The Evolving Role of Positron Emission Tomography PET in Hodgkins Disease

1
The Evolving Role of Positron Emission Tomography
(PET) in Hodgkins Disease

• Hematology / Oncology Grand Rounds
• January 30th 2009

2
Disclosures

• No financial interests to disclose, unfortunately!

3
Overview

• Clinical case
• Hodgkins Disease
• PET imaging
• Early interim PET in HL
• PET and response-adapted therapy for HL
• PET in salvage and pre-transplant setting for HL
• Summary
• Up-coming / on-going trials
• References

4
Clinical Case

• 26 year-old Caucasian female with no significant
  past medical history presenting with a 2 month
  history of fevers and drenching night sweats, and
  a 4 day history of severe abdominal pain.
• Presented to an outside hospital emergency room
  and found to have retroperitoneal and
  peripancreatic, paraesophageal and right hilar
  lymphadenopathy and splenomegaly
• Lymph node excisional biopsy consistent with
  Hodgkins, nodular sclerosing type
• Bone marrow biopsy, bilateral iliac crests,
  negative for lymphomatous involvement
• Initial PET-CT scan here with hypermetabolic
  adenopathy involving the left lower neck,
  mediastinum, porta hepatis, peripancreatic and
  retroperitoneum
• Stage III B with IPS score of 2 on basis of
  anemia and hypoalbuminemia
• Started on ABVD chemotherapy for treatment
• Interim PET-CT scan after 2 cycles of ABVD showed
  no residual areas of abnormally increased FDG
  uptake, and decrease in size of previously
  FDG-avid mediastinal and retroperitoneal lymph
  nodes without associated increase in FDG uptake
• Patient proceeded to complete 6 cycles of ABVD

5
Hodgkins Lymphoma (HL)

• Hodgkins Disease is a fairly uncommon malignancy
  involving the lymph nodes and lymphatic system
• Estimated 8,220 new cases in 2008
• Most patients between ages 15 and 30 years of age
• 2nd peak in adults aged 55 and older
• Fairly curable cancer with modern therapy (i.e.
  chemotherapy /- radiation therapy)
• Divided into classical and lymphocyte-predominant
  HL
• Classical includes 4 subtypes nodular
  sclerosing, mixed cellularity, lymphocyte-depleted
  , and lymphocyte-rich. Characterized by presence
  of Reed-Sternberg cells in an inflammatory
  background
• Lymphocyte-predominant lacks Reed-Sternberg
  cells, but characterized by presence of
  lymphocyte predominant cells (popcorn cells)
• Staging is based on the Ann Arbor staging system

6
Hodgkin Lymphoma (HL)

• Primary therapy - chemotherapy regimens include
• ABVD (adriamycin, bleomycin, vinblastine, and
  dacarbazine)
• BEACOPP (bleomycin, etoposide, doxorubicin,
  cyclophosphamide, vincristine, procarbazine, and
  prednisone)
• BEACOPP standard
• BEACOPP escalated
• BEACOPP14
• Stanford V
• Other regimens used in HL include
• MOPP - Mechlorethamine, Vincristine, Prednisone,
  Procarbazine
• MOPP alternating with ABV
• MOPP alternating with ABVD
• COPP / ABVD - Cyclophosphamide, vincristine,
  procarbazine, and prednisone alternating with
  ABVD
• ChlVPP - Chlorambucil, Vinblastine, Procarbazine,
  Prednisone

7
Hodgkin Lymphoma (HL)

• Serious long-term adverse effects of treatment,
  including heart and lung disease and secondary
  malignancies
• Risk stratification and tailoring of therapy
  can we identify early in treatment patients in
  whom the chances of cure by conventional
  treatment are low and for whom intensification of
  therapy with autologous transplant would be
  warranted? Can we de-escalate therapy for others?
• International Prognostic Score (IPS) Seven
  factors had similar independent prognostic
  effects
• Serum albumin level of less than 4 g per
  deciliter
• Hemoglobin level of less than 10.5 g per
  deciliter
• Male sex
• Age of 45 years or older
• Stage IV disease (according to the Ann Arbor
  classification)
• Leukocytosis (a white-cell count of at least
  15,000 per cubic millimeter)
• Lymphopenia (a lymphocyte count of less than 600
  per cubic millimeter, a count that was less than
  8 percent of the white-cell count, or both)

8
Hodgkin Lymphoma (HL)

• Usually divided into 3 groups
• Early-stage favorable
• Stage I or II with no B symptoms or large
  mediastinal adenopathy
• Early-stage unfavorable
• Stage I or II with large mediastinal mass with or
  without B symptoms
• Stage I or II with B symptoms, numerous sites of
  disease, or significantly elevated ESR (gt50)
• Advanced stage disease
• Response criteria now revised to incorporate IHC,
  flow cytometry and PET imaging
• Elimination of Complete response uncertain
  (i.e. unable to determine whether residual masses
  on CT scan represented residual HL, scarring or
  some other non-malignant process)
• Response characterized as complete response,
  partial response, stable disease, relapsed
  disease, or progressive disease

9
Hodgkin Lymphoma (HL)

• Patients relapsing after primary chemotherapy or
  chemo-radiation can be salvaged successfully in
  about 60 of cases
• Adverse prognostic factors include early relapse,
  stage III or IV disease and anemia at the time of
  relapse
• Chemosensitivity also strongly influences outcome
• Salvage therapy induction regimens ideally
  should have high response rates and concurrently
  have favorable toxicity profile with little or no
  stem cell toxicity
• Examples of salvage regimens include ICE, DHAP,
  ESHAP, and others
• HDT/ASCT
• In patients with NLPHL, rituximab can be
  considered as an alternative, or as
  supplementation

10
PET Imaging

• First introduced for the management of lymphomas
  in the early 1990s
• Relies on administered positron emitters as
  radiation source, which are created by bombarding
  stable isotopes with protons
• FDG aka 2-fluoro-2-deoxy-D-glucose is commonly
  used. Fluorine-18 is the positron emitting
  radioactive isotope
• FDG, a glucose analog, is taken up by cells where
  phosphorylation prevents the glucose from being
  released intact
• The 2-oxygen in glucose is needed for further
  glycolysis, so that FDG cannot be further
  metabolized in cells, and FDG-6-phosphate that is
  formed does not undergo glycolysis before
  radioactive decay (Fluorine-18 decays to
  oxygen-18)
• Distribution of 18F-FDG is a good reflection of
  the distribution of glucose uptake and
  phosphorylation
• Shortly after emission, the positron interacts
  with an electron to form two gamma rays that are
  emitted - most significant fraction of
  electron-positron decays result in two 511 keV
  gamma photons being emitted at almost 180 degrees
  to each other

11
PET Imaging

• It is possible to localize the source of the two
  gamma photons along a straight line of
  coincidence, aka line of response or LOR
• Using statistics collected from tens-of-thousands
  of coincidence events, a set of simultaneous
  equations for the total activity of each voxel of
  tissue along many LORs can be solved, and a map
  of radioactivities can hence be constructed
• Map of radioactivity can be quantified by
  estimating a parameter referred to as the
  specific uptake value (SUV)
• SUV is an estimate of the relative concentration
  of the imaging probe in the structure of interest
  compared with the average throughout the entire
  body
• Lower spatial resolution of functional PET has
  led to development of dual scanners where PET
  images are co-registered with MRI or CT images
  (typically CT rather than MRI) that have higher
  spatial resolution
• Interpretation can be qualitative (i.e. visual
  interpretation by experienced radiologists) vs.
  semi-quantitative (using SUV as a parameter in
  some fashion)

12
FDG-PET in Lymphoma

• FDG-PET is an important tool for staging and for
  assessing treatment response in HL and NHL
• More recently, emerged as a useful prognostic
  tool when done after 2 to 3 cycles of
  chemotherapy
• Multiple variables to consider that affect the
  performance of PET as a biomarker / prognostic
  tool
• Physiologic FDG uptake influenced by histology,
  grade, viable tumor cell fraction, tumor cell
  proliferation, up-regulation of glucose
  metabolism, local perfusion, mimics, etc
• Equipment and data acquisition (e.g. PET vs
  PET-CT, scanner electronics)
• Image processing techniques and image
  reconstruction algorithms
• Interpretation of data
• Qualitative vs semi-quantitative approach most
  studies to date employ a qualitative approach
  visual analysis
• Dichomatous interpretation are we making full
  use of the available information?
• Interobserver and intraobserver variability
• Whats the gold standard?

13
FDG-PET in Lymphoma

• Given the statistics, one would predict that an
  imaging test in HL would have a high negative
  predictive value as not many patients have
  residual disease after treatment, and a negative
  test result is most likely a true negative
• Conversely, one would predict that a low positive
  predictive value as not many patients have
  residual disease after treatment, and a positive
  test result is most likely a false positive
• When interpreting published studies on PET
  imaging in lymphoma, it is important to bear in
  mind that there have been advances to PET
  technology (e.g. the increasing prevalence of
  dual scanners, innovations in image processing /
  reconstruction, etc) that may affect its
  performance

14
Early Interim PET in HL

• Retrospective study with 85 consecutive patients
  (May 1993 to January 2004) with HL underwent
  FDG-PET after two or three cycle of chemotherapy
• 55 patients were scanned after 2 cycles, and 30
  after 3 cycles
• All patients underwent initial staging FDG-PET as
  well as interim FDG-PET
• Patients were given ABVD as their chemotherapy
  regimen
• Scans interpreted by two experienced nuclear
  medicine physicians and differences decided by
  consensus
• Scored as negative, minimal residual uptake
  (low-grade uptake of FDG just above background in
  a focus within an area of previously noted
  disease felt not likely to represent malignancy),
  and positive
• Follow-up is variable 8 patients were lost to
  follow-up before 2 years after first presentation
• PFS and OS were endpoints for prognostic effect
  of interim FDG-PET
• PPV was 62 and NPV was 94 in this study

Hutchings et al. Ann Oncol 161160-1168, 2005
15
Interim PET in HL

• (A) Progression free survival was 46 over 2
  years for PET positive, and 97 over 2 years for
  PET negative and (B) Overall survival

Hutchings et al. Ann Oncol 161160-1168, 2005
16
Early Interim PET in HL

• Progression free survival in (A) Stage I and II
  and (B) Stage III and IV

Hutchings et al. Ann Oncol 161160-1168, 2005
17
Interim PET in HL

• Prospective study with 40 consecutive newly
  diagnosed patients with advanced HL, stage IIB to
  IVB, mostly NS subtype (June 2003 Sept 2004)
  treated with ABVD x 6 cycles at an Italian center
• PET scans after 2 cycles, 4 cycles, and 6 cycles
• PET2 was positive in 8/40 (20), negative in
  28/40 (70), and MRU in 4 (10)
• PET4 was negative in the 28 PET2 negative
  patients and 2 PET2 MRU patients became PET4
  negative
• PETend was negative in the 30 that were PET4
  negative, and two who were MRU at PET2 and PET4
• No early relapse or PD noted in the 28 PET2
  negative patients
• The 8 PET2 positive patients all had early
  progression/refractory
• 3 of 4 PET2 MRU patients were in CR, and one
  relapsed 5 months after last cycle of ABVD

Zinzani et al. Ann Oncol 171296-1300, 2006
18
Interim PET in HL

• Prospective study with 99 consecutive
  newly-diagnosed HL patients treated at 3 Danish
  centers from 11/2001 to 6/2004
• Stage I (22), stage II (42), stage III (27),
  stage IV (8)
• Majority of patients (85) received ABVD, and
  others received ABV/MOPP (3), ABVD/COPP (2),
  BEACOPPesc (2), and PVAG(2), and RT only (5)
• 77 patients had interim PET 5 RT patients, 1
  died after cycle 1, 2 patients too ill to be
  scanned, and 7 patients non-compliant, 7 patients
  missed scans secondary to scheduling issues
• PFS and OS are endpoints
• All 77 patients had abnormal staging FDG-PET
• PET2 was read as positive in 16 cases
• PPV was 69 and NPV was 95
• PET4 was positive in 13 of 64 cases
• PPV was 85 and NPV was 96
• PETend was positive in 9 of 65 cases

Hutchings et al. Blood 10752-59, 2006
19
Interim PET in HL

• Kaplan-Meier survival curves depicting PFS
  according to FDG-PET and CT results after 2
  cycles of chemotherapy

Hutchings et al. Blood 10752-59, 2006
20
Interim PET in HL

• PET2 was positive in 16 patients
• Positive PET2 predicted primary refractory
  disease in 7 cases
• 4 PET2 positive patients relapsed after having
  reached satisfactory response with first-line
  chemo
• 5 PET2 positive patients were in remission at the
  end of the follow-up period
• 60/61 of PET2 negative patients reached
  remission after first line therapy
• 3 PET2 negative patients subsequently relapsed
• Of the 14 patients with progressive disease, one
  died after rapid clinical progression and was too
  frail to tolerate second-line treatment. 13
  patients went on to second-line chemotherapy and
  autologous transplant

Hutchings et al. Blood 10752-59, 2006
21
PET after 4 cycles in HL

• Kaplan-Meier survival curves depicting PFS
  according to FDG-PET and CT results after 4
  cycles of chemotherapy

Hutchings et al. Blood 10752-59, 2006
22
Post-treatment PET in HL

• Kaplan-Meier survival curves depicting PFS
  according to FDG-PET and CT results at completion
  of chemotherapy

Hutchings et al. Blood 10752-59, 2006
23
Interim PET in HL

• PFS separated by PET/clinical stage PET/presence
  or absence of extranodal disease

Hutchings et al. Blood 10752-59, 2006
24
Interim PET in HL

• Prospective study with 260 patients with newly
  diagnosed advanced-stage HL (stage IIA with at
  least one adverse prognostic factor, IIB- IVB)
• 108 enrolled in Italian centers from Nov 2001, 55
  in Danish centers from Jan 2002 and then the two
  studies were unified beginning 2006, and further
  97 patients recruited
• Most patients treated with 6 cycles of ABVD (249
  patients), 8 received COPP/EBV/CAD for 6 cycles,
  3 received ABVD-like regimen
• 104 patients received consolidation RT
• 137 of 260 patients scanned with PET-CT
• Median follow up was 2.19 years (0.32 to 5.18)
• 205 patients in continued complete remission, 2
  patients in PR, 43 progressed during therapy or
  immediately after (within 6 months), and 10
  relapsed
• PFS and OS chosen as end points
• PPV was 92 and NPV was 95

Gallamini et al. JCO 253746-52, 2007
25
PET as a Prognostic Tool in HL
Gallamini et al. JCO 253746-52, 2007
26
IPS as a Predictor of PFS

• PFS by IPS score

Gallamini et al. JCO 253746-52, 2007
27
Interim PET as a Predictor of PFS

• PFS separated by IPS and PET2 status

Gallamini et al. JCO 253746-52, 2007
28
FDG-PET After Chemotherapy

• Advani et al. looked at the impact of FDG-PET for
  prediction of freedom from progression after
  chemotherapy with Stanford V
• Retrospectively analyzed 81 patients with HL
  (representing about 35 of the number of patients
  treated at the institution during that period)
  who had serial PET scans at baseline and at
  completion of Stanford V chemo but prior to RT
• PET scored by visual analysis by experienced
  board-certified nuclear medicine physician
• After chemo, 6 of 81 patients had residual PET
  activity in sites for which RT was originally
  planned
• 4 of 6 PET positive patients experienced
  progression compared with 3 of 75 patients with
  negative PET scans
• At median follow-up of 4 years, FFP was 96 in
  PET negative patients, and 33 in PET positive
  patients

Advani et al. JCO 253902-7, 2007
29
Negative Predictive Value of PET

• HD15 multicenter European trial involving 1788
  patients (Jan 2003 to May 2007)
• After clinical staging, patients were randomly
  assigned to 3 arms
• Standard arm A had 8 cycles of BEACOPP escalated
• Arm B had 6 cycles of BEACOPP escalated
• Arm C had 8 cycles of time-condensed BEACOPP14
• After 4 cycles of chemotherapy, an interim
  staging was performed, including CT of all
  initially involved regions. PET was performed at
  a median of 21 days after the last administration
  of chemotherapy
• In analysis set 1, 817 patients were included, of
  whom 311 had residual tissue measuring more than
  or equal to 2.5 cm by CT scan after 6 to 8 cycles
  of BEACOPP
• PET scan was positive in 66 patients (21) and
  negative in 245 patients (79)

Kobe et al, Blood 1123989-94, 2008
30
Negative Predictive Value of PET

• Local radiotherapy (30 Gy) was restricted to
  patients in the subset who were PET positive
  after chemotherapy except for one patient who was
  PET negative but had very large initial and
  residual mediastinal mass which was irradiated
  per recommendations by the review panel
• NPV defined as portion of patients without
  progression or relapse within 12 months
• NPV was 94 in this study, which suggested that
  it may be possible to omit consolidation
  radiotherapy in PET negative patients without
  increasing the risk for progression or early
  relapse
• ? Impact of omitting radiation in PET negative
  patients on overall survival still awaiting
  longer term follow-up from this study

Kobe et al, Blood 1123989-94, 2008
31
Negative Predictive Value of Interim PET

• HD15-PET demonstrating a NPV of 94 after 6 to 8
  cycles of BEACOPP for PET patients.

Kobe et al, Blood 1123989-94, 2008
32
Interim PET and Response-Adapted Therapy

• Prospective multicenter study for patients, aged
  18 to 65 years, with classical Hodgkin disease
  (1999-2004)
• Stage I-II with one or more unfavorable features
  B symptoms, bulky disease, 4 or more sites of
  disease, age 50 years or older, erythrocyte
  sedimentation rate (ESR) 50 mm/h or higher,
  lymphocyte-depleted histology, "E" site or stage
  III-IV disease
• Low-risk patients with an early unfavorable
  disease and standard-risk patients with an IPS of
  2 or less were treated with 2 cycles of standard
  BEACOPP (SB)
• High-risk patients were defined as patients with
  an IPS of 3 or higher and received 2 cycles of
  escalated BEACOPP (EB)
• PET scan done after 2 cycles

Dann et al. Blood 109904-909, 2007
33
Study Design

• Includes
• 58 early unfavorable or
• standard risk
• 31 high risk

69
39

• Includes
• 10 early unfavorable or
• standard risk
• 7 high risk

• Overview of study design

Dann et al. Blood 109904-909, 2007
34
Results
Dann et al. Blood 109904-909, 2007
35
Clinical Case - Continued

• Post chemotherapy, patient underwent a repeat
  PET-CT (approximately one month after completion
  of chemotherapy) in Nov 2008
• Read as Interval development of enlarged FDG
  avid pancreaticoduodenal and left paraaortic
  lymph nodes, as well as moderately increased
  metabolic activity in normal sized left
  supraclavicular lymph nodes, most consistent with
  recurrence
• Follow-up PET-CT in January 2009
• Read as Progression of disease with new or
  increased FDG-avid pancreaticoduodenal,
  mesentery, retroperitoneal, pelvic, mediastinal,
  and left supraclavicular lymphadenopathy
• Left supraclavicular lymph node biopsy confirms
  HD
• Repeat bone marrow biopsy for restaging negative
• Now undergoing salvage chemotherapy with ICE and
  referred for evaluation for transplant

36
PET in Salvage and Pre-Transplant Setting

• Transplant-eligible patients with relapsed and
  primary refractory HL
• 3 pre-second line chemotherapy risk factors
• Remission duration of lt1 yr, extra-nodal disease
  and B symptoms
• Ongoing phase II risk-adapted study
• Favorable risk (01 RF) - one cycle of standard
  dose ifosfamide, carboplatin and etoposide (ICE)
  followed by one cycle of augmented ICE
• Unfavorable risk (2-RF)- 2 cycles of augmented
  ICE.
• All pts then underwent a restaging FDG-PET and
  the results determined the next treatment
• PET negative -gt HDT/ASCT
• PET positive -gt four biweekly cycles of GVD
  (gemcitabine, vinorelbine and liposomal
  doxorubicin) -gt PET scan -gt if without
  progression -gt HDT/ASCT
• Radiation therapy-naïve patients -gt involved
  field radiotherapy (IFRT) followed by total
  lymphoid irradiation
• Selected previously irradiated patients -gt only
  IFRT

Moskowitz et al. Blood (ASH Annual Meeting
Abstracts) 2008 112 Abstract 775
37
PET in Salvage and Pre-Transplant Setting

• 62 evaluable patients, 48 of whom had remission
  duration lt 1 year 28 primary refractory, 28
  extra-nodal disease, 11 with B symptoms
• All patients previously failed doxorubicin-based
  chemo, 18 had prior XRT, 13 of those failed in
  radiation field
• Median follow-up of surviving patients is 30
  months and median age was 35.
• After first salvage ICE
• 37 normalized PET scan of whom 31 were event free
• 25 with improving CT scans but positive PET, who
  then received GVD
• 13 normalized PET scan, of whom 11 were event
  free
• 12 had persistently positive PET, of whom 4 were
  event free
• Total of 46/62 (65) patients were event-free at
  time of report, and one died from sepsis

Moskowitz et al. Blood (ASH Annual Meeting
Abstracts) 2008 112 Abstract 775
38
PET and EFS

• EFS separated by PET

Moskowitz et al. Blood (ASH Annual Meeting
Abstracts) 2008 112 Abstract 775
39
Summary

• FDG-PET is a modality capable of providing
  functional data for assessing treatment response
  and prognosis in lymphoma
• Many published studies suffer from suboptimal
  methodology, in part secondary to the fact that
  there have been advances in imaging technology
  since the studies were conducted, and the lack of
  established guidelines for interpretation
• Despite the limitations, a negative PET appears
  to exclude residual disease with reasonably high
  certainty (our case aside)
• Positive PET should be approached cautiously
• Prospective clinical trials are needed to
  investigate whether response-adapted therapy
  modifications (e.g. de-escalation of therapy)
  based on early interim PET is in fact prudent
• At this time, there is insufficient evidence to
  support abbreviation of treatment on the basis of
  a negative interim PET

40
Upcoming/on-going trials

• PET as a tool for response-adapted therapy

41
Clinical Trials PET and Response-Adapted Therapy

• German Hodgkin Study Group (GHSG) HD16 trial
• Early favorable stage patients
• Two double cycles of ABVD and PET after the end
  of chemotherapy
• Standard arm will receive 30 Gy of involved field
  radiation (IF-RT) irrespective of PET results
• Experimental arm will receive IF-RT only if PET
  is positive after chemotherapy. No further
  therapy will be given if PET is negative

2 double cycles of AVBD
Standard Arm
Experimental Arm
IF-RT regardless of PET results
PET positive
PET negative
IF-RT
No further treatment
42
Clinical Trials PET and Response-Adapted Therapy

• EORTC / GELA H10U trial (Unfavorable group)
• ABVD x 2 cycles, then PET scan after 2 cycles
• Standard arm to receive ABVD x 4 cycles
  involved node RT (IN-RT) 30 Gy ( boost of 6 Gy
  to residual lesions) regardless of PET scan
  results
• Experimental arm will receive therapy based on
  PET results. If PET negative, to receive 2
  further cycles of ABVD with no further RT. If PET
  positive, presumed poor-risk, and will receive
  escalated BEACOPP x 2 and INRT 30 Gy (boost 6 Gy
  to residual lesions)

Standard Arm
Total of ABVD x 4 cycles INRT
Escalated BEACOPP x 2 INRT
ABVD x 2 cycles PET scan
PET positive
Experimental Arm
2 further cycles of ABVD No RT
PET negative
43
Clinical Trials PET and Response-Adapted Therapy

• EORTC / GELA H10F trial (Favorable group)
• Stage I-II supradiaphragmatic patients stratified
  into favorable and unfavorable groups
• ABVD x 2 cycles, then PET scan after 2 cycles
• Standard arm to receive ABVD x 3 cycles
  involved node RT (IN-RT) 30 Gy ( boost of 6 Gy
  to residual lesions) regardless of PET scan
  results
• Experimental arm will receive therapy based on
  PET results. If PET negative, to receive 2
  further cycles of ABVD with no futher RT. If PET
  positive, presumed poor-risk, and will receive
  escalated BEACOPP x 2 and INRT 30 Gy (boost 6 Gy
  to residual lesions)

Standard Arm
Total of ABVD x 3 cycles INRT
Escalated BEACOPP x 2 INRT
ABVD x 2 cycles PET scan
PET positive
Experimental Arm
2 further cycles of ABVD No RT
PET negative
44
Clinical Trials PET and Response-Adapted Therapy

• UK NCRI, Italian and Nordic Trial for advanced HL

Staging, including baseline PET-CT
ABVD x 2 then PET-CT
PET negative
PET positive
Randomization
BEACOPP-14 x 4 then PET-CT
ABVD x 4
AVD x 4
PET negative
PET positive
BEACOPP-14 x 2
Radiation or Salvage
Treatment assessment at end of treatment
45
References

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  Mar46(2)225-41
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• Dann EJ, Bar-Shalom R, Tamir A, et al.
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  predictive value for progression or early relapse
  for patients with residual disease after
  first-line chemotherapy in advanced-stage Hodgkin
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  Normalization of FDG-PET Pre-ASCT with
  Additional Non-Cross Resistant Chemotherapy
  Improves EFS in Patients with Relapsed and
  Primary Refractory Hodgkin Lymphoma-Memorial
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