 29 30 (2005). FDG PET after two to three cycles of chemotherapy predicts 31 32 progression free and overall survival in high grade non Hodgkin lymphoma. 33 34 Ann Oncol, 16 (9), 1514 1523. doi: 10.1093/annonc/mdi272 35 36 Mocikova, H., Pytlik, R., Markova, J., Steinerova, K., Kral, Z., Belada, D., Trnkova, 37 38 39 M., Trneny, M., Koza, V., Mayer, J., Zak, P., & Kozak, T. (2011). Pre 40 41 transplant positron emission tomography in patients with relapsed Hodgkin 42 43 lymphoma. [Research Support, Non U.S. Gov't]. Leukemia & lymphoma, 44 45 52 (9), 1668 1674. 46 47 Moskowitz, C. H., Matasar, M. J., Zelenetz, A. D., Nimer, S. D., Gerecitano, J., 48 49 50 Hamlin, P., Horwitz, S., Moskowitz, A. J., Noy, A., Palomba, L., Perales, M. 51 52 A., Portlock, C., Straus, D., Maragulia, J. C., Schoder, H., & Yahalom, J. 53 54 (2012). Normalization of pre ASCT, FDG PET imaging with second line, non 55 56 57 58 59 60 48
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Barrington&Mikhaeel 1 2 3 cross resistant, chemotherapy programs improves event free survival in 4 5 patients with Hodgkin lymphoma. [Clinical Trial, Phase II 6 7 Multicenter Study 8 9 10 Research Support, Non U.S. Gov't]. Blood, 119 (7), 1665 1670. 11 12 Naumann, R., Beuthien Baumann, B., Reiss, A., Schulze, J., Hanel, A., Bredow, J., 13 14 Kuhnel, G., Kropp, J., Hanel, M., Laniado, M., Kotzerke, J., & Ehninger, G. 15 16 (2004). Substantial impact of FDG PET imaging on the therapy decision in 17 18 For Peer Review 19 patients with early stage Hodgkin's lymphoma. [Clinical Conference 20 21 Multicenter Study]. British Journal of Cancer, 90 (3), 620 625. 22 23 O'Doherty, M. J., Barrington, S. F., Campbell, M., Lowe, J., & Bradbeer, C. S. (1997). 24 25 PET scanning and the human immunodeficiency virus positive patient. 26 27 Journal of Nuclear Medicine, 38 (10), 1575 1583. 28 29 30 Otero, H. J., Jagannathan, J. P., Prevedello, L. M., Johnston, C. J., Ramaiya, N. H., 31 32 Van den Abbeele, A. D., & DiPiro, P. J. (2009). CT and PET/CT findings of T 33 34 cell lymphoma. AJR, 193 (2), 349 358. 35 36 Palmer, J., Goggins, T., Broadwater, G., Chao, N., Horwitz, M., Beaven, A., Sullivan, 37 38 39 K., Coleman, R. E., & Rizzieri, D. (2011). Early post transplant (F 18) 2 fluoro 40 41 2 deoxyglucose positron emission tomography does not predict outcome for 42 43 patients undergoing auto SCT in non Hodgkin and Hodgkin lymphoma. Bone 44 45 Marrow Transplantation, 46 (6), 847 851. doi: 10.1038/bmt.2010.203 46 47 Partridge, S., Timothy, A., O'Doherty, M. J., Hain, S. F., Rankin, S., & Mikhaeel, G. 48 49 50 (2000). 2 Fluorine 18 fluoro 2 deoxy D glucose positron emission tomography 51 52 in the pretreatment staging of Hodgkin's disease: influence on patient 53 54 management in a single institution. Annals of oncology : official journal of the 55 56 European Society for Medical Oncology / ESMO, 11 (10), 1273 1279. 57 58 59 60 49
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Barrington&Mikhaeel 1 2 3 Pelosi, E., Pregno, P., Penna, D., Deandreis, D., Chiappella, A., Limerutti, G., Vitolo, 4 5 U., Mancini, M., Bisi, G., & Gallo, E. (2008). Role of whole body [18F] 6 7 fluorodeoxyglucose positron emission tomography/computed tomography 8 9 10 (FDG PET/CT) and conventional techniques in the staging of patients with 11 12 Hodgkin and aggressive non Hodgkin lymphoma. [Comparative Study]. La 13 14 Radiologia medica, 113 (4), 578 590. 15 16 Pinilla, I., Gomez Leon, N., Del Campo Del Val, L., Hernandez Maraver, D., 17 18 For Peer Review 19 Rodriguez Vigil, B., Jover Diaz, R., & Coya, J. (2011). Diagnostic value of CT, 20 21 PET and combined PET/CT performed with low dose unenhanced CT and 22 23 full dose enhanced CT in the initial staging of lymphoma. [Comparative 24 25 Study]. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 26 27 55 (5), 567 575. 28 29 30 Pregno, P., Chiappella, A., Bello, M., Botto, B., Ferrero, S., Franceschetti, S., Giunta, 31 32 F., Ladetto, M., Limerutti, G., Menga, M., Nicolosi, M., Priolo, G., Puccini, B., 33 34 Rigacci, L., Salvi, F., Vaggelli, L., Passera, R., Bisi, G., & Vitolo, U. (2012). 35 36 Interim 18 FDG PET/CT failed to predict the outcome in diffuse large B cell 37 38 39 lymphoma patients treated at the diagnosis with rituximab CHOP. [Multicenter 40 41 Study 42 43 Research Support, Non U.S. Gov't]. Blood, 119 (9), 2066 2073. 44 45 Quarles van Ufford, H. M., van Tinteren, H., Stroobants, S. G., Riphagen, II, & 46 47 Hoekstra, O. S. (2010). Added value of baseline 18F FDG uptake in serial 48 49 50 18F FDG PET for evaluation of response of solid extracerebral tumors to 51 52 systemic cytotoxic neoadjuvant treatment: a meta analysis. [Meta Analysis]. J 53 54 Nucl Med, 51 (10), 1507 1516. 55 56 57 58 59 60 50
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Barrington&Mikhaeel 1 2 3 Raanani, P., Shasha, Y., Perry, C., Metser, U., Naparstek, E., Apter, S., Nagler, A., 4 5 Polliack, A., Ben Bassat, I., & Even Sapir, E. (2006). Is CT scan still 6 7 necessary for staging in Hodgkin and non Hodgkin lymphoma patients in the 8 9 10 PET/CT era? [Comparative Study 11 12 Multicenter Study]. Ann Oncol, 17 (1), 117 122. doi: 10.1093/annonc/mdj024 13 14 Radford, J., Barrington, S., Counsell, N., Pettengell, R., Johnson, P., Wimperis, J., 15 16 Coltart, S., Culligan, D., Lister, A., Bessell, E., Kruger, A., Popova, B., 17 18 For Peer Review 19 Hancock, B., Hoskin, P., Illidge, T., & O'Doherty, M. (2012). Involved Field 20 21 Radiotherapy Versus No Further Treatment in Patients with Clinical Stages IA 22 23 and IIA Hodgkin Lymphoma and a 'Negative' PET Scan After 3 Cycles ABVD. 24 25 Results of the UK NCRI RAPID Trial. Blood; ASH Annual Meeting Abstracts, 26 27 120 , 547. 28 29 30 Safar, V., Dupuis, J., Itti, E., Jardin, F., Fruchart, C., Bardet, S., Vera, P., Copie 31 32 Bergman, C., Rahmouni, A., Tilly, H., Meignan, M., & Haioun, C. (2012). 33 34 Interim [18F]fluorodeoxyglucose positron emission tomography scan in diffuse 35 36 large B cell lymphoma treated with anthracycline based chemotherapy plus 37 38 39 rituximab. [Research Support, N.I.H., Intramural 40 41 Research Support, Non U.S. Gov't]. J Clin Oncol, 30 (2), 184 190. doi: 42 43 10.1200/JCO.2011.38.2648 44 45 Saint Hubert, M. D., Brepoels, L., Devos, E., Vermaelen, P., Groot, T. D., Tousseyn, 46 47 T., Mortelmans, L., & Mottaghy, F. M. (2012). Molecular imaging of therapy 48 49 50 response with (18)F FLT and (18)F FDG following cyclophosphamide and 51 52 mTOR inhibition. American journal of nuclear medicine and molecular 53 54 imaging, 2 (1), 110 121. 55 56 57 58 59 60 51
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Barrington&Mikhaeel 1 2 3 Schaefer, N. G., Hany, T. F., Taverna, C., Seifert, B., Stumpe, K. D., von Schulthess, 4 5 G. K., & Goerres, G. W. (2004). Non Hodgkin lymphoma and Hodgkin 6 7 disease: coregistered FDG PET and CT at staging and restaging do we 8 9 10 need contrast enhanced CT? [Comparative Study]. Radiology, 232 (3), 823 11 12 829. 13 14 Schoder, H., Noy, A., Gonen, M., Weng, L., Green, D., Erdi, Y. E., Larson, S. M., & 15 16 Yeung, H. W. (2005). Intensity of 18fluorodeoxyglucose uptake in positron 17 18 For Peer Review 19 emission tomography distinguishes between indolent and aggressive non 20 21 Hodgkin's lymphoma. [Comparative Study]. J Clin Oncol, 23 (21), 4643 4651. 22 23 Shrimpton, P., Hillier, M., MA, L., & M, D. (2005). NRPB W67 Doses from 24 25 Computed Tomography (CT) Examinations in the UK 2003 Review Oxford: 26 27 National Radiological Protection Board. 28 29 30 Smeltzer, J. P., Cashen, A. F., Zhang, Q., Homb, A., Dehdashti, F., Abboud, C. N., 31 32 Dipersio, J. F., Stockerl Goldstein, K. E., Uy, G. L., Vij, R., Westervelt, P., 33 34 Bartlett, N. L., & Fehniger, T. A. (2011). Prognostic significance of FDG PET 35 36 in relapsed or refractory classical Hodgkin lymphoma treated with standard 37 38 39 salvage chemotherapy and autologous stem cell transplantation. [Research 40 41 Support, N.I.H., Extramural 42 43 Research Support, Non U.S. Gov't]. Biology of Blood and Marrow Transplantation, 44 45 17 (11), 1646 1652. 46 47 Spaepen, K., Stroobants, S., Dupont, P., Van Steenweghen, S., Thomas, J., 48 49 50 Vandenberghe, P., Vanuytsel, L., Bormans, G., Balzarini, J., De Wolf Peeters, 51 52 C., Mortelmans, L., & Verhoef, G. (2001). Prognostic value of positron 53 54 emission tomography (PET) with fluorine 18 fluorodeoxyglucose ([18F]FDG) 55 56 after first line chemotherapy in non Hodgkin's lymphoma: is [18F]FDG PET a 57 58 59 60 52
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Barrington&Mikhaeel 1 2 3 valid alternative to conventional diagnostic methods? [Research Support, 4 5 Non U.S. Gov't 6 7 Validation Studies]. J Clin Oncol, 19 (2), 414 419. 8 9 10 Spaepen, K., Stroobants, S., Dupont, P., Vandenberghe, P., Thomas, J., de Groot, 11 12 T., Balzarini, J., De Wolf Peeters, C., Mortelmans, L., & Verhoef, G. (2002). 13 14 Early restaging positron emission tomography with ( 18)F fluorodeoxyglucose 15 16 predicts outcome in patients with aggressive non Hodgkin's lymphoma. 17 18 For Peer Review 19 [Research Support, Non U.S. Gov't]. Ann Oncol, 13 (9), 1356 1363. 20 21 Specht, L., Yahalom, J., Illidge, T., Berthelsen, A. K., Constine, L. S., Eich, H. T., 22 23 Girinsky, T., Hoppe, R. T., Mauch, P., Mikhaeel, N. G., & Ng, A. (2013). 24 25 Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose 26 27 Guidelines From the International Lymphoma Radiation Oncology Group 28 29 30 (ILROG). [Journal article]. International journal of radiation oncology, biology, 31 32 physics . 33 34 Strobel, K., Schaefer, N. G., Renner, C., Veit Haibach, P., Husarik, D., Koma, A. Y., 35 36 & Hany, T. F. (2007). Cost effective therapy remission assessment in 37 38 39 lymphoma patients using 2 [fluorine 18]fluoro 2 deoxy D glucose positron 40 41 emission tomography/computed tomography: is an end of treatment exam 42 43 necessary in all patients? Annals of oncology : official journal of the European 44 45 Society for Medical Oncology / ESMO, 18 (4), 658 664. 46 47 Sucak, G. T., Ozkurt, Z. N., Suyani, E., Yasar, D. G., Akdemir, O. U., Aki, Z., Yegin, 48 49 50 Z. A., Yagci, M., & Kapucu, O. L. (2011). Early post transplantation positron 51 52 emission tomography in patients with Hodgkin lymphoma is an independent 53 54 prognostic factor with an impact on overall survival. Annals of Hematology, 55 56 90 (11), 1329 1336. doi: 10.1007/s00277 011 1209 0 57 58 59 60 53
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Barrington&Mikhaeel 1 2 3 Terasawa, T., Dahabreh, I. J., & Nihashi, T. (2010). Fluorine 18 Fluorodeoxyglucose 4 5 Positron Emission Tomography in Response Assessment Before High Dose 6 7 Chemotherapy for Lymphoma: A Systematic Review and Meta Analysis. 8 9 10 Oncologist, 15 (7), 750 759. doi: 10.1634/theoncologist.2010 0054 11 12 Troost, E. G., Vogel, W. V., Merkx, M. A., Slootweg, P. J., Marres, H. A., Peeters, W. 13 14 J., Bussink, J., van der Kogel, A. J., Oyen, W. J., & Kaanders, J. H. (2007). 15 16 18F FLT PET does not discriminate between reactive and metastatic lymph 17 18 For Peer Review 19 nodes in primary head and neck cancer patients. [Randomized Controlled 20 21 Trial 22 23 Research Support, Non U.S. Gov't]. J Nucl Med, 48 (5), 726 735. 24 25 Trotman, J., Fournier, M., Lamy, T., Seymour, J. F., Sonet, A., Janikova, A., 26 27 Shpilberg, O., Gyan, E., Tilly, H., Estell, J., Forsyth, C., Decaudin, D., Fabiani, 28 29 30 B., Gabarre, J., Salles, B., Van den Neste, E., Canioni, D., Garin, E., Fulham, 31 32 M., Vander Borght, T., & Salles, G. (2011). Positron Emission Tomography 33 34 Computed Tomography (PET CT) After Induction Therapy Is Highly Predictive 35 36 of Patient Outcome in Follicular Lymphoma: Analysis of PET CT in a Subset 37 38 39 of PRIMA Trial Participants. Journal of Clinical Oncology, 29 (23), 3194 3200. 40 41 doi: 10.1200/jco.2011.35.0736 42 43 Tsukamoto, N., Kojima, M., Hasegawa, M., Oriuchi, N., Matsushima, T., Yokohama, 44 45 A., Saitoh, T., Handa, H., Endo, K., & Murakami, H. (2007). The usefulness of 46 47 (18)F fluorodeoxyglucose positron emission tomography ((18)F FDG PET) 48 49 50 and a comparison of (18)F FDG pet with (67)gallium scintigraphy in the 51 52 evaluation of lymphoma: relation to histologic subtypes based on the World 53 54 Health Organization classification. [Comparative Study 55 56 Evaluation Studies]. Cancer, 110 (3), 652 659. 57 58 59 60 54
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Barrington&Mikhaeel 1 2 3 Watanabe, R., Tomita, N., Takeuchi, K., Sakata, S., Tateishi, U., Tanaka, M., Fujita, 4 5 H., Inayama, Y., & Ishigatsubo, Y. (2010). SUVmax in FDG PET at the biopsy 6 7 site correlates with the proliferation potential of tumor cells in non Hodgkin 8 9 10 lymphoma. Leukemia & lymphoma, 51 (2), 279 283. 11 12 Weiler Sagie, M., Bushelev, O., Epelbaum, R., Dann, E. J., Haim, N., Avivi, I., Ben 13 14 Barak, A., Ben Arie, Y., Bar Shalom, R., & Israel, O. (2010). (18)F FDG 15 16 avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med, 51 (1), 17 18 For Peer Review 19 25 30. 20 21 Wirth, A., Foo, M., Seymour, J. F., Macmanus, M. P., & Hicks, R. J. (2008). Impact of 22 23 [18f] fluorodeoxyglucose positron emission tomography on staging and 24 25 management of early stage follicular non hodgkin lymphoma. [Evaluation 26 27 Studies]. International journal of radiation oncology, biology, physics, 71 (1), 28 29 30 213 219. doi: 10.1016/j.ijrobp.2007.09.051 31 32 Yang, D. H., Min, J. J., Song, H. C., Jeong, Y. Y., Chung, W. K., Bae, S. Y., Ahn, J. 33 34 S., Kim, Y. K., Bom, H. S., Chung, I. J., Kim, H. J., & Lee, J. J. (2011). 35 36 Prognostic significance of interim (18)F FDG PET/CT after three or four 37 38 39 cycles of R CHOP chemotherapy in the treatment of diffuse large B cell 40 41 lymphoma. European Journal of Cancer, 47 (9), 1312 1318. doi: 42 43 10.1016/j.ejca.2010.12.027 44 45 Yang, D. H., Ahn, J. S., Byun, B. H., Min, J. J., Kweon, S. S., Chae, Y. S., Sohn, S. 46 47 K., Lee, S. W., Kim, H. W., Jung, S. H., Kim, Y. K., Kim, H. J., Bom, H. S., & 48 49 50 Lee, J. J. (2013). Interim PET/CT based prognostic model for the treatment of 51 52 diffuse large B cell lymphoma in the post rituximab era. Annals of 53 54 Hematology, 92 (4), 471 479. 55 56 57 58 59 60 55
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Barrington&Mikhaeel 1 2 3 Yoo, C., Lee, D. H., Kim, J. E., Jo, J., Yoon, D. H., Sohn, B. S., Kim, S. W., Lee, J. 4 5 S., & Suh, C. (2011). Limited role of interim PET/CT in patients with diffuse 6 7 large B cell lymphoma treated with R CHOP. Annals of Hematology, 90 (7), 8 9 10 797 802. doi: 10.1007/s00277 010 1135 6 11 12 Zhao, S., Kuge, Y., Kohanawa, M., Takahashi, T., Zhao, Y., Yi, M., Kanegae, K., 13 14 Seki, K., & Tamaki, N. (2008). Usefulness of 11C methionine for 15 16 differentiating tumors from granulomas in experimental rat models: a 17 18 For Peer Review 19 comparison with 18F FDG and 18F FLT. [Comparative Study 20 21 Research Support, Non U.S. Gov't]. J Nucl Med, 49 (1), 135 141. 22 23 Zinzani, P. L. (2011). PET in T Cell Lymphoma. Current hematologic malignancy 24 25 reports, 6 (4), 241 244. 26 27 Zinzani, P. L., Gandolfi, L., Broccoli, A., Argnani, L., Fanti, S., Pellegrini, C., Stefoni, 28 29 30 V., Derenzini, E., Quirini, F., & Baccarani, M. (2011). Midtreatment 18F 31 32 fluorodeoxyglucose positron emission tomography in aggressive non Hodgkin 33 34 lymphoma. [Evaluation Studies 35 36 Research Support, Non U.S. Gov't]. Cancer, 117 (5), 1010 1018. doi: 37 38 39 10.1002/cncr.25579 40 41 Zinzani, P. L., Rigacci, L., Stefoni, V., Broccoli, A., Puccini, B., Castagnoli, A., 42 43 Vaggelli, L., Zanoni, L., Argnani, L., Baccarani, M., & Fanti, S. (2012). Early 44 45 interim 18F FDG PET in Hodgkin's lymphoma: evaluation on 304 patients. 46 47 [Research Support, Non U.S. Gov't]. European Journal of Nuclear Medicine 48 49 50 and Molecular Imaging, 39 (1), 4 12. 51 52 Zinzani, P. L., Tani, M., Trisolini, R., Fanti, S., Stefoni, V., Alifano, M., Castellucci, P., 53 54 Musuraca, G., Dalpiaz, G., Alinari, L., Marchi, E., Fina, M., Pellegrini, C., 55 56 Farsad, M., Cancellieri, A., Busca, A., Canini, R., Pileri, S., Baccarani, M., & 57 58 59 60 56
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Barrington&Mikhaeel 1 2 3 Boaron, M. (2007). Histological verification of positive positron emission 4 5 tomography findings in the follow up of patients with mediastinal lymphoma. 6 7 Haematologica, 92 (6), 771 777. doi: 10.3324/haematol.10798 8 9 10 11 12 Acknowledgements 13 14 15 16 Sally Barrington and George Mikhaeel reviewed the literature and wrote the 17 18 For Peer Review 19 paper together. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 57
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 4 5 6 7 When should FDG-PET be used in the modern management of 8 9 lymphoma? 10 11 12 1 2 13 SF Barrington and NG Mikhaeel 14 15 16 17 18 For Peer Review 19 1 PET Imaging Centre at St Thomas’ Hospital, Division of Imaging and 20 21 Biomechanical Engineering, King’s College, London 22 23 2 24 Department of Clinical Oncology, Guy’s & St Thomas’ Foundation Trust, London 25 26 27 28 Running title: PET CT in the management of lymphoma 29 30 31 32 33 Corresponding Author: 34 35 Sally Barrington 36 37 PET Imaging Centre 38 39 Westminster Bridge Road 40 41 London SE1 7EH 42 43 44 0044 207 188 4988 45 46 [email protected] 47 48 49 50 BJH-2013-01212; 6300 words, 3 tables, 4 figures 51 52 53 54 55 56 57 58 59 60 1
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Summary 4 5 6 Positron Emission Tomography (PET) is a functional imaging technique which 7 8 9 combined with CT (PET CT) is increasingly used in lymphoma. Most subtypes 10 11 accumulate Fluorodeoxyglucose (FDG) and the increased sensitivity of PET CT, 12 13 especially for extranodal disease, compared to CT, makes PET CT an attractive 14 15 staging tool. The availability of a staging PET CT scan also improves the accuracy 16 17 of subsequent response assessment. ‘Interim’ PET CT can be used to assess early 18 For Peer Review 19 20 response and end of treatment PET CT to assess remission. Clinical trials are 21 22 currently seeking to establish whether the predictive value of PET CT can be 23 24 successfully used to guide individual treatment to reduce toxicity and/or to improve 25 26 outcomes. Standardised methods for performing and reporting PET have been 27 28 29 developed in the context of trials. The role of PET in transplantation selection is 30 31 evolving as PET appears to be more accurate and prognostic than CT. The role of 32 33 FDG PET CT throughout the management course in patients with lymphoma is 34 35 explored in this review with areas discussed that may limit the use of PET CT 36 37 38 imaging which clinicians should be familiar with to inform practice. (174 words) 39 40 41 42 43 44 Keywords: Positron Emission Tomography, Hodgkin Lymphoma, 45 46 Non-Hodgkin Lymphoma, Clinical Trials, Imaging. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 What is PET? 4 5 6 Positron Emission Tomography (PET) images physiological processes by detecting 7 8 radioactive emissions from Positron Emitting radioisotopes or ‘tracers’ injected into a 9 10 patient. The most commonly used tracer is 18F Fluorodeoxyglucose (FDG) which is 11 12 13 a glucose analogue which has increased uptake in cancer due to enhanced glucose 14 15 transport, turnover and trapping. Other processes with increased glycolysis, such as 16 17 infection and inflammation have increased FDG uptake, but often to a lesser degree 18 For Peer Review 19 than malignancy. 20 21 22 Modern PET cameras are now combined with a CT scanner, enabling functional and 23 24 25 anatomical information to be obtained together. CT and PET can be viewed 26 27 separately, side by side and ‘fused’ with the PET scan overlaid on the CT in colour. 28 29 30 PET scans are usually reported using visual assessment. The intensity and 31 32 locations of FDG avid disease are described and distinguished from areas with high 33 34 physiological uptake, such as the brain and the urinary system, where FDG is 35 36 37 excreted. Scans are usually displayed scaled according to the standardised uptake 38 39 value (SUV) which is the activity of the tracer, corrected for patient weight and the 40 41 administered radioactivity (Figure 1). The use of a fixed SUV display aids 42 43 consistency of reporting, by enabling uptake to be to be assessed at successive 44 45 time points within the same patient during treatment and by reducing the effect of 46 47 48 weight on uptake across different patients. SUV measures may be used to quantify 49 50 uptake; most commonly the ‘maximum’ (SUVmax) is used to describe intensity. The 51 52 CT is used to localise the PET abnormalities and any additional findings on CT 53 54 reported. 55 56 57 58 59 60 3
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 The CT may be acquired at full dose with intravenous and/or bowel contrast, similar 4 5 to a ‘stand alone’ CT but must be acquired during normal breathing rather than full 6 7 inspiration, to fuse with the PET which is acquired in steps over 15 25 minutes. 8 9 10 Alternatively the CT may be acquired at lower dose, which is more common practice 11 12 for PET CT imaging. Then the CT is used a) to measure how Xrays are attenuated 13 14 in the patient and apply a correction to the FDG images to give a truer appreciation 15 16 of tracer distribution and b) to accurately localise sites of uptake. 17 18 For Peer Review 19 Which Lymphomas can be imaged with PET ? 20 21 22 Most Lymphomas are FDG avid. In a series of 766 patients imaged with lymphoma, 23 24 25 100% of Hodgkin lymphoma (HL), 97% of Diffuse Large B cell Lymphoma (DLBCL) 26 27 and 95% of Follicular Lymphomas (FL) were FDG avid (Weiler Sagie et al., 2010). 28 29 Less common aggressive subtypes were also universally FDG avid including Burkitt 30 31 lymphoma, Mantle Cell lymphoma and aggressive T cell lymphomas. More variable 32 33 34 avidity has been reported for small lymphocytic lymphoma (50 83%), extranodal 35 36 marginal zone lymphoma (54 67%), and lymphomas that involve the skin (Elstrom et 37 38 al., 2003; Tsukamoto et al., 2007; Weiler Sagie et al., 2010). 39 40 41 Aggressive lymphomas mostly have higher uptake than indolent lymphomas. In a 42 43 study of 97 patients with NHL, although some patients with indolent and aggressive 44 45 disease had SUVs in the lower range, all patients with indolent lymphoma had 46 47 48 SUVmax <13 (Schoder et al., 2005). Using an SUVmax ≥ 10 distinguished 49 50 aggressive from indolent disease with 81% specificity and 71% sensitivity. SUVmax 51 52 also correlates with proliferation, measured by the Ki 67 index in lymph node and 53 54 extranodal biopsies obtained from patients with indolent and aggressive lymphomas 55 56 57 (Watanabe et al., 2010). 58 59 60 4
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 This suggests that FDG PET may be used in patients with suspected transformation 4 5 to direct biopsy. 6 7 8 What is the added value of PET for staging? 9 10 11 PET is more sensitive and specific than CT (Schaefer et al., 2004) because 12 13 14 abnormal FDG uptake may be observed in normal sized nodes and seen without 15 16 changes in organ architecture (Figure 2). Equally, slightly enlarged nodes which 17 18 may be reactive willFor not accumulate Peer FDG. UpstagingReview occurs more commonly than 19 20 downstaging, although both occur. Extranodal disease is more often identified with 21 22 PET than CT within the bone and bone marrow (Figure 3), liver and spleen (Raanani 23 24 25 et al., 2006) and occasionally in the peritoneum. Small lung nodules may not be 26 27 resolved by PET but these are usually visible on the accompanying CT. Cutaneous 28 29 lesions are less FDG avid than extracutaneous disease and PET may have a role to 30 31 detect extracutaneous disease in patients with Mycosis Fungoides, which confers a 32 33 34 worse prognosis (Feeney et al., 2010; Otero et al., 2009). The brain has high 35 36 physiological FDG uptake which limits the ability to detect metastatic disease in other 37 38 diseases (Larcos & Maisey, 1996) but intracerebral lymphoma is highly avid and 39 40 PET has been used to distinguish toxoplasmosis from intracerebral lymphoma in HIV 41 42 patients (O'Doherty et al., 1997). Nonetheless, leptomeningeal disease which is 43 44 45 diffuse and may be low volume is difficult to assess and MR is the investigation of 46 47 choice for initial assessment of CNS lymphoma. 48 49 50 The presence of a baseline scan improves the accuracy of subsequent response 51 52 assessment and improves reporter agreement (Meignan, Itti, et al., 2009) . The 53 54 availability of a baseline scan has been reported to affect the classification of 55 56 57 metabolic response in 19 34% of lymphoma patients. (S.F. Barrington et al., 2011; 58 59 60 5
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Quarles van Ufford et al., 2010). Baseline PET is also important for planning of 4 5 radiotherapy, especially using newer techniques treating smaller volumes than 6 7 traditional involved field radiotherapy (IFRT). It is recommended that the use of 8 9 10 ‘involved site’ radiotherapy (Specht et al., 2013) and ‘involved node’ radiotherapy 11 12 (INRT) (Girinsky et al., 2007) should ideally be based on staging PET CT rather than 13 14 CT alone. 15 16 17 The frequency of management change from using PET CT for staging ranges from 18 For Peer Review 19 approximately 10 50%, but is typically around 15% (M. Hutchings et al., 2006; 20 21 22 Naumann et al., 2004; Partridge et al., 2000; Pelosi et al., 2008; Raanani et al., 23 24 2006; Wirth et al., 2008). In patients with ‘apparently’ limited stage Follicular 25 26 Lymphoma on CT, PET may have an important impact because up to 60% (Karam 27 28 et al., 2006; Luminari et al., 2013; Wirth et al., 2008) will have more advanced 29 30 disease demonstrated. The upstaging has significant implications on the choice of 31 32 33 therapy. Patients with limited stage FL are commonly treated with radiotherapy alone 34 35 however patients with more advanced disease usually require systemic treatment. 36 37 38 The presence of focal uptake in the bone marrow on PET CT is more sensitive for 39 40 bone marrow involvement than bone marrow biopsy in HL (T. C. El Galaly et al., 41 42 2012) and aggressive NHL (Berthet et al., 2013; Khan et al., 2013). Diffuse 43 44 45 homogenous FDG uptake may be seen with reactive hyperplasia in the marrow, 46 47 especially in HL and does not necessarily indicate involvement. In a study in 454 48 49 patients with HL, no patients with stage I or II disease on PET CT were upstaged by 50 51 biopsy. Eighty two patients had marrow involvement by PET, 27 by biopsy. Of 52 53 54 these 27 patients, 22 had extranodal disease elsewhere on PET, the remaining five 55 56 were upstaged from stage 3 to 4 by biopsy but this did not change treatment. Thus 57 58 59 60 6
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 biopsy did not alter management in a single patient (T. C. El Galaly et al., 2012) 4 5 suggesting that staging PET CT may be used in preference (B.D. Cheson, 2012). 6 7 8 In aggressive NHL, small volume disease, typically ≤ 10% marrow involvement or 9 10 coexistent low grade lymphoma (Paone et al., 2009) may be missed by PET but this 11 12 13 has not been shown to affect prognosis or treatment (Campbell et al., 2006; 14 15 Ghesquieres et al., 2006; Sehn et al., 2011). In a study of 130 patients with DLBCL, 16 17 33 patients had marrow involvement on PET, 14 on biopsy (Khan et al., 2013). No 18 For Peer Review 19 case was classified as stage 4 based on biopsy alone. Patients with PET and biopsy 20 21 22 evidence of marrow involvement had worse prognosis than the rest of the study 23 24 population but these patients frequently had other adverse factors predictive of high 25 26 risk disease. Two patients with marrow involvement on biopsy had normal marrow 27 28 appearances on PET with <10% of the marrow involved. In a further study of 133 29 30 patients with DLBCL, marrow involvement with PET and the IPI were independent 31 32 33 predictors of PFS, whereas bone marrow biopsy was not (Berthet et al., 2013). This 34 35 also suggests a restricted role for bone marrow biopsy in DLBCL patients staged by 36 37 PET CT. 38 39 40 PET CT is less sensitive than biopsy for marrow involvement in indolent lymphomas, 41 42 which is frequently diffuse, can be small volume and have low grade FDG uptake. 43 44 45 The sensitivity was reported as 46% in indolent lymphomas in a recent meta 46 47 analysis (Chen et al., 2011). Biopsy with histological examination including 48 49 immunohistochemistry and testing for clonality remains the gold standard in indolent 50 51 lymphomas. 52 53 54 55 56 57 58 59 60 7
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Is contrast enhanced CT necessary in addition to PET (CT) ? 4 5 6 PET CT is routinely used for staging patients but whether a full dose contrast 7 8 enhanced CT is required in addition to the low dose non contrast CT that is usually 9 10 performed as part of the PET CT examination is less clear. Several studies have 11 12 13 reported that PET with low dose CT demonstrated more lesions than contrast 14 15 enhanced CT alone (Elstrom et al., 2008; Raanani et al., 2006; Schaefer et al., 16 17 2004). The use of contrast enhanced CT did not alter stage nor change 18 For Peer Review 19 management in three series (Elstrom et al., 2008; Gollub et al., 2007; Pinilla et al., 20 21 22 2011) but in one series, contrast enhanced CT altered stage in 8/68 patients with 23 24 NHL and 4/35 patients with HL, affecting management in nine (Raanani et al., 2006) 25 26 however the details of management change were not reported. In two further 27 28 publications (Pinilla et al., 2011), the use of contrast was felt to improve disease 29 30 detection in the small bowel and pancreas in two patients, affecting management in 31 32 33 one (Schaefer et al., 2004) . 34 35 36 Pragmatically, many patients will have a contrast enhanced CT scan performed prior 37 38 to PET CT, then a low dose CT will suffice for PET CT. If PET CT is performed first, 39 40 contrast enhanced CT may be preferred in patients likely to undergo radiotherapy, 41 42 preferably in the anticipated treatment position. For clinical trials, contrast enhanced 43 44 45 CT is necessary if accurate size measurements are required, and would be more 46 47 convenient performed during a single PET CT scanning session. For other patients, 48 49 whether the additional radiation incurred with a full dose contrast enhanced CT is 50 51 justified should be considered. Additional findings reported with contrast enhanced 52 53 54 CT were due to using contrast rather than the increased X ray dose and there may 55 56 be a role for regional low dose CT with contrast after PET CT. If a contrast 57 58 59 60 8
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 enhanced CT is performed at staging and there is no additional benefit, subsequent 4 5 examinations should be performed at lower dose. 6 7 8 What is the role of PET in early response assessment? 9 10 11 Metabolic changes precede changes in tumour size, which enables response to be 12 13 14 assessed earlier during treatment with PET than CT. Rapid reduction in FDG uptake 15 16 during chemotherapy is associated with a good prognosis in patients with HL and 17 18 persistent FDG uptakeFor with aPeer poor prognosis Review in advanced HL patients. The group at 19 20 Guy’s and St Thomas’ reported in 2005 a retrospective analysis of 85 HL patients 21 22 where PFS and OS were significantly different according to whether the PET scan 23 24 25 performed after 2 or 3 cycles of chemotherapy was reported as ‘negative’, showing 26 27 ‘minimal residual uptake’ or ‘positive’(Hutchings et al., 2005). Patients with a 28 29 negative scan or minimal residual uptake had 5y PFS rates of 92% compared with 30 31 39% for patients with a positive scan. This was followed by further reports after 2 32 33 34 cycles of chemotherapy in HL, involving 1066 patients treated with ABVD (Biggi et 35 36 al., 2013; Cerci, Pracchia, et al., 2010; Andrea Gallamini et al., 2007; M.; Hutchings 37 38 et al., 2006; P. L. Zinzani et al., 2012). These studies also reported ≥2y PFS rates of 39 40 90 96% for patients with complete metabolic response (CMR) and PFS rates of 0%, 41 42 13%, 28%, 28%, 53% respectively for patients with positive scans, with poorer 43 44 45 outcomes in advanced disease (Andrea Gallamini et al., 2007; M.; Hutchings et al., 46 47 2006). PET was a better predictor than the IPS (Andrea Gallamini et al., 2007). A 48 49 study reporting outcomes in 96 patients with early stage non bulky HL (Barnes et al., 50 51 2011) found no difference in PFS according to early or ‘interim’ PET (iPET) although 52 53 54 the end of treatment PET was predictive of outcome, probably due to the excellent 55 56 prognosis of this patient group and the effect of radiotherapy. Radiotherapy was 57 58 given to 56% of patients in the study and used more often in patients with positive 59 60 9
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 than negative interim scans (88% v 54%). A report in 69 patients treated with 4 5 BEACOPP reported 4y PFS of 98% and 78% for patients with positive and negative 6 7 iPET scans respectively (p=0.016)(Markova et al., 2012). The ability of interim PET 8 9 10 to predict prognosis early in treatment is clearly influenced by its timing in relation to 11 12 chemotherapy, the disease stage and the treatment regimen. At present, iPET at 2 13 14 3 cycles has been shown to be predictive of outcome in advanced stage, ABVD 15 16 treated patients but extrapolation of these results to BEACOPP treated patients is 17 18 For Peer Review 19 not advisable. 20 21 22 These studies highlighted the potential to use PET to tailor treatment for the 23 24 individual according to their response during chemotherapy. The good prognosis 25 26 associated with negative iPET has led to the question whether short course 27 28 chemotherapy without radiotherapy is an option for patients with early stage 29 30 favourable HL who have a negative iPET scan during ABVD treatment rather than 31 32 33 combined modality treatment. 34 35 36 The UK National Cancer Research Institute study group recently presented the first 37 38 results of the RAPID trial involving 602 patients with HL who had a PET scan 39 40 performed after 3 cycles of ABVD (Radford et al., 2012). The study included non 41 42 bulky stage I & IIA disease and was designed to exclude a difference of ≥7% 43 44 45 between radiotherapy and no further treatment. Patients with a complete metabolic 46 47 response (defined as score 1 & 2 using a 5 point scale) were randomised to receive 48 49 IFRT or no treatment, whilst patients with a positive scan (score 3 5) received one 50 51 further cycle of ABVD and 30Gy IFRT. 3y PFS in 420 randomised patients with PET 52 53 54 negative scans was 93.8% in the group receiving RT and 90.7% in the group 55 56 receiving no further treatment, (risk difference 2.9%, 95%CI 10.7 to 1.4%). 3 year 57 58 OS was 97.0% in the RT group versus 99.5% in the no further treatment group. PFS 59 60 10
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 and OS in the PET positive group was 85.9 % and 93.9% respectively with a median 4 5 follow up of 46 months. These preliminary data suggest that patients with iPET score 6 7 1 2 after three ABVD cycles have excellent prognosis with three ABVD alone but 8 9 10 longer follow up is required to assess the trade off between disease control and risks 11 12 of late treatment effects. This is especially relevant in patients for whom the risks 13 14 associated with radiotherapy may be lower, such as patients >35 years and when 15 16 irradiation of female breast tissue and/or the heart is not required. 17 18 For Peer Review 19 The H10 study from the EORTC is ongoing and was designed with randomisation to 20 21 22 experimental or standard arms. Treatment in the standard arm is 3 or 4 cycles of 23 24 ABVD for favourable (F) or unfavourable (U) disease respectively followed by INRT 25 26 30Gy + 6Gy boost to residual lesions. The experimental arm adopted a PET based 27 28 strategy with 2 cycles of ABVD followed by PET. If PET showed CMR, patients 29 30 received 3 (F) or 4 (U) cycles of ABVD and no radiotherapy. If PET was positive, 31 32 33 patients received 2 cycles of escBEACOPP. The first interim analysis of 1137 34 35 patients was recently presented (Andre et al., 2012). In the favourable group, ten 36 37 events occurred; 1 in the standard arm, 9 in the experimental arm (1y PFS 100% 38 39 and 94.9% for standard and experimental arms respectively, HR 9.36 (CI : 2.45 – 40 41 42 35.73)). In the unfavourable group, 23 events occurred; 7 in the standard arm, 16 in 43 44 the experimental arm (1y PFS 97.3% and 94.7% for standard and experimental 45 46 arms, HR = 2.42 (CI: 1.5 4.36)). The Steering Committee declared futility according 47 48 to previously set rules and considered that the risk of early relapse for non irradiated 49 50 51 patients with stage I II cHL was significantly higher than for patients receiving 52 53 standard combined modality, even for patients with early PET negativity. 54 55 Consequently the no radiotherapy arm was closed but the study continued, to 56 57 58 59 60 11
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 investigate the secondary aim to determine the effect of treatment escalation for 4 5 patients with PET positive scans. 6 7 8 Both H10 and RAPID investigated the application of a PET “response adapted 9 10 strategy” for early stage classicalHL but apparently came to opposite conclusions 11 12 13 regarding the possibility of omitting radiotherapy in patients with PET negative 14 15 scans. Final results with longer follow up of both studies will be required before firm 16 17 conclusions can be made on this promising therapeutic strategy. 18 For Peer Review 19 20 Two further studies from the German Hodgkin Study Group are examining a 21 22 response guided approach in early stage disease, (HD16, HD17) with ABVD 23 24 25 treatment for favourable disease or a combination of ABVD and escBEACOPP for 26 27 unfavourable disease. (All study identifiers are listed in table 1). Both include 28 29 randomisation to a standard arm of combined modality treatment versus an 30 31 experimental arm where radiotherapy is given to patients with iPET positive scans 32 33 34 but omitted for patients with iPET negative scans. 35 36 37 In advanced HL, trials are also testing whether treatment outcomes can be improved 38 39 in poor responders on iPET as well as safely de escalated in good responders. 40 41 42 For patients receiving ABVD chemotherapy: 43 44 45 De escalation strategies on the basis of a negative iPET include 46 47 48 randomisation to ABVD vs AVD (RATHL), 49 50 IFRT vs. no IFRT after ABVD for patients with bulky disease (HD0801). 51 52 Escalation strategies on the basis of a positive interim PET include switching to 53 54 55 BEACOPP (RATHL, HD0607, Rambam Health Care/RHC, SWOGS0816) 56 57 58 59 60 12
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 high dose chemotherapy and autologous stem cell transplant (ASCT) 4 5 (HD0801). 6 7 For patients receiving escBEACOPP chemotherapy: 8 9 10 De escalation strategies on the basis of a negative iPET include 11 12 13 14 randomisation to escBEACOPP vs ABVD (AHL 11) 15 16 randomisation to 4 vs. 8 cycles escBEACOPP (HD18) 17 18 switching toFor ABVD (RHC). Peer Review 19 20 Escalation strategies include randomisation to escBEACOPP vs escBEACOPP and 21 22 rituximab (HD18). 23 24 25 In aggressive NHL including Diffuse Large B cell Lymphoma (DLBCL), rapid 26 27 28 reduction in FDG during chemotherapy is associated with good prognosis. In studies 29 30 involving 924 patients treated with CHOP or ACVBP ± rituximab and scanned after 31 32 2 4 cycles of treatment, 2 5y PFS/EFS rates have been reported between 73 86% 33 34 for patients with CMR (Cashen et al., 2011; Haioun et al., 2005; Micallef et al., 2011; 35 36 37 Mikhaeel et al., 2005; Safar et al., 2012; Spaepen et al., 2002; D. H. Yang et al., 38 39 2011; Yoo et al., 2011; P. L. Zinzani et al., 2011). Studies from 2005 and earlier 40 41 reported poorer outcomes for patients with PET ‘positive’ scans with 2 5y PFS/EFS 42 43 rates of 0 43% (Haioun et al., 2005; Mikhaeel et al., 2005; Spaepen et al., 2002). 44 45 Two recent studies also reported poor outcomes with 3 5y PFS rates of 18 29% (D. 46 47 48 H. Yang et al., 2011; P. L. Zinzani et al., 2011) but four other studies reported more 49 50 favourable outcomes for patients with iPET positive scans (Cashen et al., 2011; 51 52 Micallef et al., 2011; Safar et al., 2012; Yoo et al., 2011) with 2 3y PFS rates of 47 – 53 54 66%. Possible reasons may be the improved prognosis in DLBCL with rituximab 55 56 57 treatment and the inflammatory induced FDG uptake associated with rituximab. In 58 59 60 13
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 this disease where salvage treatment has become less effective since the 4 5 introduction of rituximab, it is disappointing that early response assessment with PET 6 7 appears to be less predictive of primary treatment failure than initially thought. 8 9 10 Methods to improve the predictive value of early PET include the use of quantitative 11 12 13 approaches, such as measuring the reduction of the maximum SUV in the ‘hottest’ 14 15 lesion before and during treatment, referred to as ‘ ∆SUV’ (Emmanuel Itti et al., 2009; 16 17 Lin et al., 2007). Using receiver operating curves to define the best threshold to 18 For Peer Review 19 20 discriminate between good and poor treatment response groups, the French GELA 21 22 group have published data to suggest that ‘ ∆SUV’ predicts outcome better than 23 24 visual assessment in DLBCL (Casasnovas et al., 2011; Emmanuel Itti et al., 2009; E. 25 26 Itti et al., 2013; Lin et al., 2007). The optimal cut off varies according to when the 27 28 29 scan is performed during treatment, as FDG uptake declines during chemotherapy, 30 31 so a higher threshold of 70% is used at 4 cycles to define response (Emmanuel Itti et 32 33 al., 2009). The ∆SUV is being used to measure response in the PETAL study 34 35 (Duhrsen et al., 2009). After 2 cycles of R CHOP, poor responders with ∆SUV < 36 37 38 66% are randomised to receive either escalated treatment with 6 cycles of a B ALL 39 40 regimen or 6 R CHOP. Good responders with ∆SUV ≥66% are randomised to 41 42 receive a further 4 or 6 cycles of R CHOP. Using the 66% cut off, one retrospective 43 44 45 study reported that ∆SUV was predictive of response in DLBCL (Safar et al., 2012) 46 47 but another was unable to demonstrate an association between ∆SUV with PFS 48 49 (Pregno et al., 2012). Other published studies have reported that ∆SUV is predictive 50 51 52 of response but using different cut offs for the ∆SUV of 76% and 92% respectively 53 54 (Fuertes et al., 2013; D. H. Yang et al., 2013). The application of ∆SUV clearly 55 56 requires further study and is dependent on proper standardisation of PET methods, 57 58 59 60 14
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 including scan acquisition, cross calibration of cameras and appropriate 4 5 maintenance and quality control of imaging equipment prior to widespread use. 6 7 Guidelines have been published regarding the best methods to perform PET for 8 9 10 multicentre trials which are also recommended for best clinical practice and make 11 12 such quantitative applications a realistic future goal (Boellaard et al., 2010). 13 14 15 In Follicular Lymphoma with high tumour burden, interim PET is predictive of 16 17 response to initial therapy, but the end of treatment scan appears to be a better 18 For Peer Review 19 predictor (Dupuis et al., 2012), perhaps because the response to chemotherapy is 20 21 22 slower than in HL and DLBCL. 23 24 25 Currently there is insufficient evidence to change standard treatment based on the 26 27 results of an interim PET CT scan. Nonetheless an interim scan may be helpful to 28 29 confirm that patients are responding to treatment and exclude progression of 30 31 disease. PET CT could replace CT in the interim setting if a mid treatment scan is 32 33 34 indicated. The results of the PET CT scan should always be interpreted in the 35 36 context of the clinical situation and anticipated prognosis of disease, ideally in a 37 38 multidisciplinary setting. If an interim scan shows a complete metabolic response, 39 40 then there is no need to perform a treatment at the end of therapy if the clinical 41 42 course is uncomplicated (M.; Hutchings et al., 2006; Strobel et al., 2007). 43 44 45 What is the role of PET in end-of-treatment remission assessment? 46 47 48 There is a high predictive value for remission assessment using FDG PET. In HL 49 50 51 the NPV for ≥ 2 yPFS is 94 100% for patients treated with ABVD (Barnes et al., 52 53 2011; Cerci, Trindade, et al., 2010; Spaepen et al., 2001) with PPV of 91 92% 54 55 (Cerci, Trindade, et al., 2010; Spaepen et al., 2001) for all stages but 46% in early 56 57 58 59 60 15
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 stage non bulky disease, again reflecting the good prognosis of patients in this group 4 5 (Barnes et al., 2011). 6 7 8 In aggressive NHL including DLBCL, the NPV for end of treatment PET is also high, 9 10 reported at 90 100% (Micallef et al., 2011; Pregno et al., 2012; Spaepen et al., 2001) 11 12 13 but the PPV is lower and more variable, reported at 50 82% (Micallef et al., 2011; 14 15 Pregno et al., 2012; Spaepen et al., 2001). The lower PPV can be attributed to the 16 17 non specific nature of FDG as a tracer which is taken up in inflammation, such as 18 For Peer Review 19 may be seen following chemotherapy and radiotherapy treatment. For this reason, it 20 21 22 is recommended that scanning takes place >10 days after chemotherapy, two weeks 23 24 after GCSF treatment and three months after radiotherapy (Boellaard et al., 2010). 25 26 Biopsy confirmation of suspected residual disease is advisable before giving second 27 28 line treatment in HL and aggressive NHL, however if biopsy is difficult or is negative 29 30 but the clinical suspicion of residual disease is high, additional treatment may be 31 32 33 considered in carefully selected cases. If the clinical suspicion of residual disease is 34 35 low, an alternative approach would be to perform an interval scan. 36 37 38 The improved remission assessment using PET led to its incorporation in the 39 40 International Working Group (IWG) criteria in 2007. Residual masses with negative 41 42 FDG uptake were included in the Complete Response Category (Bruce D. Cheson et 43 44 45 al., 2007). In a previous study in NHL this led to better discrimination of response 46 47 categories and the removal of the category of CR ‘unconfirmed’ as patients were 48 49 reclassified as CR or PR according to FDG uptake (Juweid et al., 2005). Nowadays 50 51 an end of treatment scan is usually performed in HL and DLBCL to confirm 52 53 54 remission or to direct biopsy in the case of residual FDG uptake if further treatment is 55 56 being considered. 57 58 59 60 16
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 FDG PET may have a role in selecting patients with advanced HL who will benefit 4 5 from consolidation radiotherapy after a full course of chemotherapy. In patients 6 7 treated with escBEACOPP in the HD 15 study, 739 patients with residual masses 8 9 10 >2.5cm were treated with radiotherapy according to the results of an end of 11 12 treatment PET scan (Engert et al., 2012). 191 patients with PET positive residual 13 14 masses received radiotherapy. Patients with negative residual masses were not 15 16 treated with radiotherapy and had the same PFS as patients with complete 17 18 For Peer Review 19 radiological response. This strategy reduced the use of radiotherapy in advanced 20 21 stage HL from 70% in HD12 to 11% in HD15. Radiotherapy is therefore not required 22 23 in advanced stage HL patients treated with BEACOPP who achieve complete 24 25 metabolic response after chemotherapy, even in the presence of a residual mass. 26 27 However it is important to note that these results may not apply to ABVD treated 28 29 30 patients or patients with early stage bulky disease where similar evidence is lacking. 31 32 33 In high tumor burden FL, end of treatment PET appears to be a good predictor of 34 35 outcome. Two studies involving 122 and 116 patients respectively have recently 36 37 reported inferior outcomes for patients according to PET CT after rituximab and 38 39 chemotherapy treatment (Dupuis et al., 2012; Trotman et al., 2011). PFS rates of 40 41 42 33% and 51% for patients with residual uptake were reported compared to 71% and 43 44 87% for patients with CMR. OS rates were 78% and 88% for patients with residual 45 46 uptake compared to 96% and 100% for patients with CMR. Maintenance rituximab 47 48 was not given in one study (Dupuis et al., 2012) and in the other too few patients 49 50 51 were included who had received maintenance rituximab to demonstrate a difference 52 53 in PFS according to maintenance therapy (Trotman et al., 2011). Whilst the role of 54 55 PET in patients who receive maintenance rituximab may require further clarification, 56 57 both studies found that response assessment with PET was prognostic whilst CT 58 59 60 17
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 was not. In the prospective study, where a priori criteria were defined for PET 4 5 reporting, a visual graded response assessment using the Deauville criteria were 6 7 superior to 2007 IWG criteria (Dupuis et al., 2012). These data suggest that 8 9 10 evaluating patients for trials with novel agents after initial treatment is best 11 12 undertaken with PET CT. 13 14 15 What is meant by a PET negative or positive scan? 16 17 18 PET scans are oftenFor referred Peer to as ‘negative’ Review or ‘positive’ but FDG uptake represents 19 20 a continuum. The likelihood of malignancy increases with the intensity of FDG 21 22 uptake. The Guy’s and St Thomas’ group reported PET scans using 3 categories as 23 24 25 ‘negative’ with ‘minimal residual uptake’ or ‘positive’ (Hutchings et al., 2005; 26 27 Mikhaeel et al., 2005) and reported that the interpretation of minimal residual uptake 28 29 differed according to subtype and stage. For example, the PFS of patients with 30 31 limited stage HL and aggressive NHL was similar at interim for patients with no 32 33 34 uptake and patients with minimal residual uptake, likely due to the effectiveness of 35 36 treatment (Hutchings et al., 2005; Mikhaeel et al., 2005). Conversely minimal 37 38 residual uptake in advanced stage aggressive NHL was predictive of poor prognosis 39 40 (Mikhaeel et al., 2005). The interpretation of FDG uptake is also time dependent. 41 42 The International Harmonisation Project (IHP) criteria which were recommended for 43 44 45 end of treatment assessment, chose to use the mediastinum to define a ‘negative’ 46 47 scan in lesions ≥ 2cm or the adjacent background in smaller lesions (Juweid et al., 48 49 2007). However uptake higher than this is often associated with good prognosis, 50 51 especially during the course of treatment (Andrea Gallamini et al., 2007). The need 52 53 54 for criteria that could be interpreted according to clinical context and timing in relation 55 56 to chemotherapy led to the development of a five point scale which may better reflect 57 58 differing degrees of FDG uptake. This scale was recommended for reporting PET at 59 60 18
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 the first international workshop on PET and lymphoma held in Deauville and is often 4 5 referred to as the ‘Deauville criteria’ (Meignan, Gallamini, et al., 2009) (Table 2). The 6 7 five point scale has good interobserver agreement (Sally F. Barrington et al., 2010; 8 9 10 Biggi et al., 2013; Dupuis et al., 2012; Furth et al., 2011; Le Roux et al., 2011). The 11 12 scale appears to improve the PPV (Dupuis et al., 2012; Le Roux et al., 2011; D. H. 13 14 Yang et al., 2011) if higher thresholds than the mediastinum are used to differentiate 15 16 good from less good response whilst maintaining the high NPV compared with 2007 17 18 For Peer Review 19 criteria, especially for interim scans. It is being used in response adapted trials 20 21 (RAPID, RATHL, HD0607,NCT0822120,IELSG37, identifiers in Table1) with the 22 23 advantage that the threshold of FDG uptake chosen to define response can be 24 25 higher for a trial involving escalation (to avoid risk of over treatment) than a trial 26 27 investigating de escalation (to avoid under treatment). Scores 1,2,3 were 28 29 30 considered to represent a negative scan in the UK led RATHL study with patients 31 32 with scores 4,5 escalated to BEACOPP from ABVD. Scores 1, 2 were however used 33 34 to define a negative scan in the UK RAPID study where patients with early stage 35 36 non bulky disease and a negative scan were randomised to radiotherapy or no 37 38 39 further treatment after 3 cycles of ABVD. 40 41 42 The use of the five point scale relies on consistency in scanning conditions for serial 43 44 scans and attention to patient preparation, scan acquisition and the quality control of 45 46 imaging equipment as well as reporting methods is crucial (Boellaard et al., 2010). 47 48 49 What confounding factors may affect the use of FDG PET in lymphoma 50 51 management? 52 53 54 FDG is not specific for malignancy; uptake occurs in inflammatory cells and infection 55 56 57 which also have increased glucose metabolism. Indeed it has been suggested that 58 59 60 19
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 one reason why FDG is a good biomarker in HL is its ability to image inflammatory 4 5 cells in the tumour microenvironment (A Gallamini, 2010). Clinicians must be aware 6 7 of potential confounding causes of increased FDG (S. F. Barrington & O'Doherty, 8 9 10 2003; Cook et al., 2004) including infection, inflammation, granulomatous disease 11 12 (Figure 4), synchronous malignancy and physiological variants such as thymic 13 14 hyperplasia. It is important to question findings that are at variance with the clinical 15 16 course or where there is a ‘mixed response’ with apparent improvement in some 17 18 For Peer Review 19 areas of disease, but persistent or increased FDG uptake or new lesions elsewhere. 20 21 These situations are best discussed in a multidisciplinary team. 22 23 24 What is the role in relapse and pre transplant assessment of PET? 25 26 27 PET can be used for restaging of patients at relapse as it is used in staging of de 28 29 novo lymphomas (Elstrom et al., 2008; Janikova et al., 2008; Schaefer et al., 2004). 30 31 For patients undergoing autologous stem cell transplant (ASCT) for relapsed or 32 33 34 refractory disease, a PET scan performed after salvage treatment has prognostic 35 36 value. Patients with a positive scan are 3 7 times more likely to relapse or progress 37 38 than patients with a negative scan (Terasawa et al., 2010). Series are mostly 39 40 retrospective and have used different salvage regimens, but all appear to support a 41 42 role for PET in pre transplant assessment with ASCT with PFS rates of 23 41% 43 44 45 reported for patients with residual uptake and 71 82% for patients with CMR 46 47 (Devillier et al., 2012; Mocikova et al., 2011; Moskowitz et al., 2012; Smeltzer et al., 48 49 2011; Sucak et al., 2011). It remains controversial whether to offer transplantation to 50 51 patients with less than CMR, with some series reporting successful outcomes in up 52 53 54 to 40% of PET positive patients or to offer extended salvage therapy on the basis of 55 56 a positive scan (Moskowitz et al., 2012). A PET response adapted approach has 57 58 recently been reported to select patients with HL for transplantation(Thomson et al., 59 60 20
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 2013). Patients with CMR on PET, defined as scores 1 3 on Deauville criteria were 4 5 offered ASCT following salvage, whilst patients who did not achieve CMR with at 6 7 least stable disease and a suitable donor proceeded to allograft. 4y OS for 61 8 9 10 patients in the study was 77% with 3 y PFS and OS of 86% and 93% respectively for 11 12 patients undergoing ASCT and 68% and 88% undergoing allograft. PET is also a 13 14 reliable early end point which will prove valuable in testing novel agents such as 15 16 SGN 35 (Hutchings, 2011). Post transplant assessment with PET has been 17 18 For Peer Review 19 reported as being predictive of PFS/OS in a small study with 43 patients with HL 20 21 (Sucak et al., 2011) but not in another study of 68 patients with HL and NHL (Palmer 22 23 et al., 2011). Prior to reduced intensity conditioning allogeneic transplant, one study 24 25 in a mixed population of 80 patients (Dodero et al., 2010) reported that PET status 26 27 was predictive of PFS and OS, whilst another in mixed population of 80 patients did 28 29 30 not (Lambert et al., 2010). The authors of the latter study reported that PET 31 32 detected relapse post allogeneic transplant earlier than CT and that PET might be a 33 34 useful tool during surveillance to select PET positive patients for donor lymphocyte 35 36 infusion. These patients experienced a low incidence of graft versus host disease. 37 38 39 Is there a role for PET in surveillance of patients ? 40 41 42 Relapses are more likely to be detected in symptomatic than asymptomatic patients 43 44 45 (Goldschmidt et al., 2011) although surveillance scanning with PET has been 46 47 reported to detect unsuspected relapses in up to 10% of patients with HL and 48 49 aggressive NHL (Cheah et al., 2013; Pier Luigi Zinzani et al., 2007). Lead time bias 50 51 is a potential problem in studies reporting surveillance imaging as earlier detection of 52 53 54 disease may give false impressions of longer survival. As yet, no data exist to 55 56 demonstrate that earlier detection improves patient outcomes. The positive 57 58 predictive value for surveillance scans is variable, ranging between 21% 74% for 59 60 21
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 patients with HL and aggressive NHL in first remission (Avivi et al., 2013; Cheah et 4 5 al., 2013; Tarec El Galaly et al., 2011; Lee et al., 2010). False positive scans can 6 7 lead to unnecessary biopsies and patient anxiety. The cost to detect a single event 8 9 10 was estimated at US$100 000 in one study (Lee et al., 2010). CT was similarly 11 12 associated with a low PPV of 29% but lower financial cost. The associated radiation 13 14 burden must also be considered. Currently there is no clear evidence to support 15 16 surveillance imaging with PET CT. However, it may be justified in selected cases 17 18 For Peer Review 19 with high risk of relapse (Cheah et al., 2013; T El Galaly et al., 2013). 20 21 22 What is the Radiation dose typically associated with PET-CT? 23 24 25 The effective dose for a half body PET scan is 8mSv for 400MBq FDG, the UK 26 27 diagnostic reference level ("Administration of Radioactive Substances Advisory 28 29 Committee Notes for Guidance," 2006,revised 2011). With recent advances including 30 31 3D imaging, time of flight and better reconstruction algorithms, lower activities could 32 33 34 be used or faster imaging times employed using the same activity. The effective 35 36 dose could be reduced as low as 4 5 mSv with the most up to date cameras 37 38 (Boellaard et al., 2010). If a low dose CT scan is used, the effective dose is 7 9mSv, 39 40 with a combined effective dose of around 11 17mSv. This equates to 5 8 years of 41 42 natural background radiation. The National Reference Dose Level for a full dose 43 44 45 contrast enhanced CT of the chest, abdomen and pelvis of 940 mGycm (Shrimpton 46 47 et al., 2005) corresponds to an Effective Dose of approximately 16 mSv ("The 2007 48 49 Recommendations of the International Commission on Radiological Protection," 50 51 2007) which is comparable to a PET CT examination. 52 53 54 55 56 57 58 59 60 22
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 What about the use of PET-CT for T-cell Lymphomas? 4 5 6 Most reports about PET CT involve patients with B cell malignancy but some reports 7 8 in aggressive NHL have included patients with T cell lymphomas. As a separate 9 10 entity however, there are limited data reporting FDG PET in patients with T cell and 11 12 13 NK cell lymphomas. Most are FDG avid, with higher uptake in more aggressive 14 15 subtypes but lower uptake in cutaneous disease (Feeney et al., 2010; P. L. Zinzani, 16 17 2011). Patients with Mycosis Fungoides have higher FDG uptake in the presence of 18 For Peer Review 19 large cell transformation and it has been suggested that suspected transformation 20 21 22 may be an indication for PET CT, analogous to its use in Follicular Lymphoma 23 24 (Feeney et al., 2010). Higher uptake is also seen in systemic manifestations of 25 26 cutaneous lymphomas and a role in the detection of visceral involvement has been 27 28 suggested as this alters management (Otero et al., 2009). Although PET also 29 30 detects more lesions than CT in nodal and leukaemic variants of T cell lymphomas, 31 32 33 this rarely affects management (Casulo et al., 2013). Interim assessment with FDG 34 35 was reported to be predictive of PFS, but not OS, in one study of 50 patients with 36 37 peripheral T cell lymphomas (Casulo et al., 2013), but not in another study involving 38 39 54 patients (Cahu et al., 2011); in the latter study the post therapy scan was not 40 41 42 predictive of outcome. It is important not to extrapolate data relating to B cell 43 44 lymphomas to patients with T cell lymphomas. As yet, there is no clearly defined 45 46 role for FDG PET in this disease group with the possible exceptions of excluding 47 48 visceral involvement with Mycosis Fungoides and suspected transformation. 49 50 51 Because the numbers of patients are small, prospective multicentre trials are 52 53 required. A UK study opened in 2012 investigating the response rate of CHOP 54 55 versus gemcitabine, methylprednisolone and cisplatin and is prospectively 56 57 58 59 60 23
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 measuring the complete metabolic response rate in patients with T cell lymphoma 4 5 (Chemo T, Table 1). 6 7 8 Conclusion 9 10 11 PET CT has an important role in the modern management of lymphoma, including 12 13 14 staging, response and remission assessment and the selection of patients with 15 16 refractory/relapsed disease for transplantation with HL and NHL, summarised in 17 18 Table 3. For Peer Review 19 20 21 The role of response adapted treatment in HL and DLBCL according to interim PET 22 23 is being explored in multicentre international trials. Preliminary reports from RAPID 24 25 and H10 studies are emerging on the role of iPET in selecting patients who may not 26 27 28 require radiotherapy in early stage classical HL but final reports of these studies are 29 30 awaited. Data relating to the use of FDG in T cell lymphomas is limited and further 31 32 studies are required. In cutaneous T cell lymphoma, PET does not have a routine 33 34 role in staging or response assessment with the exception of the detection of visceral 35 36 37 involvement in Mycosis Fungoides. 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 4 5 6 7 Figures 8 9 10 Figure 1 Coronal slices with low dose CT (left), PET (middle) and fused (right) 11 12 images are shown of a patient with HL. Note the PET and fused images are 13 14 15 displayed to a maximum SUV of 10 (colour scale on far right of figure, CT Hounsfield 16 17 units displayed in grey). The SUV fixed scale is used for reporting at our Centre. 18 For Peer Review 19 20 Figure 2 Coronal slices (low dose CT, PET and fused images) show focal uptake 21 22 (arrowed) in the spleen which is not enlarged and has normal appearances on CT. 23 24 25 Figure 3 Sagittal slices (low dose CT, PET and fused images) are shown of a patient 26 27 with DLBCL and marrow involvement, pre (part A) and post treatment (part B). Note 28 29 30 how some vertebrae eg T12 with increased uptake become photopaenic with 31 32 ablation of marrow, whilst other vertebrae with normal uptake at baseline have 33 34 increased uptake relative to baseline due to the effects of chemotherapy. The 35 36 images demonstrate a ‘mirror’ effect. 37 38 39 Figure 4 Coronal slices (low dose CT, PET and fused images) are shown of a patient 40 41 42 with sarcoid like reaction with a typical distribution of FDG uptake in nodes in the 43 44 mediastinum and within the lung. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25
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1 2 Barrington&Mikhaeel resubmitted 3Sept2013 3 4 5 Table 1 Registration details of selected Clinical Trials 6 7 Study group Trial identifier Patient group Clinical trial registration details 8 9 GHSG HD16 Early stage HL (http://www.clinicaltrials.gov/ NCT00736320 ) 10 GHSG HD17 Early stage HL (http://www.clinicaltrials.gov/ NCT01356680 ) 11 UK-NCRI RATHL Advanced HL http://www.clinicaltrials.gov/ct2/show/NCT00678327 12 GITIL HD0801 Advanced HL http://www.clinicaltrials.gov/ct2 /NCT00784537 13 GITIL HD0607For PeerAdvanced HL Reviewhttp://www.clinicaltrials.gov/ct2/show/NCT00795613 14 Rambam Health Care RHC Advanced HL http://www.clinicaltrials.gov/ct2/show/NCT00392314 15 US -SWOG SWOG0816 Advanced HL http://www.clinicaltrials.gov/ct2/show/NCT00822120 16 LYSA AHL11 Advanced HL http://clinicaltrials.gov/ct2/show/NCT01358747 17 GHSG HD18 Advanced HL http://www.clinicaltrials.gov/ct2/show/NCT00515554 18 19 US-SWOG& CALG-B NCT0822120 Advanced HL http://clinicaltrials.gov/ct2/ NCT00822120 20 IELSG IELSG37 Primary mediastinal B http://clinicaltrials.gov/ct2 /NCT01599559 21 cell lymphoma 22 UK-NCRI Chemo T T cell lymphpma http://www.clinicaltrials.gov/ct2/NCT01719835 23 24 25 Key to abbreviations 26 27 GHSG German Hodgkin Study Group 28 29 NCRI National Cancer Research Institute (UK) 30 31 GITIL Gruppo Italiano Terapie Innovative nei Linfomi 32 33 34 SWOG South Western Oncology Group 35 36 LYSA Lymphoma Study Association 37 38 CALG B Cancer and Leukemia Group B 39 40 IELSG International Extranodal Lymphoma Study Group 41 42 26 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 84 of 115
1 2 Barrington&Mikhaeel resubmitted 3Sept2013 3 4 5 6 7 8 Table 2 – The Five point scale (5PS/Deauville criteria) 9 10 11 The 5PS scores the most intense residual uptake in a site of initial disease as: 12 13 1. no uptake For Peer Review 14 15 2. uptake ≤ mediastinum ** 16 17 3. uptake > mediastinum but ≤ liver 18 19 20 4. uptake moderately higher than liver 21 22 5. uptake markedly higher than liver and/or new lesions 23 24 X new areas of uptake unlikely to be related to lymphoma 25 26 27 **NOTE if MBP ≥ liver activity, the uptake within lesions should be compared with liver (uptake 28 lesion < liver is score 2; lesion = liver is score 3) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 27 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 85 of 115 British Journal of Haematology
1 2 Barrington&Mikhaeel resubmitted 3Sept2013 3 4 5 6 7 8 9 10 11 Table 3 Indications and Benefits for using PET CT in Lymphomas 12 13 For Peer Review 14 15 Indication/s Benefit/s 16 17 PRE TREATMENT 18 19 Staging of patients with FDG avid Lymphomas Increased staging accuracy especially for extranodal disease 20 21 22 Improved treatment selection 23 24 Improved accuracy of response assessment and improved 25 26 reporter agreement for response scans 27 28 To direct biopsy in suspected transformation of FL Improved disease characterisation and treatment selection 29 30 31 Assessment of bone marrow involvement in HL and DLBCL Improved accuracy compared to biopsy 32 33 Avoidance of morbidity associated with bone marrow biopsy 34 35 Radiotherapy planning for patients with HL and DLBCL More refined definition of radiotherapy volume + less irradiation 36 37 of normal tissue. 38 39 40 41 42 28 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 86 of 115
1 2 Barrington&Mikhaeel resubmitted 3Sept2013 3 4 5 Essential for techniques less than IFRT 6 7 8 DURING TREATMENT 9 10 Mid treatment imaging to monitor response in HL and DLBCL More accurate monitoring of response than mid treatment CT 11 12 (and earlier assessment) 13 For Peer Review 14 No evidence to modify treatment as yet, but useful to detect poor 15 16 17 or no response early 18 19 POST TREATMENT 20 21 End of treatment assessment in HL DLBCL and FL (unless More accurate assessment of remission than CT especially in 22 23 patients have had mid treatment imaging showing complete cases of CRu or PR 24 25 26 metabolic response) to confirm disease remission or to direct Part of IWG criteria for response assessment 27 28 biopsy if residual disease is suspected Possible role to select patients for consolidation RT (e.g. 29 30 advanced stage classical HL after BEACOPP) 31 32 RELAPSE 33 34 35 Pre transplant assessment in patients undergoing ASCT with HL More accurate and prognostic than CT 36 37 or DLBCL 38 39 40 41 42 29 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 87 of 115 British Journal of Haematology
Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 References 4 5 6 7 The 2007 Recommendations of the International Commission on Radiological 8 9 10 Protection. (2007). Annals of the International Commission on Radiological 11 12 Protection, 37 (2 4). 13 14 . Administration of Radioactive Substances Advisory Committee Notes for Guidance. 15 16 (2006,revised 2011). Oxford: Health Protection Agency. 17 18 For Peer Review 19 Andre, M. P., Reman, O., Federico, M., Girinski, T., Brice, P., Brusamolino, E., 20 21 Ferme, C., vander Maazen, R., Bellei, M., Sebban, C., Morschhauser, F., 22 23 Lugtenburg, E., Stamatoulas, A., Fortpied, C., Meignan, M., Versari, A., 24 25 Hutchings, M., & Raemaekers, J. (2012). Interim Analysis of the Randomized 26 27 Eortc/Lysa/Fil Intergroup H10 Trial On Early PET Scan Driven Treatment 28 29 30 Adaptation in Stage I/II Hodgkin Lymphoma. Blood,ASH Annual Meeting 31 32 Abstracts 120 , 549. 33 34 Avivi, I., Zilberlicht, A., Dann, E. J., Leiba, R., Faibish, T., Rowe, J. M., & Bar 35 36 Shalom, R. (2013). Strikingly high false positivity of surveillance FDG PET/CT 37 38 39 scanning among patients with diffuse large cell lymphoma in the rituximab 40 41 era. [Comparative Study 42 43 Evaluation Studies]. American journal of hematology, 88 (5), 400 405. 44 45 Barnes, J. A., LaCasce, A. S., Zukotynski, K., Israel, D., Feng, Y., Neuberg, D., 46 47 Toomey, C. E., Hochberg, E. P., Canellos, G. P., & Abramson, J. S. (2011). 48 49 50 End of treatment but not interim PET scan predicts outcome in nonbulky 51 52 limited stage Hodgkin's lymphoma. Annals of Oncology, 22 (4), 910 915. doi: 53 54 10.1093/annonc/mdq549 55 56 57 58 59 60 30
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Barrington, S. F., MacKewn, J. E., Schleyer, P., Marsden, P. K., Mikhaeel, N. G., 4 5 Qian, W., Mouncey, P., Patrick, P., Popova, B., Johnson, P., Radford, J., & 6 7 O'Doherty, M. J. (2011). Establishment of a UK wide network to facilitate the 8 9 10 acquisition of quality assured FDG PET data for clinical trials in lymphoma. 11 12 Annals of Oncology, 22 (3), 739 745. doi: 10.1093/annonc/mdq428 13 14 Barrington, S. F., & O'Doherty, M. J. (2003). Limitations of PET for imaging 15 16 lymphoma. European Journal of Nuclear Medicine and Molecular Imaging, 30 , 17 18 For Peer Review 19 S117 S127. doi: 10.1007/s00259 003 1169 2 20 21 Barrington, S. F., Qian, W., Somer, E. J., Franceschetto, A., Bagni, B., Brun, E., 22 23 Almquist, H., Loft, A., Hojgaard, L., Federico, M., Gallamini, A., Smith, P., 24 25 Johnson, P., Radford, J., & O'Doherty, M. J. (2010). Concordance between 26 27 four European centres of PET reporting criteria designed for use in 28 29 30 multicentre trials in Hodgkin lymphoma. European Journal of Nuclear 31 32 Medicine and Molecular Imaging, 37 (10), 1824 1833. doi: 10.1007/s00259 33 34 010 1490 5 35 36 Berthet, L., Cochet, A., Kanoun, S., Berriolo Riedinger, A., Humbert, O., Toubeau, 37 38 39 M., Dygai Cochet, I., Legouge, C., Casasnovas, O., & Brunotte, F. (2013). In 40 41 Newly Diagnosed Diffuse Large B Cell Lymphoma, Determination of Bone 42 43 Marrow Involvement with 18F FDG PET/CT Provides Better Diagnostic 44 45 Performance and Prognostic Stratification Than Does Biopsy. J Nucl Med, 46 47 54 (8), 1244 1250. 48 49 50 Biggi, A., Gallamini, A., Chauvie, S., Hutchings, M., Kostakoglu, L., Gregianin, M., 51 52 Meignan, M., Malkowski, B., Hofman, M. S., & Barrington, S. F. (2013). 53 54 International Validation Study for Interim PET in ABVD Treated, Advanced 55 56 57 58 59 60 31
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Stage Hodgkin Lymphoma: Interpretation Criteria and Concordance Rate 4 5 Among Reviewers. [Journal article]. J Nucl Med . 6 7 Boellaard, R., O'Doherty, M. J., Weber, W. A., Mottaghy, F. M., Lonsdale, M. N., 8 9 10 Stroobants, S. G., Oyen, W. J., Kotzerke, J., Hoekstra, O. S., Pruim, J., 11 12 Marsden, P. K., Tatsch, K., Hoekstra, C. J., Visser, E. P., Arends, B., 13 14 Verzijlbergen, F. J., Zijlstra, J. M., Comans, E. F., Lammertsma, A. A., Paans, 15 16 A. M., Willemsen, A. T., Beyer, T., Bockisch, A., Schaefer Prokop, C., 17 18 For Peer Review 19 Delbeke, D., Baum, R. P., Chiti, A., & Krause, B. J. (2010). FDG PET and 20 21 PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. 22 23 European Journal of Nuclear Medicine and Molecular Imaging, 37 (1), 181 24 25 200. 26 27 Cahu, X., Bodet Milin, C., Brissot, E., Maisonneuve, H., Houot, R., Morineau, N., 28 29 30 Solal Celigny, P., Godmer, P., Gastinne, T., Moreau, P., Moreau, A., Lamy, 31 32 T., Kraber Bodere, F., & Le Gouill, S. (2011). 18F fluorodeoxyglucose 33 34 positron emission tomography before, during and after treatment in mature 35 36 T/NK lymphomas: a study from the GOELAMS group. [Research Support, 37 38 39 Non U.S. Gov't]. Annals of oncology : official journal of the European Society 40 41 for Medical Oncology / ESMO, 22 (3), 705 711. 42 43 Campbell, J., Seymour, J. F., Matthews, J., Wolf, M., Stone, J., & Juneja, S. (2006). 44 45 The prognostic impact of bone marrow involvement in patients with diffuse 46 47 large cell lymphoma varies according to the degree of infiltration and 48 49 50 presence of discordant marrow involvement. [Comparative Study 51 52 Multicenter Study]. European journal of haematology, 76 (6), 473 480. 53 54 Casasnovas, R. O., Meignan, M., Berriolo Riedinger, A., Bardet, S., Julian, A., 55 56 Thieblemont, C., Vera, P., Bologna, S., Briere, J., Jais, J. P., Haioun, C., 57 58 59 60 32
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Coiffier, B., Morschhauser, F., & Gela. (2011). SUVmax reduction improves 4 5 early prognosis value of interim positron emission tomography scans in 6 7 diffuse large B cell lymphoma. Blood, 118 (1), 37 43. doi: 10.1182/blood 2010 8 9 10 12 327767 11 12 Cashen, A. F., Dehdashti, F., Luo, J., Homb, A., Siegel, B. A., & Bartlett, N. L. 13 14 (2011). (18)F FDG PET/CT for Early Response Assessment in Diffuse Large 15 16 B Cell Lymphoma: Poor Predictive Value of International Harmonization 17 18 For Peer Review 19 Project Interpretation. Journal of Nuclear Medicine, 52 (3), 386 392. doi: 20 21 10.2967/jnumed.110.082586 22 23 Casulo, C., Schoder, H., Feeney, J., Lim, R., Maragulia, J., Zelenetz, A. D., & 24 25 Horwitz, S. (2013). FDG PET in the Staging and Prognosis of T cell 26 27 Lymphoma. [Journal article]. Leukemia & lymphoma (in press) . 28 29 30 Cerci, J. J., Pracchia, L. F., Linardi, C. C. G., Pitella, F. A., Delbeke, D., Izaki, M., 31 32 Trindade, E., Soares Junior, J., Buccheri, V., & Meneghetti, J. C. (2010). 33 34 (18)F FDG PET After 2 Cycles of ABVD Predicts Event Free Survival in Early 35 36 and Advanced Hodgkin Lymphoma. Journal of Nuclear Medicine, 51 (9), 1337 37 38 39 1343. doi: 10.2967/jnumed.109.073197 40 41 Cerci, J. J., Trindade, E., Pracchia, L. F., Pitella, F. A., Linardi, C. C., Soares, J., Jr., 42 43 Delbeke, D., Topfer, L. A., Buccheri, V., & Meneghetti, J. C. (2010). Cost 44 45 effectiveness of positron emission tomography in patients with Hodgkin's 46 47 lymphoma in unconfirmed complete remission or partial remission after first 48 49 50 line therapy. [Research Support, Non U.S. Gov't]. J Clin Oncol, 28 (8), 1415 51 52 1421. 53 54 Cheah, C. Y., Hofman, M. S., Dickinson, M., Wirth, A., Westerman, D., Harrison, S. 55 56 J., Burbury, K., Wolf, M., Januszewicz, H., Herbert, K., Prince, H. M., Carney, 57 58 59 60 33
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 D. A., Ritchie, D. S., Hicks, R. J., & Seymour, J. F. (2013). Limited role for 4 5 surveillance PET CT scanning in patients with diffuse large B cell lymphoma 6 7 in complete metabolic remission following primary therapy. British Journal of 8 9 10 Cancer, 109 (2), 312 317. 11 12 Chen, Y. K., Yeh, C. L., Tsui, C. C., Liang, J. A., Chen, J. H., & Kao, C. H. (2011). F 13 14 18 FDG PET for evaluation of bone marrow involvement in non Hodgkin 15 16 lymphoma: a meta analysis. [Meta Analysis 17 18 For Peer Review 19 Research Support, Non U.S. Gov't]. Clinical Nuclear Medicine, 36 (7), 553 559. 20 21 Cheson, B. D. (2012). Hodgkin lymphoma: protecting the victims of our success. 22 23 [Comment 24 25 Editorial]. J Clin Oncol, 30 (36), 4456 4457. 26 27 Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. 28 29 30 J., Coiffier, B., Fisher, R. I., Hagenbeek, A., Zucca, E., Rosen, S. T., 31 32 Stroobants, S., Lister, T. A., Hoppe, R. T., Dreyling, M., Tobinai, K., Vose, J. 33 34 M., Connors, J. M., Federico, M., & Diehl, V. (2007). Revised response criteria 35 36 for malignant lymphoma. Journal of Clinical Oncology, 25 (5), 579 586. doi: 37 38 39 10.1200/jco.2006.09.2403 40 41 Cook, G. J., Wegner, E. A., & Fogelman, I. (2004). Pitfalls and artifacts in 18FDG 42 43 PET and PET/CT oncologic imaging. [Research Support, Non U.S. Gov't 44 45 Review]. Seminars in Nuclear Medicine, 34 (2), 122 133. 46 47 Devillier, R., Coso, D., Castagna, L., Brenot Rossi, I., Anastasia, A., Chiti, A., Ivanov, 48 49 50 V., Schiano, J. M., Santoro, A., Chabannon, C., Balzarotti, M., Blaise, D., & 51 52 Bouabdallah, R. (2012). Positron emission tomography response at the time 53 54 of autologous stem cell transplantation predicts outcome of patients with 55 56 57 58 59 60 34
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage 4 5 therapy. Haematologica, 97 (7), 1073 1079. 6 7 Dodero, A., Crocchiolo, R., Patriarca, F., Miceli, R., Castagna, L., Ciceri, F., 8 9 10 Bramanti, S., Frungillo, N., Milani, R., Crippa, F., Fallanca, F., Englaro, E., & 11 12 Corradini, P. (2010). Pretransplantation 18 F Fluorodeoxyglucose Positron 13 14 Emission Tomography Scan Predicts Outcome in Patients With Recurrent 15 16 Hodgkin Lymphoma or Aggressive Non Hodgkin Lymphoma Undergoing 17 18 For Peer Review 19 Reduced Intensity Conditioning Followed by Allogeneic Stem Cell 20 21 Transplantation. Cancer, 116 (21), 5001 5011. doi: 10.1002/cncr.25357 22 23 Duhrsen, U., Huttmann, A., Jockel, K. H., & Muller, S. (2009). Positron emission 24 25 tomography guided therapy of aggressive non Hodgkin lymphomas the 26 27 PETAL trial. Leukemia & lymphoma, 50 (11), 1757 1760. doi: 28 29 30 10.3109/10428190903308031 31 32 Dupuis, J., Berriolo Riedinger, A., Julian, A., Brice, P., Tychyj Pinel, C., Tilly, H., 33 34 Mounier, N., Gallamini, A., Feugier, P., Soubeyran, P., Colombat, P., Laurent, 35 36 G., Berenger, N., Casasnovas, R. O., Vera, P., Paone, G., Xerri, L., Salles, 37 38 39 G., Haioun, C., Meignan, M., Ghesquieres, H., Cartron, G., Seymour, J. F., 40 41 Delfau Larue, M. H., Offner, F., Soubeyran, P., Perrot, A., Brice, P., 42 43 Bouabdallah, R., Sonet, A., Dupuis, J., Casasnovas, O., Catalano, J. V., 44 45 Delmer, A., Jardin, F., Verney, A., Dartigues, P., Salles, G., Le Gouill, S., De 46 47 Guibert, S., Planche, L., Brice, P., Dupuis, J., Cartron, G., Van Hoof, A., 48 49 50 Casasnovas, O., Gyan, E., Tilly, H., Fruchart, C., Deconinck, E., Fitoussi, O., 51 52 Gastaud, L., Delwail, V., Gabarre, J., Gressin, R., Blanc, M., Foussard, C., & 53 54 Salles, G. (2012). Impact of [18F]Fluorodeoxyglucose Positron Emission 55 56 Tomography Response Evaluation in Patients With High Tumor Burden 57 58 59 60 35
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Follicular Lymphoma Treated With Immunochemotherapy: A Prospective 4 5 Study From the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. 6 7 [Multicenter Study 8 9 10 Randomized Controlled Trial 11 12 Research Support, Non U.S. Gov't 13 14 Clinical Trial, Phase III]. J Clin Oncol, 30 (35), 4317 4322. 15 16 El Galaly, T., Mylam, K., Brown, P., Rossing, M., Gang, A., Haglund, A., Arboe, B., 17 18 For Peer Review 19 Clausen, M., Jensen, P., Pedersen, M., Bukh, A., Amdi Jensen, B., Poulsen, 20 21 C., D'Amore, F., & Hutchings, M. (2013). Patient Reported Symptoms are still 22 23 the Single Most Important Factor for detecting Lymphoma Relapse 31 (S1), 24 25 Abstract 225. 26 27 El Galaly, T., Prakash, V., Christiansen, I., Madsen, J., Johansen, P., Boegsted, M., 28 29 30 Johnsen, H. E., & Bukh, A. (2011). Efficacy of routine surveillance with 31 32 positron emission tomography/computed tomography in aggressive non 33 34 Hodgkin lymphoma in complete remission: status in a single center. Leukemia 35 36 & Lymphoma, 52 (4), 597 603. doi: 10.3109/10428194.2010.547642 37 38 39 El Galaly, T. C., d'Amore, F., Mylam, K. J., de Nully Brown, P., Bogsted, M., Bukh, 40 41 A., Specht, L., Loft, A., Iyer, V., Hjorthaug, K., Nielsen, A. L., Christiansen, I., 42 43 Madsen, C., Johnsen, H. E., & Hutchings, M. (2012). Routine Bone Marrow 44 45 Biopsy Has Little or No Therapeutic Consequence for Positron Emission 46 47 Tomography/Computed Tomography Staged Treatment Naive Patients With 48 49 50 Hodgkin Lymphoma. [Journal article]. J Clin Oncol, 30 (36), 4508 4514. 51 52 Elstrom, R., Guan, L., Baker, G., Nakhoda, K., Vergilio, J. A., Zhuang, H., Pitsilos, 53 54 S., Bagg, A., Downs, L., Mehrotra, A., Kim, S., Alavi, A., & Schuster, S. J. 55 56 57 58 59 60 36
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 (2003). Utility of FDG PET scanning in lymphoma by WHO classification. 4 5 Blood, 101 (10), 3875 3876. doi: 10.1182/blood 2002 09 2778 6 7 Elstrom, R., Leonard, J. P., Coleman, M., & Brown, R. K. (2008). Combined PET and 8 9 10 low dose, noncontrast CT scanning obviates the need for additional 11 12 diagnostic contrast enhanced CT scans in patients undergoing staging or 13 14 restaging for lymphoma. [Research Support, N.I.H., Extramural]. Annals of 15 16 Oncology, 19 (10), 1770 1773. 17 18 For Peer Review 19 Engert, A., Haverkamp, H., Kobe, C., Markova, J., Renner, C., Ho, A., Zijlstra, J., 20 21 Kral, Z., Fuchs, M., Hallek, M., Kanz, L., Dohner, H., Dorken, B., Engel, N., 22 23 Topp, M., Klutmann, S., Amthauer, H., Bockisch, A., Kluge, R., Kratochwil, C., 24 25 Schober, O., Greil, R., Andreesen, R., Kneba, M., Pfreundschuh, M., Stein, 26 27 H., Eich, H. T., Muller, R. P., Dietlein, M., Borchmann, P., & Diehl, V. (2012). 28 29 30 Reduced intensity chemotherapy and PET guided radiotherapy in patients 31 32 with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open 33 34 label, phase 3 non inferiority trial. [Clinical Trial, Phase III 35 36 Comparative Study 37 38 39 Multicenter Study 40 41 Randomized Controlled Trial 42 43 Research Support, Non U.S. Gov't]. Lancet, 379 (9828), 1791 1799. 44 45 Feeney, J., Horwitz, S., Gonen, M., & Schoder, H. (2010). Characterization of T cell 46 47 lymphomas by FDG PET/CT. AJR, 195 (2), 333 340. 48 49 50 Fuertes, S., Setoain, X., Lopez Guillermo, A., Carrasco, J. L., Rodriguez, S., Rovira, 51 52 J., & Pons, F. (2013). Interim FDG PET/CT as a prognostic factor in diffuse 53 54 large B cell lymphoma. European Journal of Nuclear Medicine and Molecular 55 56 Imaging, 40 (4), 496 504. 57 58 59 60 37
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Furth, C., Amthauer, H., Hautzel, H., Steffen, I. G., Ruf, J., Schiefer, J., 4 5 Schoenberger, S., Henze, G., Grandt, R., Hundsdoerfer, P., Dietlein, M., & 6 7 Kobe, C. (2011). Evaluation of interim PET response criteria in paediatric 8 9 10 Hodgkin's lymphoma results for dedicated assessment criteria in a blinded 11 12 dual centre read. Annals of Oncology, 22 (5), 1198 1203. doi: 13 14 10.1093/annonc/mdq557 15 16 Gallamini, A. (2010). Positron emission tomography scanning: a new paradigm for 17 18 For Peer Review 19 the management of Hodgkin's lymphoma. [Editorial 20 21 Review]. Haematologica, 95 (7), 1046 1048. 22 23 Gallamini, A., Hutchings, M., Rigacci, L., Specht, L., Merli, F., Hansen, M., Patti, C., 24 25 Loft, A., Di Raimondo, F., D'Amore, F., Biggi, A., Vitolo, U., Stelitano, C., 26 27 Sancetta, R., Trentin, L., Luminari, S., Iannitto, E., Viviani, S., Pierri, I., & 28 29 30 Levis, A. (2007). Early interim 2 F 18 Fluoro 2 Deoxy D Glucose positron 31 32 emission tomography is prognostically superior to international prognostic 33 34 score in advanced stage Hodgkin's lymphoma: A report from a joint Italian 35 36 Danish study. Journal of Clinical Oncology, 25 (24), 3746 3752. doi: 37 38 39 10.1200/jco.2007.11.6525 40 41 Ghesquieres, H., Berger, F., Felman, P., Callet Bauchu, E., Bryon, P. A., Traverse 42 43 Glehen, A., Thieblemont, C., Baseggio, L., Michallet, A. S., Coiffier, B., & 44 45 Salles, G. (2006). Clinicopathologic characteristics and outcome of diffuse 46 47 large B cell lymphomas presenting with an associated low grade component 48 49 50 at diagnosis. J Clin Oncol, 24 (33), 5234 5241. 51 52 Girinsky, T., Ghalibafian, M., Bonniaud, G., Bayla, A., Magne, N., Ferreira, I., & 53 54 Lumbroso, J. (2007). Is FDG PET scan in patients with early stage Hodgkin 55 56 lymphoma of any value in the implementation of the involved node 57 58 59 60 38
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 radiotherapy concept and dose painting? [Research Support, Non U.S. Gov't]. 4 5 Radiotherapy and oncology : journal of the European Society for Therapeutic 6 7 Radiology and Oncology, 85 (2), 178 186. 8 9 10 Goldschmidt, N., Or, O., Klein, M., Savitsky, B., & Paltiel, O. (2011). The role of 11 12 routine imaging procedures in the detection of relapse of patients with 13 14 Hodgkin lymphoma and aggressive non Hodgkin lymphoma. Annals of 15 16 Hematology, 90 (2), 165 171. 17 18 For Peer Review 19 Gollub, M. J., Hong, R., Sarasohn, D. M., & Akhurst, T. (2007). Limitations of CT 20 21 during PET/CT. [Comparative Study 22 23 Evaluation Studies]. J Nucl Med, 48 (10), 1583 1591. doi: 24 25 10.2967/jnumed.107.043109 26 27 Haioun, C., Itti, E., Rahmouni, A., Brice, P., Rain, J. D., Belhadj, K., Gaulard, P., 28 29 30 Garderet, L., Lepage, E., Reyes, F., & Meignan, M. (2005). F 18 fluoro 2 31 32 deoxy D glucose positron emission tomography (FDG PET) in aggressive 33 34 lymphoma: an early prognostic tool for predicting patient outcome. Blood, 35 36 106 (4), 1376 1381. doi: 10.1182/blood 2005 01 0272 37 38 39 Hutchings, M. (2011). Pre transplant positron emission tomography/computed 40 41 tomography (PET/CT) in relapsed Hodgkin lymphoma: time to shift gears for 42 43 PET positive patients? [Comment]. Leukemia & lymphoma, 52 (9), 1615 1616. 44 45 doi: 10.3109/10428194.2011.601477 46 47 Hutchings, M., Loft, A., Hansen, M., Pedersen, L. M., Berthelsen, A. K., Keiding, S., 48 49 50 D'Amore, F., Boesen, A. M., Roemer, L., & Specht, L. (2006). Position 51 52 emission tomography with or without computed tomography in the primary 53 54 staging of Hodgkin's lymphoma. Haematologica-the Hematology Journal, 55 56 91 (4), 482 489. 57 58 59 60 39
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Hutchings, M., Loft, A., Hansen, M., Pedersen, L. M., Buhl, T., Jurlander, J., Buus, 4 5 S., Keiding, S., D'Amore, F., Boesen, A. M., Berthelsen, A. K., & Specht, L. 6 7 (2006). FDG PET after two cycles of chemotherapy predicts treatment failure 8 9 10 and progression free survival in Hodgkin lymphoma. Blood, 107 (1), 52 59. 11 12 doi: 10.1182/blood 2005 06 2252 13 14 Hutchings, M., Mikhaeel, N. G., Fields, P. A., Nunan, T., & Timothy, A. R. (2005). 15 16 Prognostic value of interim FDG PET after two or three cycles of 17 18 For Peer Review 19 chemotherapy in Hodgkin lymphoma. Annals of Oncology, 16 (7), 1160 1168. 20 21 doi: 10.1093/annonc/mdi200 22 23 Itti, E., Lin, C., Dupuis, J., Paone, G., Capacchione, D., Rahmouni, A., Haioun, C., & 24 25 Meignan, M. (2009). Prognostic Value of Interim (18)F FDG PET in Patients 26 27 with Diffuse Large B Cell Lymphoma: SUV Based Assessment at 4 Cycles of 28 29 30 Chemotherapy. Journal of Nuclear Medicine, 50 (4), 527 533. doi: 31 32 10.2967/jnumed.108.057703 33 34 Itti, E., Meignan, M., Berriolo Riedinger, A., Biggi, A., Cashen, A. F., Vera, P., Tilly, 35 36 H., Siegel, B. A., Gallamini, A., Casasnovas, R. O., & Haioun, C. (2013). An 37 38 39 international confirmatory study of the prognostic value of early PET/CT in 40 41 diffuse large B cell lymphoma: comparison between Deauville criteria and 42 43 DeltaSUVmax. [Journal article]. European Journal of Nuclear Medicine and 44 45 Molecular Imaging . 46 47 Janikova, A., Bolcak, K., Pavlik, T., Mayer, J., & Kral, Z. (2008). Value of 48 49 50 [18F]fluorodeoxyglucose positron emission tomography in the management of 51 52 follicular lymphoma: the end of a dilemma? [Research Support, Non U.S. 53 54 Gov't]. Clinical lymphoma & myeloma, 8 (5), 287 293. 55 56 57 58 59 60 40
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Juweid, M. E., Stroobants, S., Hoekstra, O. S., Mottaghy, F. M., Dietlein, M., 4 5 Guermazi, A., Wiseman, G. A., Kostakoglu, L., Scheidhauer, K., Buck, A., 6 7 Naumann, R., Spaepen, K., Hicks, R. J., Weber, W. A., Reske, S. N., 8 9 10 Schwaiger, M., Schwartz, L. H., Zijlstra, J. M., Siegel, B. A., Cheson, B. D., & 11 12 Imaging Subcommittee of International Harmonization Project in, L. (2007). 13 14 Use of positron emission tomography for response assessment of lymphoma: 15 16 consensus of the Imaging Subcommittee of International Harmonization 17 18 For Peer Review 19 Project in Lymphoma. [Consensus Development Conference 20 21 Practice Guideline]. J Clin Oncol, 25 (5), 571 578. doi: 10.1200/JCO.2006.08.2305 22 23 Juweid, M. E., Wiseman, G. A., Vose, J. M., Ritchie, J. M., Menda, Y., Wooldridge, J. 24 25 E., Mottaghy, F. M., Rohren, E. M., Blumstein, N. M., Stolpen, A., Link, B. K., 26 27 Reske, S. N., Graham, M. M., & Cheson, B. D. (2005). Response assessment 28 29 30 of aggressive non Hodgkin's lymphoma by integrated International Workshop 31 32 Criteria and fluorine 18 fluorodeoxyglucose positron emission tomography. 33 34 [Comparative Study 35 36 Research Support, N.I.H., Extramural 37 38 39 Research Support, Non U.S. Gov't 40 41 Research Support, U.S. Gov't, P.H.S.]. J Clin Oncol, 23 (21), 4652 4661. doi: 42 43 10.1200/JCO.2005.01.891 44 45 Karam, M., Novak, L., Cyriac, J., Ali, A., Nazeer, T., & Nugent, F. (2006). Role of 46 47 fluorine 18 fluoro deoxyglucose positron emission tomography scan in the 48 49 50 evaluation and follow up of patients with low grade lymphomas. [Comparative 51 52 Study]. Cancer, 107 (1), 175 183. 53 54 Khan, A. B., Barrington, S. F., Mikhaeel, N. G., Hunt, A. A., Cameron, L., Morris, T., 55 56 & Carr, R. (2013). PET CT staging of DLBCL accurately identifies and 57 58 59 60 41
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 provides new insight into the clinical significance of bone marrow involvement. 4 5 Blood, 122 (1), 61 67. 6 7 Lambert, J. R., Bomanji, J. B., Peggs, K. S., Thomson, K. J., Chakraverty, R. K., 8 9 10 Fielding, A. K., Kottaridis, P. D., Roughton, M., Morris, E. C., Goldstone, A. H., 11 12 Linch, D. C., Ell, P. J., & Mackinnon, S. (2010). Prognostic role of PET 13 14 scanning before and after reduced intensity allogeneic stem cell 15 16 transplantation for lymphoma. [Research Support, Non U.S. Gov't]. Blood, 17 18 For Peer Review 19 115 (14), 2763 2768. 20 21 Larcos, G., & Maisey, M. N. (1996). FDG PET screening for cerebral metastases in 22 23 patients with suspected malignancy. Nuclear Medicine Communications, 24 25 17 (3), 197 198. 26 27 Le Roux, P. Y., Gastinne, T., Le Gouill, S., Nowak, E., Bodet Milin, C., Querellou, S., 28 29 30 Mahe, B., Dubruille, V., Blin, N., Salaun, P. Y., & Bodere Kraeber, F. (2011). 31 32 Prognostic value of interim FDG PET/CT in Hodgkin's lymphoma patients 33 34 treated with interim response adapted strategy: comparison of International 35 36 Harmonization Project (IHP), Gallamini and London criteria. [Comparative 37 38 39 Study]. Eur J Nucl Med Mol Imaging, 38 (6), 1064 1071. doi: 10.1007/s00259 40 41 011 1741 0 42 43 Lee, A. I., Zuckerman, D. S., Van den Abbeele, A. D., Aquino, S. L., Crowley, D., 44 45 Toomey, C., Lacasce, A. S., Feng, Y., Neuberg, D. S., & Hochberg, E. P. 46 47 (2010). Surveillance imaging of Hodgkin lymphoma patients in first remission: 48 49 50 a clinical and economic analysis. [Evaluation Studies]. Cancer, 116 (16), 3835 51 52 3842. 53 54 Lin, C., Itti, E., Haioun, C., Petegnief, Y., Luciani, A., Dupuis, J., Paone, G., Talbot, J. 55 56 N., Rahmouni, A., & Meignan, M. (2007). Early 18F FDG PET for prediction of 57 58 59 60 42
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 prognosis in patients with diffuse large B cell lymphoma: SUV based 4 5 assessment versus visual analysis. [Research Support, Non U.S. Gov't]. J 6 7 Nucl Med, 48 (10), 1626 1632. doi: 10.2967/jnumed.107.042093 8 9 10 Luminari, S., Biasoli, I., Arcaini, L., Versari, A., Rusconi, C., Merli, F., Spina, M., 11 12 Ferreri, A. J., Zinzani, P. L., Gallamini, A., Mastronardi, S., Boccomini, C., 13 14 Gaidano, G., D'Arco, A. M., Di Raimondo, F., Carella, A. M., Santoro, A., 15 16 Musto, P., & Federico, M. (2013). The use of FDG PET in the initial staging of 17 18 For Peer Review 19 142 patients with follicular lymphoma: a retrospective study from the FOLL05 20 21 randomized trial of the Fondazione Italiana Linfomi. [Journal article]. Annals of 22 23 oncology : official journal of the European Society for Medical Oncology / 24 25 ESMO . 26 27 Markova, J., Kahraman, D., Kobe, C., Skopalova, M., Mocikova, H., Klaskova, K., 28 29 30 Dedeckova, K., Eich, H. T., Boll, B., Dietlein, M., & Kozak, T. (2012). Role of 31 32 [18F] fluoro 2 deoxy D glucose positron emission tomography in early and 33 34 late therapy assessment of patients with advanced Hodgkin lymphoma 35 36 treated with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, 37 38 39 procarbazine and prednisone. Leukemia & lymphoma, 53 (1), 64 70. 40 41 Meignan, M., Gallamini, A., Meignan, M., Gallamini, A., & Haioun, C. (2009). Report 42 43 on the First International Workshop on Interim PET Scan in Lymphoma. 44 45 [Congresses]. Leukemia & lymphoma, 50 (8), 1257 1260. doi: 46 47 10.1080/10428190903040048 48 49 50 Meignan, M., Itti, E., Bardet, S., Lumbroso, J., Edeline, V., Olivier, P., Borght, T. V., 51 52 Reman, O., Karcher, G., Mundler, O., Mounier, N., Ricci, R., Federico, M., 53 54 Raemaekers, J., & Andre, M. (2009). Development and application of a real 55 56 time on line blinded independent central review of interim PET scans to 57 58 59 60 43
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 determine treatment allocation in lymphoma trials. [Letter]. J Clin Oncol, 4 5 27 (16), 2739 2741. 6 7 Micallef, I. N., Maurer, M. J., Wiseman, G. A., Nikcevich, D. A., Kurtin, P. J., Cannon, 8 9 10 M. W., Perez, D. G., Soori, G. S., Link, B. K., Habermann, T. M., & Witzig, T. 11 12 E. (2011). Epratuzumab with rituximab, cyclophosphamide, doxorubicin, 13 14 vincristine, and prednisone chemotherapy in patients with previously 15 16 untreated diffuse large B cell lymphoma. [Clinical Trial, Phase II 17 18 For Peer Review 19 Multicenter Study 20 21 Research Support, N.I.H., Extramural 22 23 Research Support, U.S. Gov't, P.H.S.]. Blood, 118 (15), 4053 4061. doi: 24 25 10.1182/blood 2011 02 336990 26 27 Mikhaeel, N. G., Hutchings, M., Fields, P. A., O'Doherty, M. J., & Timothy, A. R. 28 29 30 (2005). FDG PET after two to three cycles of chemotherapy predicts 31 32 progression free and overall survival in high grade non Hodgkin lymphoma. 33 34 Ann Oncol, 16 (9), 1514 1523. doi: 10.1093/annonc/mdi272 35 36 Mocikova, H., Pytlik, R., Markova, J., Steinerova, K., Kral, Z., Belada, D., Trnkova, 37 38 39 M., Trneny, M., Koza, V., Mayer, J., Zak, P., & Kozak, T. (2011). Pre 40 41 transplant positron emission tomography in patients with relapsed Hodgkin 42 43 lymphoma. [Research Support, Non U.S. Gov't]. Leukemia & lymphoma, 44 45 52 (9), 1668 1674. 46 47 Moskowitz, C. H., Matasar, M. J., Zelenetz, A. D., Nimer, S. D., Gerecitano, J., 48 49 50 Hamlin, P., Horwitz, S., Moskowitz, A. J., Noy, A., Palomba, L., Perales, M. 51 52 A., Portlock, C., Straus, D., Maragulia, J. C., Schoder, H., & Yahalom, J. 53 54 (2012). Normalization of pre ASCT, FDG PET imaging with second line, non 55 56 57 58 59 60 44
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 cross resistant, chemotherapy programs improves event free survival in 4 5 patients with Hodgkin lymphoma. [Clinical Trial, Phase II 6 7 Multicenter Study 8 9 10 Research Support, Non U.S. Gov't]. Blood, 119 (7), 1665 1670. 11 12 Naumann, R., Beuthien Baumann, B., Reiss, A., Schulze, J., Hanel, A., Bredow, J., 13 14 Kuhnel, G., Kropp, J., Hanel, M., Laniado, M., Kotzerke, J., & Ehninger, G. 15 16 (2004). Substantial impact of FDG PET imaging on the therapy decision in 17 18 For Peer Review 19 patients with early stage Hodgkin's lymphoma. [Clinical Conference 20 21 Multicenter Study]. British Journal of Cancer, 90 (3), 620 625. 22 23 O'Doherty, M. J., Barrington, S. F., Campbell, M., Lowe, J., & Bradbeer, C. S. (1997). 24 25 PET scanning and the human immunodeficiency virus positive patient. 26 27 Journal of Nuclear Medicine, 38 (10), 1575 1583. 28 29 30 Otero, H. J., Jagannathan, J. P., Prevedello, L. M., Johnston, C. J., Ramaiya, N. H., 31 32 Van den Abbeele, A. D., & DiPiro, P. J. (2009). CT and PET/CT findings of T 33 34 cell lymphoma. AJR, 193 (2), 349 358. 35 36 Palmer, J., Goggins, T., Broadwater, G., Chao, N., Horwitz, M., Beaven, A., Sullivan, 37 38 39 K., Coleman, R. E., & Rizzieri, D. (2011). Early post transplant (F 18) 2 fluoro 40 41 2 deoxyglucose positron emission tomography does not predict outcome for 42 43 patients undergoing auto SCT in non Hodgkin and Hodgkin lymphoma. Bone 44 45 Marrow Transplantation, 46 (6), 847 851. doi: 10.1038/bmt.2010.203 46 47 Paone, G., Itti, E., Haioun, C., Gaulard, P., Dupuis, J., Lin, C., & Meignan, M. (2009). 48 49 50 Bone marrow involvement in diffuse large B cell lymphoma: correlation 51 52 between FDG PET uptake and type of cellular infiltrate. [Research Support, 53 54 Non U.S. Gov't]. Eur J Nucl Med Mol Imaging, 36 (5), 745 750. doi: 55 56 10.1007/s00259 008 1021 9 57 58 59 60 45
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Partridge, S., Timothy, A., O'Doherty, M. J., Hain, S. F., Rankin, S., & Mikhaeel, G. 4 5 (2000). 2 Fluorine 18 fluoro 2 deoxy D glucose positron emission tomography 6 7 in the pretreatment staging of Hodgkin's disease: influence on patient 8 9 10 management in a single institution. Annals of oncology : official journal of the 11 12 European Society for Medical Oncology / ESMO, 11 (10), 1273 1279. 13 14 Pelosi, E., Pregno, P., Penna, D., Deandreis, D., Chiappella, A., Limerutti, G., Vitolo, 15 16 U., Mancini, M., Bisi, G., & Gallo, E. (2008). Role of whole body [18F] 17 18 For Peer Review 19 fluorodeoxyglucose positron emission tomography/computed tomography 20 21 (FDG PET/CT) and conventional techniques in the staging of patients with 22 23 Hodgkin and aggressive non Hodgkin lymphoma. [Comparative Study]. La 24 25 Radiologia medica, 113 (4), 578 590. 26 27 Pinilla, I., Gomez Leon, N., Del Campo Del Val, L., Hernandez Maraver, D., 28 29 30 Rodriguez Vigil, B., Jover Diaz, R., & Coya, J. (2011). Diagnostic value of CT, 31 32 PET and combined PET/CT performed with low dose unenhanced CT and 33 34 full dose enhanced CT in the initial staging of lymphoma. [Comparative 35 36 Study]. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 37 38 39 55 (5), 567 575. 40 41 Pregno, P., Chiappella, A., Bello, M., Botto, B., Ferrero, S., Franceschetti, S., Giunta, 42 43 F., Ladetto, M., Limerutti, G., Menga, M., Nicolosi, M., Priolo, G., Puccini, B., 44 45 Rigacci, L., Salvi, F., Vaggelli, L., Passera, R., Bisi, G., & Vitolo, U. (2012). 46 47 Interim 18 FDG PET/CT failed to predict the outcome in diffuse large B cell 48 49 50 lymphoma patients treated at the diagnosis with rituximab CHOP. [Multicenter 51 52 Study 53 54 Research Support, Non U.S. Gov't]. Blood, 119 (9), 2066 2073. 55 56 57 58 59 60 46
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Quarles van Ufford, H. M., van Tinteren, H., Stroobants, S. G., Riphagen, II, & 4 5 Hoekstra, O. S. (2010). Added value of baseline 18F FDG uptake in serial 6 7 18F FDG PET for evaluation of response of solid extracerebral tumors to 8 9 10 systemic cytotoxic neoadjuvant treatment: a meta analysis. [Meta Analysis]. J 11 12 Nucl Med, 51 (10), 1507 1516. 13 14 Raanani, P., Shasha, Y., Perry, C., Metser, U., Naparstek, E., Apter, S., Nagler, A., 15 16 Polliack, A., Ben Bassat, I., & Even Sapir, E. (2006). Is CT scan still 17 18 For Peer Review 19 necessary for staging in Hodgkin and non Hodgkin lymphoma patients in the 20 21 PET/CT era? [Comparative Study 22 23 Multicenter Study]. Ann Oncol, 17 (1), 117 122. doi: 10.1093/annonc/mdj024 24 25 Radford, J., Barrington, S., Counsell, N., Pettengell, R., Johnson, P., Wimperis, J., 26 27 Coltart, S., Culligan, D., Lister, A., Bessell, E., Kruger, A., Popova, B., 28 29 30 Hancock, B., Hoskin, P., Illidge, T., & O'Doherty, M. (2012). Involved Field 31 32 Radiotherapy Versus No Further Treatment in Patients with Clinical Stages IA 33 34 and IIA Hodgkin Lymphoma and a 'Negative' PET Scan After 3 Cycles ABVD. 35 36 Results of the UK NCRI RAPID Trial. Blood; ASH Annual Meeting Abstracts, 37 38 39 120 , 547. 40 41 Safar, V., Dupuis, J., Itti, E., Jardin, F., Fruchart, C., Bardet, S., Vera, P., Copie 42 43 Bergman, C., Rahmouni, A., Tilly, H., Meignan, M., & Haioun, C. (2012). 44 45 Interim [18F]fluorodeoxyglucose positron emission tomography scan in diffuse 46 47 large B cell lymphoma treated with anthracycline based chemotherapy plus 48 49 50 rituximab. [Research Support, N.I.H., Intramural 51 52 Research Support, Non U.S. Gov't]. J Clin Oncol, 30 (2), 184 190. doi: 53 54 10.1200/JCO.2011.38.2648 55 56 57 58 59 60 47
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Schaefer, N. G., Hany, T. F., Taverna, C., Seifert, B., Stumpe, K. D., von Schulthess, 4 5 G. K., & Goerres, G. W. (2004). Non Hodgkin lymphoma and Hodgkin 6 7 disease: coregistered FDG PET and CT at staging and restaging do we 8 9 10 need contrast enhanced CT? [Comparative Study]. Radiology, 232 (3), 823 11 12 829. 13 14 Schoder, H., Noy, A., Gonen, M., Weng, L., Green, D., Erdi, Y. E., Larson, S. M., & 15 16 Yeung, H. W. (2005). Intensity of 18fluorodeoxyglucose uptake in positron 17 18 For Peer Review 19 emission tomography distinguishes between indolent and aggressive non 20 21 Hodgkin's lymphoma. [Comparative Study]. J Clin Oncol, 23 (21), 4643 4651. 22 23 Sehn, L. H., Scott, D. W., Chhanabhai, M., Berry, B., Ruskova, A., Berkahn, L., 24 25 Connors, J. M., & Gascoyne, R. D. (2011). Impact of concordant and 26 27 discordant bone marrow involvement on outcome in diffuse large B cell 28 29 30 lymphoma treated with R CHOP. [Research Support, Non U.S. Gov't]. J Clin 31 32 Oncol, 29 (11), 1452 1457. 33 34 Shrimpton, P., Hillier, M., MA, L., & M, D. (2005). NRPB W67 Doses from 35 36 Computed Tomography (CT) Examinations in the UK 2003 Review Oxford: 37 38 39 National Radiological Protection Board. 40 41 Smeltzer, J. P., Cashen, A. F., Zhang, Q., Homb, A., Dehdashti, F., Abboud, C. N., 42 43 Dipersio, J. F., Stockerl Goldstein, K. E., Uy, G. L., Vij, R., Westervelt, P., 44 45 Bartlett, N. L., & Fehniger, T. A. (2011). Prognostic significance of FDG PET 46 47 in relapsed or refractory classical Hodgkin lymphoma treated with standard 48 49 50 salvage chemotherapy and autologous stem cell transplantation. [Research 51 52 Support, N.I.H., Extramural 53 54 Research Support, Non U.S. Gov't]. Biology of Blood and Marrow Transplantation, 55 56 17 (11), 1646 1652. 57 58 59 60 48
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Spaepen, K., Stroobants, S., Dupont, P., Van Steenweghen, S., Thomas, J., 4 5 Vandenberghe, P., Vanuytsel, L., Bormans, G., Balzarini, J., De Wolf Peeters, 6 7 C., Mortelmans, L., & Verhoef, G. (2001). Prognostic value of positron 8 9 10 emission tomography (PET) with fluorine 18 fluorodeoxyglucose ([18F]FDG) 11 12 after first line chemotherapy in non Hodgkin's lymphoma: is [18F]FDG PET a 13 14 valid alternative to conventional diagnostic methods? [Research Support, 15 16 Non U.S. Gov't 17 18 For Peer Review 19 Validation Studies]. J Clin Oncol, 19 (2), 414 419. 20 21 Spaepen, K., Stroobants, S., Dupont, P., Vandenberghe, P., Thomas, J., de Groot, 22 23 T., Balzarini, J., De Wolf Peeters, C., Mortelmans, L., & Verhoef, G. (2002). 24 25 Early restaging positron emission tomography with ( 18)F fluorodeoxyglucose 26 27 predicts outcome in patients with aggressive non Hodgkin's lymphoma. 28 29 30 [Research Support, Non U.S. Gov't]. Ann Oncol, 13 (9), 1356 1363. 31 32 Specht, L., Yahalom, J., Illidge, T., Berthelsen, A. K., Constine, L. S., Eich, H. T., 33 34 Girinsky, T., Hoppe, R. T., Mauch, P., Mikhaeel, N. G., & Ng, A. (2013). 35 36 Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose 37 38 39 Guidelines From the International Lymphoma Radiation Oncology Group 40 41 (ILROG). [Journal article]. International journal of radiation oncology, biology, 42 43 physics . 44 45 Strobel, K., Schaefer, N. G., Renner, C., Veit Haibach, P., Husarik, D., Koma, A. Y., 46 47 & Hany, T. F. (2007). Cost effective therapy remission assessment in 48 49 50 lymphoma patients using 2 [fluorine 18]fluoro 2 deoxy D glucose positron 51 52 emission tomography/computed tomography: is an end of treatment exam 53 54 necessary in all patients? Annals of oncology : official journal of the European 55 56 Society for Medical Oncology / ESMO, 18 (4), 658 664. 57 58 59 60 49
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Sucak, G. T., Ozkurt, Z. N., Suyani, E., Yasar, D. G., Akdemir, O. U., Aki, Z., Yegin, 4 5 Z. A., Yagci, M., & Kapucu, O. L. (2011). Early post transplantation positron 6 7 emission tomography in patients with Hodgkin lymphoma is an independent 8 9 10 prognostic factor with an impact on overall survival. Annals of Hematology, 11 12 90 (11), 1329 1336. doi: 10.1007/s00277 011 1209 0 13 14 Terasawa, T., Dahabreh, I. J., & Nihashi, T. (2010). Fluorine 18 Fluorodeoxyglucose 15 16 Positron Emission Tomography in Response Assessment Before High Dose 17 18 For Peer Review 19 Chemotherapy for Lymphoma: A Systematic Review and Meta Analysis. 20 21 Oncologist, 15 (7), 750 759. doi: 10.1634/theoncologist.2010 0054 22 23 Thomson, K. J., Kayani, I., Ardeshna, K., Morris, E. C., Hough, R., Virchis, A., 24 25 Goldstone, A. H., Linch, D. C., & Peggs, K. S. (2013). A response adjusted 26 27 PET based transplantation strategy in primary resistant and relapsed Hodgkin 28 29 30 Lymphoma. [Letter 31 32 Research Support, Non U.S. Gov't]. Leukemia, 27 (6), 1419 1422. 33 34 Trotman, J., Fournier, M., Lamy, T., Seymour, J. F., Sonet, A., Janikova, A., 35 36 Shpilberg, O., Gyan, E., Tilly, H., Estell, J., Forsyth, C., Decaudin, D., Fabiani, 37 38 39 B., Gabarre, J., Salles, B., Van den Neste, E., Canioni, D., Garin, E., Fulham, 40 41 M., Vander Borght, T., & Salles, G. (2011). Positron Emission Tomography 42 43 Computed Tomography (PET CT) After Induction Therapy Is Highly Predictive 44 45 of Patient Outcome in Follicular Lymphoma: Analysis of PET CT in a Subset 46 47 of PRIMA Trial Participants. Journal of Clinical Oncology, 29 (23), 3194 3200. 48 49 50 doi: 10.1200/jco.2011.35.0736 51 52 Tsukamoto, N., Kojima, M., Hasegawa, M., Oriuchi, N., Matsushima, T., Yokohama, 53 54 A., Saitoh, T., Handa, H., Endo, K., & Murakami, H. (2007). The usefulness of 55 56 (18)F fluorodeoxyglucose positron emission tomography ((18)F FDG PET) 57 58 59 60 50
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 and a comparison of (18)F FDG pet with (67)gallium scintigraphy in the 4 5 evaluation of lymphoma: relation to histologic subtypes based on the World 6 7 Health Organization classification. [Comparative Study 8 9 10 Evaluation Studies]. Cancer, 110 (3), 652 659. 11 12 Watanabe, R., Tomita, N., Takeuchi, K., Sakata, S., Tateishi, U., Tanaka, M., Fujita, 13 14 H., Inayama, Y., & Ishigatsubo, Y. (2010). SUVmax in FDG PET at the biopsy 15 16 site correlates with the proliferation potential of tumor cells in non Hodgkin 17 18 For Peer Review 19 lymphoma. Leukemia & lymphoma, 51 (2), 279 283. 20 21 Weiler Sagie, M., Bushelev, O., Epelbaum, R., Dann, E. J., Haim, N., Avivi, I., Ben 22 23 Barak, A., Ben Arie, Y., Bar Shalom, R., & Israel, O. (2010). (18)F FDG 24 25 avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med, 51 (1), 26 27 25 30. 28 29 30 Wirth, A., Foo, M., Seymour, J. F., Macmanus, M. P., & Hicks, R. J. (2008). Impact of 31 32 [18f] fluorodeoxyglucose positron emission tomography on staging and 33 34 management of early stage follicular non hodgkin lymphoma. [Evaluation 35 36 Studies]. International journal of radiation oncology, biology, physics, 71 (1), 37 38 39 213 219. doi: 10.1016/j.ijrobp.2007.09.051 40 41 Yang, D. H., Min, J. J., Song, H. C., Jeong, Y. Y., Chung, W. K., Bae, S. Y., Ahn, J. 42 43 S., Kim, Y. K., Bom, H. S., Chung, I. J., Kim, H. J., & Lee, J. J. (2011). 44 45 Prognostic significance of interim (18)F FDG PET/CT after three or four 46 47 cycles of R CHOP chemotherapy in the treatment of diffuse large B cell 48 49 50 lymphoma. European Journal of Cancer, 47 (9), 1312 1318. doi: 51 52 10.1016/j.ejca.2010.12.027 53 54 Yang, D. H., Ahn, J. S., Byun, B. H., Min, J. J., Kweon, S. S., Chae, Y. S., Sohn, S. 55 56 K., Lee, S. W., Kim, H. W., Jung, S. H., Kim, Y. K., Kim, H. J., Bom, H. S., & 57 58 59 60 51
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 Lee, J. J. (2013). Interim PET/CT based prognostic model for the treatment of 4 5 diffuse large B cell lymphoma in the post rituximab era. Annals of 6 7 Hematology, 92 (4), 471 479. 8 9 10 Yoo, C., Lee, D. H., Kim, J. E., Jo, J., Yoon, D. H., Sohn, B. S., Kim, S. W., Lee, J. 11 12 S., & Suh, C. (2011). Limited role of interim PET/CT in patients with diffuse 13 14 large B cell lymphoma treated with R CHOP. Annals of Hematology, 90 (7), 15 16 797 802. doi: 10.1007/s00277 010 1135 6 17 18 For Peer Review 19 Zinzani, P. L. (2011). PET in T Cell Lymphoma. Current hematologic malignancy 20 21 reports, 6 (4), 241 244. 22 23 Zinzani, P. L., Gandolfi, L., Broccoli, A., Argnani, L., Fanti, S., Pellegrini, C., Stefoni, 24 25 V., Derenzini, E., Quirini, F., & Baccarani, M. (2011). Midtreatment 18F 26 27 fluorodeoxyglucose positron emission tomography in aggressive non Hodgkin 28 29 30 lymphoma. [Evaluation Studies 31 32 Research Support, Non U.S. Gov't]. Cancer, 117 (5), 1010 1018. doi: 33 34 10.1002/cncr.25579 35 36 Zinzani, P. L., Rigacci, L., Stefoni, V., Broccoli, A., Puccini, B., Castagnoli, A., 37 38 39 Vaggelli, L., Zanoni, L., Argnani, L., Baccarani, M., & Fanti, S. (2012). Early 40 41 interim 18F FDG PET in Hodgkin's lymphoma: evaluation on 304 patients. 42 43 [Research Support, Non U.S. Gov't]. European Journal of Nuclear Medicine 44 45 and Molecular Imaging, 39 (1), 4 12. 46 47 Zinzani, P. L., Tani, M., Trisolini, R., Fanti, S., Stefoni, V., Alifano, M., Castellucci, P., 48 49 50 Musuraca, G., Dalpiaz, G., Alinari, L., Marchi, E., Fina, M., Pellegrini, C., 51 52 Farsad, M., Cancellieri, A., Busca, A., Canini, R., Pileri, S., Baccarani, M., & 53 54 Boaron, M. (2007). Histological verification of positive positron emission 55 56 57 58 59 60 52
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Barrington&Mikhaeel resubmitted 3Sept2013 1 2 3 tomography findings in the follow up of patients with mediastinal lymphoma. 4 5 Haematologica, 92 (6), 771 777. doi: 10.3324/haematol.10798 6 7 8 9 10 Acknowledgements 11 12 13 14 Sally Barrington and George Mikhaeel reviewed the literature and wrote the 15 16 paper together. 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 53
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 Coronal slices with low-dose CT (left), PET (middle) and fused (right) images are shown of a patient with 29 HL. Note the PET and fused images are displayed to a maximum SUV of 10 (SUV colour scale on far right of figure, CT Hounsfield units displayed in grey). The SUV fixed scale is used for reporting at our Centre. 30 84x51mm (300 x 300 DPI) 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 112 of 115
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 Coronal slices (low-dose CT, PET and fused images) show focal uptake (arrowed) in the spleen which is not 30 enlarged and has normal appearances on CT. 31 84x55mm (300 x 300 DPI) 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 113 of 115 British Journal of Haematology
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 Sagittal slices (low-dose CT, PET and fused images) are shown of a patient with DLBCL and marrow involvement, pre (part A) and post treatment (part B). Note how some vertebrae eg T12 with increased 25 uptake become photopaenic with ablation of marrow, whilst other vertebrae with normal uptake at baseline 26 have increased uptake relative to baseline due to the effects of chemotherapy. The images demonstrate a 27 ‘mirror’ effect. 28 84x40mm (300 x 300 DPI) 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 114 of 115
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 Sagittal slices (low-dose CT, PET and fused images) are shown of a patient with DLBCL and marrow 28 involvement, pre (part A) and post treatment (part B). Note how some vertebrae eg T12 with increased 29 uptake become photopaenic with ablation of marrow, whilst other vertebrae with normal uptake at baseline have increased uptake relative to baseline due to the effects of chemotherapy. The images demonstrate a 30 ‘mirror’ effect. 31 84x49mm (300 x 300 DPI) 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 115 of 115 British Journal of Haematology
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 Coronal slices (low-dose CT, PET and fused images) are shown of a patient with sarcoid-like reaction with a 26 typical distribution of FDG uptake in nodes in the mediastinum and within the lung. 84x43mm (300 x 300 DPI) 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60