DLBCL limited stage

1. Journal
Club
Presenter: Dr. Narayan Adhikari
Moderator: Dr. Ahitagni Biswas
Date: 13/02/2016

3. Contents
•Background
•Article Proper
•Review of literature
•Strengths
•Limitations
•Conclusion

4. • DLBCL - most common histologic subtype of NHL ~ 25 % of NHL cases
• Presentation- rapidly enlarging symptomatic mass, usually nodal
enlargement in the neck or abdomen
• Systemic "B" symptoms (i.e. fever >38°C, weight loss >10% in
preceding 6 months, drenching night sweats) in ~30 % of patients
• Large, transformed B cells with prominent nucleoli and basophilic
cytoplasm, a diffuse growth pattern and a high proliferation fraction
• Express pan B cell antigens (CD19, CD20, CD22, CD79a)
Background
Morton LM, et al. Lymphoma incidence patterns by WHO subtype in the United States,
1992-2001. Blood 2006; 107:265

5. Lymph node Regions
AJCC Cancer Staging Manual, 7E (2011)

6. Ann Arbor Classification and
the Cotswold Modifications
Armitage JO. Staging non-Hodgkin’s lymphoma. CA Cancer J Clin2005;55:368–37

7. Ann Arbor Staging(contd)
AJCC Cancer Staging Manual, 7E (2011)

8. NWorkup
NCCN guidelines, version 2.2015 NHL

9. Prognostic Index
NCCN guidelines, version 2.2015 NHL

10. Treatment guidelines
NCCN guidelines, version 2.2015 NHL

11. Treatment guidelines
NCCN guidelines, version 2.2015 NHL

12. • Involved field radiotherapy (IFRT) – the pre-chemo involved lymph
node region is treated, planned with bony landmarks usually by 2D
• Involved node radiotherapy (INRT) – the only pre chemo involved
node is treated to minimise treatment volumes with co-registration
of pre-chemotherapy imaging in the treatment position
• Involved site radiotherapy (ISRT) – similar to INRT with a 1.5cm
margin superiorly and inferiorly from the INRT CTV
• Involved lesion radiotherapy (ILRT)- close to the concept of ISRT, the
term used in the article being discussed
• Current NCCN guideline recommends ISRT
• For post chemo CR, doses upto 30-36 Gy, for post chemo PR/SD,
doses upto 40-50Gy @ 1.8-2 Gy/#
Radiation Therapy
NCCN guidelines, version 4.2014 NHL

13. Radiation Therapy

14. • Stage I and II non-bulky: 3-4 cycles of R-CHOP f/b IFRT
• Stage I and II bulky: 6 cycles R-CHOP f/b IFRT
• Post chemo CR: 30Gy/15#/3wks
• Post chemo PR/SD: 36Gy/18-20#/3.5-4wks
IRCH Practice

15. Evidence(Pre - Rituximab and
Functional Imaging Era)

16. lts
MInT Trial:
• N= 824 (18 countries)
• Age 18–60 years
• No risk factors or one risk factor according to age-adjusted IPI, stage II–
IV disease, or stage I disease with bulk
• 6 CHOP-like chemo and rituximab (n=413) vs 6 CHOP-like chemo alone
(n=411)
• RT if bulky and extranodal sites
• Stage I and II =72%
• Results
• 6-year OS rate: 90.1% vs 80% (P = .0004)
• 6-year EFS rate: 74.3% vs. 55.8% (P < .0001)
• PFS rate: 80.2% vs. 63.9% (P < .0001)
Evidence
Pfreundschuh M, et al. 6-year results of an open-label randomised study of the MabThera
International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22

17. • Exploratory study of the MInT trial - addition of rituximab reduced
but did not eliminate the adverse prognostic effect of tumor bulk
• In a multivariable analysis with MTD as a linear regression variable,
• CHOP : EFS (HR 1·090 [1·051–1·130], p<0·0001) and OS (1·119 [1·057–1·184],
p=0·0001)
• R-CHOP : OS (1·089 [1·003–1·183], p=0·043), EFS significant when bulk is
taken as >10cm
Evidence
Pfreundschuh M, et al. An exploratory analysis of the MabThera International Trial Group
(MInT) study. Lancet Oncol. 2008;9:435-44

18. • The UNFOLDER study (DSHNHL 2004-3)
• RT to bulky and extralymphatic disease
• ‘No RT’ arm had to be eliminated because of compromised outcomes in
interim analysis, suggesting the definitive role of RT
Ongoing trials
R
A
N
D
O
M
I
Z
E

19. • ASPIRE trial
R
A
N
D
O
M
I
Z
E
Ongoing trials
Phase III RCT, verified in 2014, not yet recruiting, estimated
year of completion 2020

20. • No RCTs in Rituximab era to define the role of RT
• Some phase II studies, retrospective studies, showing role of RT in
limited stage DLBCL in Rituximab era
• Does the benefit of RT in pre Rituximab era still remain?
• Is the involved lesion radiotherapy as effective as involved field
radiotherapy?
Why this article?

21. Article Proper

22. Materials and Methods
213 treated patients of newly pathologically confirmed limited stage DLBCL from July
2004 to December 2012 in Seoul National University hospital, Seoul, Korea
15 who didn’t receive
R-CHOP excluded,
PCNSL excluded
No RT
n=155
RT
n=43
Analysis according to patient
demographics, treatment, clinical
outcomes

23. • Medical history including B symptoms, physical examination
• ECOG performance status
• Complete blood count
• Serum lactate dehydrogenase (LDH) concentration
• CT neck-chest-abdomen
• Positron-emission tomography/CT (PET/CT)
• Bone marrow biopsy
Materials and Methods
(Staging Workup)

24. • Pathologic review performed in all patients, and Ki-67 evaluated in
90.9% of subjects
• Limited stage defined as Ann Arbor stages I or II
• Bulky disease - any tumor mass measuring ≥7 cm regardless of site
• International Prognostic Index (IPI) scores calculation all patients
Materials and Methods
(Staging Workup contd)

25. • All patients received R-CHOP chemotherapy
• Most cases with initial bulky disease or failure to achieve complete
response to R-CHOP referred to a radiation oncologist after
chemotherapy
• Patients with poor tolerance to R-CHOP also considered for RT after 3
or 4 cycles of R-CHOP
Materials and Methods
(Treatment)

26. • RT delivered to the initial tumor volume prior to chemotherapy for all
lesions with a median 2 cm (range, 0.5-2 cm) CTV margin with or
without boost to residual lesion
• Uninvolved adjacent nodal regions not included in the CTV
• Only the initially involved parts of extranodal sites treated
• Additional PTV expansion of 0.3 to 0.5 cm performed to account for
setup variation
• Median RT dose 36 Gy (range, 25-54 Gy) at 1.8 to 2 Gy per fraction
• 3DCRT technique used in most patients (74.4%) conventional RT in
13.9% and IMRT 2.3%
Materials and Methods
(Treatment contd)

27. • Response to R-CHOP assessed according to consensus guidelines
issued by the imaging subcommittee of International Harmonization
Project in Lymphoma
• Complete response (CR) defined as
• negative FDG uptake in a PET-positive tumor prior to R-CHOP therapy
regardless of size of residual lesion on CT
• In case of variable FDG-avid or FDG-avidity unknown tumors, disappearance
of extranodal lesion or regression of nodal lesion to normal size on CT
• Other responses not meeting above definition of CR as non-CR
Materials and Methods
(Response Evaluation)

28. • PFS and OS evaluated as clinical endpoints
• PFS defined as duration between the date of first R-CHOP
administration and the date of progression, recurrence, death, or last
available follow-up
• OS defined as time between the date of first R-CHOP administration
to death or last available follow-up
• Statistical analysis performed using SPSS version 21.0 software
• Survival probabilities estimated using the Kaplan-Meier method
Materials and Methods
(Endpoints and statistical analysis)

29. • Pearson χ2 test used to determine the significance of intergroup
differences in discontinuous variables, and the independent t test
used for continuous variables
• Comparisons of survival according to clinical parameters performed
using the log-rank test
• Multivariate analysis performed using Cox regression hazard analysis
with the backward conditional selection method (variables with P
values of >.10 were sequentially removed from the model at each
step)
• P values of <.05 considered statistically significant
Materials and Methods
(Endpoints and statistical analysis contd)

30. Results
(Patients characteristics)

31. Results
(Patients characteristics contd)

32. Results
(Survival Analysis-univariate)

33. Results
(Survival Analysis-univariate)

34. Results
(Survival Analysis-multivariate)

35. Results
(Impact Of ILRT, subgroup analyses)
Fig: PFS and OS according to receipt of RT in patients with bulky disease (a and b)

36. Results
(Impact Of ILRT, subgroup analyses)
Fig: PFS and OS according to receipt of RT in patients with with elevated serum
LDH (c and d)

37. • Statistically significant 3 year PFS(P=0.041) benefit with ILRT in Stage
II patient [3 year OS(P=0.096)]
• Marginal statistically significant 3 year PFS(P=0.054) and OS(P=0.064)
benefit in non-CR to R-CHOP arm
• 3 year PFS(P=0.079), OS(P=0.081) in Ki67≥50 arm
Results
(Impact Of ILRT, subgroup analyses)

38. • Failure in 18 patients during follow up
• 12/18 (66.7%) in initial tumor bed
• Out of 12, 5 were accompanied with simultaneous distant failure
• Out of 18, only 2 (11%), received ILRT, 1 isolated distant, 1 both initial
and distant site
• Crude local control of RCHOP with ILRT 97.7%
Results
(Patterns of Failure)

39. • Chemotherapy induced
• 95/196 (48.5%) grade 3-4 neutropenia
• 60/196 (30.6%) neutropenic fever
• 19/194 (9.8%) grade 3 anemia
• 65/170 (38.2%) peripheral neurotoxicity
• 3 died of infection, 2- pneumonia, 1- liver abscess, superimposed on
treatment related neutropenic fever
• 1 chemotherapy induced acute myeloid leukemia, 1 severe bone marrow
suppression
• Radiotherapy induced
• 6/43 grade I or II toxicity (4 GI, 1 dermatitis, 1 xerostomia, 4 relieved with
conservative management)
• No grade 3 or more toxicity and secondary malignancy reported due to RT
Results
(Treatment related toxicities)

40. Review of Literature
SWOG 8736
• Median age: 59
• Normal LDH: 80%
• PS 0-1: 97%
• % stage II: 32%
• Excl. bulky stage II
Miller TP et al. N Engl J Med 1998;339:21-26

41. Review of Literature
Miller TP et al. N Engl J Med 1998;339:21-26
OS at 5 years 72% vs 82 % (P = .02)PFS at 5 years 64% vs 77 % (P = .03)
Updated data at median f/u of 8.2 yrs: FFS
and OS curves overlapped (Abstract only)

42. ECOG 1484
• Median age: 59
• % stage II: 68%
• % bulky: 31%
• N=399, CR=215
Review of Literature
Horning et al. JCO, 2004

43. Review of Literature
ECOG 1484
8 CHOP plus RT vs no RT
DFS at 6 years 73% with RT vs 56% without RT (P = .05)
Horning et al. JCO, 2004

44. Review of Literature
(A) OS (B) PFS of patients achieving CR after
treatment with RCHOP with and without RT
• N=469
• Stage I and II=40%, stage III and IV=60%
• 70% 6 cycles R-CHOP
• 84% received R-CHOP based chemotherapy
• 30% received IFRT to 30-39.6 Gy after CR
• Median follow up = 36 months
Phan et al. JCO, 2010

45. • 5-year OS and PFS rates for stage I and II disease treated with RT vs no RT
• 5 year OS 92% vs 73% (P = .0007)
• 5 year PFS 82% and 68% (P = .0003)
• Multivariate analysis influencing PFS and OS
• RT (P < .0001)
• IPI score (P = .001)
• Response to therapy (P = .001)
• Use of six to eight cycles of R-CHOP (P < .001)
• Combined presence (P = .006) or absence (P = .025) of high Ki67 (≥50), high PET
SUV (≥13), and bulky disease (≥5cm)
• 100% local control rate in those received IFRT
• Matched pair analysis also showed benefit of RT in all stages
Phan J, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-
cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 2010;28:4170-4176
Review of Literature

46. Review of Literature
• Stage I, IE, II or IIE DLBCL treated
between 1988 and 2004
• 13,420 patients met the criteria
• 41% received RT
Ballonoff et al, IJROBP 2008

47. Review of Literature
Kaplan-Meier survival curves comparing patients who underwent RT to
those who did not, showing significant survival advantage with RT
Ballonoff et al, IJROBP 2008

48. Review of Literature

49. Review of Literature
Murray et al, Clin Onc 2015

50. • Compared with ISRT, IFRT significantly increased doses to lung,
thyroid, heart and oesophagus, whereas INRT and residual volume
techniques significantly reduced doses to all OARs
• The relative risks of second cancers significantly higher with IFRT
compared with ISRT for lung, breast and thyroid
• INRT and residual volume resulted in significantly lower relative risks
compared with ISRT for lung, breast and thyroid
• The median excess absolute risks of second cancers consistently
lowest for the residual technique and highest for IFRT in terms of
thyroid, lung and breast cancers
• The risk of oesophageal cancer similar for all four techniques
• The absolute risk of second cancers was very similar for ISRT and
INRT
Review of Literature
Murray et al, Clin Onc 2015

51. • N=258, stage I/II aggressive NHL (77% DLBCL), IFRT = 191, INRT = 67
• 87 % CMT and 13% RT alone, chemo CHOP-like in 73% and CHOP-like with
Rituximab in 26%,
• RT 30–40 Gy in 15–20 fractions
• Type of RT not related to the outcome in either the uni- or multivariate
survival analysis
• Relapses in 59 of 252 (23%) of which 47 (80%) distant recurrence only
• Failure of the INRT technique noted in 1 patient
• No significant difference in acute radiation-related toxicity between RT-
groups but IFRT showed a significantly higher incidence of higher grade late
toxicities, QoL better in INRT group
Review of Literature
Verhappen et al, Radiotherapy and Oncology Oct 2013

52. Review of Literature
Verhappen et al, Radiotherapy and Oncology Oct 2013

53. Review of Literature
Verhappen et al, Radiotherapy and Oncology Oct 2013

54. • retrospective study, n=86
• limited stage head and neck DLBCL and treated with RT, delivered to
prechemotherapy tumor volumes with a 1-cm margin after chemotherapy
• 83.7% received CHOP, and 16.3% received R-CHOP therapy
• Median follow up = 57 months
• 5-year OS and PFS rates 89.2% and 88.9%
• 8 treatment failures, 8 distant, 4 locoregional, 3 in-field, 1 both in and out-field
recurrence, crude relapse rate= 9.3%
• Multivariate analyses - absence of B symptom (p = 0.022) and normal LDH (p =
0.017) related to favorable OS, age <60 years (p = 0.033) related to favorable FFP,
and IPI of 0 or 1 related to favorable OS (p = 0.003) and FFP (p = 0.03)
Review of Literature
Yu et al, IJROBP 2010

55. • Highlights the importance of consolidation RT in stage I and II DLBCL
after RCHOP based chemotherapy, especially in patients with bulky
disease and elevated serum LDH in rituximab era for which a phase III
RCT is not available and is not expected to come soon
• Benefits of ILRT over IFRT with no compromise in disease control has
been tried to be incorporated in the study
• Generates further research questions for benefits of RT in other
subgroups like high proliferation index, non CR to chemo, stage I vs
stage II
• Incorporates PET/CT for response analysis
Strengths

56. • Retrospective study with low sample size and grossly uneven
distribution of number of study subjects in 2 arms(RT vs no RT)
• ILRT is less defined term than ISRT and INRT, previously used once in
a retrospective study of Head and Neck DLBCL
• Even though role of RT is not significant in univariate analysis, it is
analysed in multivariate analysis which comes out to be significant
• Smaller follow up time
• PFS and OS of cohort with bulky disease and elevated serum LDH
treated with RT is more than PFS and OS of entire cohort treated with
RT, may be because of many other adverse prognostic factors but due
to large heterogenecity and smaller sample size of the study, it needs
further validation with well designed RCTs
Limitations

57. • RT has survival benefits in localised DLBCL after 6 cycles of RCHOP
immunochemotherapy especially in patients with bulky disease and
elevated serum LDH, may have possible survival benefit in patients
with high proliferation index, post-chemotherapy residuum & stage II
disease
• Compared to IFRT, ISRT/ILRT/INRT may reduce toxicity and chances of
second malignancy without compromising disease control, so limited
volume RT may be incorporated in the treatment algorithm unless
there is resource limitation and high patient load
• Multidisciplinary approach is a must in the treatment of localised
DLBCL
Conclusion