PET in Hodgkin lymphoma: Who, when and why?

Transcription

1 PET in Hodgkin lymphoma: Who, when and why? Lymphoma Forum 2011, Bratislava Martin Hutchings MD PhD Departments of Oncology and Haematology Copenhagen University Hospital, Denmark

2 Staging Treatment monitoring Response evaluation Radiotherapy planning Follow-up

3 Cure rates vs. late effects Risk of overtreatment vs. risk of relapse Patient-tailored therapy

4 Ideal Real world Accurate pre-treatment prognostic and predictive markers Clinical staging Prognostic indices

5 Paul R. Comparison of fluorine-18-2-fluorodeoxyglucose and gallium-67 citrate imaging for detection of lymphoma. J.Nucl.Med. 28(3), (1987). Kostakoglu L, Leonard JP, Kuji I, Coleman M, Vallabhajosula S, Goldsmith SJ. Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and Ga-67 scintigraphy in evaluation of lymphoma. Cancer 94(4), (2002). Wirth A, Seymour JF, Hicks RJ et al. Fluorine-18 fluorodeoxyglucose positron emission tomography, gallium- 67 scintigraphy, and conventional staging for Hodgkin's disease and non-hodgkin's lymphoma. Am.J.Med. 112(4), (2002). Friedberg JW, Fischman A, Neuberg D et al. FDG-PET is superior to gallium scintigraphy in staging and more sensitive in the follow-up of patients with de novo Hodgkin lymphoma: a blinded comparison. Leuk.Lymphoma 45(1), (2004). Yamamoto F, Tsukamoto E, Nakada K et al. 18F-FDG PET is superior to 67Ga SPECT in the staging of non- Hodgkin's lymphoma. Ann.Nucl.Med 18(6), (2004). Moog F, Bangerter M, Diederichs CG et al. Lymphoma: role of whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET in nodal staging. Radiology 203(3), (1997). Bangerter M, Kotzerke J, Griesshammer M, Elsner K, Reske SN, Bergmann L. Positron emission tomography with 18-fluorodeoxyglucose in the staging and follow-up of lymphoma in the chest. Acta Oncol. 38(6), (1999). Buchmann I, Reinhardt M, Elsner K et al. 2-(fluorine-18)fluoro-2-deoxy-D-glucose positron emission tomography in the detection and staging of malignant lymphoma. A bicenter trial. Cancer 91(5), (2001). Schoder H, Meta J, Yap C et al. Effect of whole-body (18)F-FDG PET imaging on clinical staging and management of patients with malignant lymphoma. J.Nucl.Med. 42(8), (2001). Sasaki M, Kuwabara Y, Koga H et al. Clinical impact of whole body FDG-PET on the staging and therapeutic decision making for malignant lymphoma. Ann.Nucl.Med 16(5), (2002). Delbeke D, Martin WH, Morgan DS et al. 2-deoxy-2-[F-18]fluoro-D-glucose imaging with positron emission tomography for initial staging of Hodgkin's disease and lymphoma. Mol.Imaging Biol. 4(1), (2002). Moog F, Bangerter M, Diederichs CG et al. Extranodal malignant lymphoma: detection with FDG PET versus CT. Radiology 206(2), (1998). Stumpe KD, Urbinelli M, Steinert HC, Glanzmann C, Buck A, von Schulthess GK. Whole-body positron emission tomography using fluorodeoxyglucose for staging of lymphoma: effectiveness and comparison with computed tomography. Eur.J.Nucl.Med. 25(7), (1998). Hoh CK, Glaspy J, Rosen P et al. Whole-body FDG-PET imaging for staging of Hodgkin's disease and lymphoma. J.Nucl.Med. 38(3), (1997). Jerusalem G, Warland V, Najjar F et al. Whole-body 18F-FDG PET for the evaluation of patients with Hodgkin's disease and non-hodgkin's lymphoma. Nucl.Med.Commun. 20(1), (1999). Shah N, Hoskin P, McMillan A, Gibson P, Lowe J, wong WL. The impact of FDG positron emission tomography imaging on the management of lymphomas. Br.J.Radiol. 73(869), (2000). Wiedmann E, Baican B, Hertel A et al. Positron emission tomography (PET) for staging and evaluation of response to treatment in patients with Hodgkin's disease. Leuk.Lymphoma 34(5-6), (1999). Partridge S, Timothy A, O'Doherty MJ, Hain SF, Rankin S, Mikhaeel G. 2-Fluorine-18-fluoro-2-deoxy-D glucose positron emission tomography in the pretreatment staging of Hodgkin's disease: influence on patient management in a single institution. Ann.Oncol. 11(10), (2000). Hueltenschmidt B, Sautter-Bihl ML, Lang O et al. Whole body positron emission tomography in the treatment of Hodgkin disease. Cancer 91(2), (2001). Jerusalem G, Beguin Y, Fassotte MF et al. Whole-body positron emission tomography using 18Ffluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease. Haematologica 86(3), (2001). Menzel C, Dobert N, Mitrou P et al. Positron emission tomography for the staging of Hodgkin's lymphoma-- increasing the body of evidence in favor of the method. Acta Oncol. 41(5), (2002). Weihrauch MR, Re D, Bischoff S et al. Whole-body positron emission tomography using 18Ffluorodeoxyglucose for initial staging of patients with Hodgkin's disease. Ann.Hematol. 81(1), (2002). Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography-clinical use, interpretation methods, diagnostic improvements. Semin.Nucl.Med 33(3), (2003). Naumann R, Beuthien-Baumann B, Reiss A et al. Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 90(3), (2004). Munker R, Glass J, Griffeth LK et al. Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease. Ann.Oncol. 15(11), (2004). Hutchings M, Loft A, Hansen M et al. Position emission tomography with or without computed tomography in the primary staging of Hodgkin's lymphoma. Haematologica 91(4), (2006). Rigacci L, Vitolo U, Nassi L et al. Positron emission tomography in the staging of patients with Hodgkin's lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi. Ann.Hematol. 86(12), (2007). Bangerter M, Moog F, Buchmann I et al. Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease. Ann.Oncol. 9(10), (1998). Carr R, Barrington SF, Madan B et al. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood 91(9), (1998). Pakos EE, Fotopoulos AD, Ioannidis JP. 18F-FDG PET for evaluation of bone marrow infiltration in staging of lymphoma: a meta-analysis. J Nucl.Med 46(6), (2005). Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography-clinical use, interpretation methods, diagnostic improvements. Semin.Nucl.Med 33(3), (2003). Hoffmann M, Vogelsang H, Kletter K, Zettinig G, Chott A, Raderer M. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma. Gut 52(3), (2003). Fuertes S, Setoain X, Lopez-Guillermo A et al. [The value of positron emission tomography/computed tomography (PET/CT) in the staging of diffuse large B-cell lymphoma.]. Med.Clin.(Barc.) 129(18), (2007). Hoffmann M, Kletter K, Becherer A, Jager U, Chott A, Raderer M. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) for staging and follow-up of marginal zone B-cell lymphoma. Oncology 64(4), (2003). Hoffmann M, Chott A, Puspok A, Jager U, Kletter K, Raderer M. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) does not visualize follicular lymphoma of the duodenum. Ann.Hematol. 83(5), (2004). Wohrer S, Jaeger U, Kletter K et al. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG- PET) visualizes follicular lymphoma irrespective of grading. Ann.Oncol. 17(5), (2006). Jerusalem G, Beguin Y, Najjar F et al. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) for the staging of low-grade non-hodgkin's lymphoma (NHL). Ann.Oncol. 12(6), (2001). Elstrom R, Guan L, Baker G et al. Utility of FDG-PET scanning in lymphoma by WHO classification. Blood 101(10), (2003). Beal KP, Yeung HW, Yahalom J. FDG-PET scanning for detection and staging of extranodal marginal zone lymphomas of the MALT type: a report of 42 cases. Ann.Oncol. 16(3), (2005). Valencak J, Becherer A, Der-Petrossian M, Trautinger F, Raderer M, Hoffmann M. Positron emission tomography with [18F] 2-fluoro-D-2- deoxyglucose in primary cutaneous T-cell lymphomas. Haematologica 89(1), (2004). Ambrosini V, Rubello D, Castellucci P et al. Diagnostic role of 18F-FDG pet in gastric MALT lymphoma. Nucl.Med Rev.Cent.East Eur. 9(1), (2006). Najjar F, Hustinx R, Jerusalem G, Fillet G, Rigo P. Positron emission tomography (PET) for staging lowgrade non-hodgkin's lymphomas (NHL). Cancer Biother.Radiopharm. 16(4), (2001). Schoder H, Noy A, Gonen M et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-hodgkin's lymphoma. J Clin.Oncol. 23(21), (2005). Radan L, Fischer D, Bar-Shalom R et al. FDG avidity and PET/CT patterns in primary gastric lymphoma. Eur.J.Nucl.Med.Mol.Imaging 35(8), (2008). Kumar R, Xiu Y, Potenta S et al. 18F-FDG PET for evaluation of the treatment response in patients with gastrointestinal tract lymphomas. J Nucl.Med 45(11), (2004). Roe RH, Finger PT, Kurli M, Tena LB, Iacob CE. Whole-body positron emission tomography/computed tomography imaging and staging of orbital lymphoma. Ophthalmology 113(10), (2006). Basu S, Mahne A, Iruvuri S, Alavi A. Potential clinical role of fluorodeoxyglucose-positron emission tomography in assessing primary or secondary lymphomas of the parotid gland. Clin.Lymphoma Myeloma. 7(4), (2007). Perry C, Herishanu Y, Metzer U et al. Diagnostic accuracy of PET/CT in patients with extranodal marginal zone MALT lymphoma. Eur.J.Haematol. 79(3), (2007). Suh C, Kang YK, Roh JL et al. Prognostic value of tumor 18F-FDG uptake in patients with untreated extranodal natural killer/t-cell lymphomas of the head and neck. J.Nucl.Med. 49(11), (2008). Allen-Auerbach M, Quon A, Weber WA et al. Comparison between 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography and positron emission tomography/computed tomography hardware fusion for staging of patients with lymphoma. Mol.Imaging Biol. 6(6), (2004).

6 PET/CT improves the accuracy of lymphoma staging Higher sensitivity than CT and other conventional staging methods, but not at the expense of the specificity 10-25% of patients are upstaged as a result of PET/CT, many to a more advanced treatment group Very few patients are downstaged

7 What is the conseqence of this improved staging accuracy? Better outcome for both early and advanced stages? So why are we not happy? Because we should be careful not to overtreat

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9 Normal PET/CT Respiratory gated PET/CT Courtesy of Annika Loft

10 What is the conseqence of this improved staging accuracy? Better outcome for both early and advanced stages So why are we not happy? Because we should be careful not to overtreat A large change in the staging should be reflected in a corresponding change in treatment strategies and/or modifications of the staging system

11 Staging Treatment monitoring Response evaluation Radiotherapy planning Follow-up

12 Positive predictive value 62-90% Negative predictive value 94-97% Hutchings et al. J Nucl Med 2009; 50: 21S-30S.

13 IPS loses its prognostic value when combined with early PET Gallamini et al. JCO 2007; 25:

14 104 patients 43 stage I-II 61 stage III-IV Early PET strongly prognostic in both early and advanced stage, regardless of IPS Cerci et al. J Nucl Med 2010; 51: 1-7.

15 10 of 18 patients Cerci et al. J Nucl Med 2010; 51: 1-7.

16 Study title/description (clinicaltrials.gov) Study group Main PET-driven intervention Study type PET-adapted chemotherapy for advanced Hodgkin lymphoma (HD0607) GITIL Intensification to BEACOPPesc if PETpositive after 2x ABVD Phase II PET response adapted threapy for advanced-stage Hodgkin lymphoma (RATHL) UK NCRI Intensification to BEACOPP if PETpositive after 2 x ABVD Phase II PET/CT and chemotherapy with or without additional chemotherapy and G-CSF in stage III-IV HL SWOG CALGB Intensification to BEACOPPesc if PETpositive after 2x ABVD Phase II HD+ASCT in patients PET-positive after 2x ABVD, RT vs. no RT in PET-2 negative patients (HD0801) IIL Salvage regimen if PET-positive after 2 x ABVD Phase II Tailored therapy for Hodgkin lymphoma using early interim PET for therapy decision Rambam Israel IPS0-2: ABVD to BEACOPP if PETpos IPS3-7: BEACOPP to ABVD if PETneg Phase II HD18 protocol for advanced-stage Hodgkin lymphoma GHSG 4x vs 8x BEACOPPesc in experimental arm if PET-negative after 2 cycles Phase III Pilot study of abbreviated chemotherapy based on PET in Hodgkin lymphoma Weill Cornell Treatment limited to 3x ABVD if PETnegative after 1 cycle Phase II

17 Pilot experience Gallamini et al. ASCO annual meeting 2010 (abstr 8006) 164 stage IIA-IV ptts. retrospectively analysed PET after 2x ABVD BEACOPPesc if PET2 pos Entire cohort 88% 2-year FFS PET2-negative 92% PET2 positive 61% Avigdor et al. Ann Oncol 2010; 21: advanced stage ptts. prospectively analysed PET after 2x BEACOPPesc ABVD if PET2 neg Entire cohort 78% 4-year PFS PET2-negative 87% PET2 positive 53%

18 H11 advanced stage HL trial Experimental Arm 1 x ABVD Standard Arm 1 x BEAesc PET/CT PET+ PET- PET+/- 3 x BEAesc 3 x ABVD 3 x BEAesc CT CR / PR PD/ SD CR / PR PD/ SD* CR / PR PD/ SD 1 x BEAesc 3 x BEAbase Off protocol 4 x ABVD Off protocol 4 x BEAbase Off protocol Post-chemotherapy PET/CT RT 36 Gy to PET-positive residual masses

19 Kostakoglu et al. Cancer 2006 Kostakoglu et al. J Nucl Med 2002 Very early treatment monitoring A treatment change should be performed as early as possible in order to avoid chemoresistance and to limit the total amount of chemotherapy delivered PET after one cycle of chemotherapy is promising and may offer a better NPV

20 Baseline After 1 cycle After 2 cycles

21 Baseline After 1 cycle After 2 cycles

22 Staging Treatment monitoring Response evaluation Radiotherapy planning Follow-up

23 Post-treatment evaluation PET has very high NPV and variable PPV for post-treatment evaluation with conventional treatment New response criteria: If PET-negative = CR Cheson et al. JCO 2007; 25(5):

24 End-of-treatment evaluation Time to next treatment (years) 60 pts., all stages Treated with Stanford V or MOPP/ABVD Additional radiotherapy in most patients Time to next treatment (years) Overall survival (years) Overall survival (years) Brepoels et al. Leuk Lymphoma 2007;48:

25 Staging Treatment monitoring Response evaluation Radiotherapy planning Follow-up

26 Radiotherapy planning Extended fields for single modality treatment Conformal fields for dual modality treatment EFRT STNI IFRT INRT

27 Radiotherapy planning Reduction in radiation to normal tissues Reduction in serious longterm sequelae Higher risk of missing viable tumour tissue Accuracy of imaging increasingly important

28 Radiotherapy planning INRT planning with planning CT and staging PET/CT vs. CT Hutchings et al. No. of patients treatment volume due to PET/CT 2 0 Girinsky et al. treatment volume due to PET/CT 7 (23%) 11 (36%) Early advanced due to PET/CT 1 2 Hutchings et al. Eur J Haematol 2007; 78: Girinsky et al. Radiother Oncol 2007; 85:

29 Radiotherapy planning However - Larger volumes are the opposite of what we want PET/CT for definition of the involved field should be accompanied by strategies to generally reduce the volumes INRT

30 Radiotherapy planning Pretreatment PET/CT is the best known tool for delineation of the initially involved nodes PET/CT is only a step forward if combined with steps to generally reduce the treated volumes All available diagnostic information should be used to determine the involved nodes No evidence for dose painting or boost to PET-avid parts of a mass Staging PET/CT images should be acquired with patient in the same position as will later be used for radiotherapy

31 Staging Treatment monitoring Response evaluation Radiotherapy planning Follow-up

32 Early diagnosis of relapse We like to identify a relapse as early as possible We know that tumour burden is a prognostic factor But do patients with minimal, asymptomatic disease do better after salvage therapy than patients with low tumour burden and discrete symptoms? We do not know! This should be kept in mind when considering different surveillance strategies

33 Most relapses are symptomatic Radford et al Retrospective study of 210 HL patients followed with regular visits incl. CXR and blood tests. The vast majority of relapses occurred with the first two years of follow-up 37 relapses only 4 patients asymptomatic at the time of diagnosis of relapse Radford et al. BMJ 1997; 314:

34 Routine CT surveillance Dryver et al Outcomes of routine clinical, radiological and laboratory follow-up Clinical CXR CT CBC Routine investigations True relapses False relapses Retrospective study of 107 HL patients followed for median 38 months w/ regular visits incl. CXR and CT Dryver et al. Br J Cancer 2003; 89:

35 Jerusalem et al. Ann Oncol 2003 Retrospective study of 36 HL patients PET-scanned every 4-6 months for 2-3 years after treatment 11 scans PET-positive 5 relapses 2 symptomatic Conclusion: The price for preclinical detection of 3 relapses was 119 PET scans (+ unnecessary biopsies) In fairness: most FP results came from thymus and GI tract would probably have been avoided with PET/CT Jerusalem et al. Ann Oncol 2003; 14:

36 - Zinzani JCO 2009 Large, prospective study of 421 lymphoma patients, including 160 with HL Patients PET/CT scanned after 6, 12, 18, 24 months, and annually thereafter Zinzani et al. JCO 2009; 27:

37 Large, prospective study of 421 lymphoma patients, including 160 with HL Patients PET/CT scanned after 6, 12, 18, 24 months, and annually thereafter 51 patients relapsed, the majority within the first 2 yrs Same relapse pattern as reported by Radford et al. Zinzani Radfordet et al. al. JCO BMJ 2009; 1997; 27: 314:

38 Zinzani et al. - Results 51 relapses 51 detected by PET/CT 37 detected by CT 35 had clinical symptoms Only 16 (4 HL) FP out of 1,789 PET/CT scans (605 HL) 24 inconclusive PET/CT: repeat scan after 1-2 months 11 continued PET-positive, of which 7 abnormal on CT 6/11 biopsy-proven relapses, of which only 2 abnormal on CT Zinzani et al. JCO 2009; 27:

39 Zinzani et al. conclusions PET/CT detects a number of unexpected relapses before CT and prior to symptoms Most relapses are detected during the first year in early interim PET-positive patients It took 1,789 PET/CT scans to detect 14 relapses earlier than CT and other methods would have done In HL patients 605 PET/CT detected 4 relapses earlier than CT and other methods Zinzani et al. JCO 2009; 27:

40 - Petrausch et al. Ann Oncol 2009 Retrospective study of 134 HL patients who had PET/CT performed at least once during follow-up (165 scans) Patients under suspicion: 31/42 had clear symptoms 42 relapses were detected with a 98% PPV for PET Risk factors for a PET-detected relapse < 24 months: residual mass after end of treatment > 24 months: advanced stage and symptoms Petrausch et al. Ann Oncol 2009; 21:

41 - Crocchiolo et al. Ann Hematol Maeda et al. ASH Mocikova et al. Ann Oncol Lee et al. Cancer 2010 Retrospective studies showing a high false-positive rate of follow-up PET/CT

42 Recommendations for follow-up There is no scientific justification for routine imaging in HL patients >2 years after 1st line therapy PET/CT has no clear role in routine follow-up There may be a role for routine PET/CT in the first 1-2 years in patients with a residual mass and/or a positive early PET PET/CT is the best method to investigate a suspected relapse

43 Overall conclusions PET in HL Staging: PET/CT is standard of care Increased staging accuracy better basis for risk stratified treatment More refined definition of radiotherapy volumes less irradiation to normal tissues Early response monitoring still experimental Early interim PET has a very high prognostic value in HL Early PET/CT may help tailor therapy to the individual patient and thus improve outcomes while still reduce unnecessary over-treatment Posttreatment evaluation PET/CT is standard of care High NPV suited for characterisation of a residual mass Moderate PPV treatment failure can only be safely determined with biopsy Follow-up when clearly clinically indicated Not indicated for routine surveillance, but indicated for the investigation of a suspected relapse

44 Thank you