limited stage dlbcl role of radiotherapy

JournalClub

Presenter: Dr. Narayan AdhikariModerator: Dr. Ahitagni Biswas

Date: 13/02/2016

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

• 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

Lymph node Regions

AJCC Cancer Staging Manual, 7E (2011)

Ann Arbor Classification and the Cotswold Modifications

Armitage JO. Staging non-Hodgkin’s lymphoma. CA Cancer J Clin2005;55:368–37

Ann Arbor Staging(contd)

AJCC Cancer Staging Manual, 7E (2011)

NWorkup

NCCN guidelines, version 2.2015 NHL

Prognostic Index


Treatment guidelines


• 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


Radiation Therapy

• 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

Evidence(Pre - Rituximab and Functional Imaging Era)

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

• 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

• 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

18-60 years patients with age adjusted IPI of 1

or IPI 0 with bulky

tumour(≥7.5cm)

R-CHOP-21

RT

No RT

R-CHOP-14

RT

No RT

RANDOMIZE

• ASPIRE trial

Localized CD20+ DLBCL

6 R-CHOP

3 R-CHOP+RT

RANDOMIZE

Ongoing trials

Phase III RCT, verified in 2014, not yet recruiting, estimated year of completion 2020

• 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?

Article Proper

Materials and Methods213 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 RTn=155

RTn=43

Analysis according to patient demographics, treatment, clinical

outcomes

• 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)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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)

Results(Patients characteristics)

Results(Patients characteristics contd)

Results(Survival Analysis-univariate)

Results(Survival Analysis-multivariate)

Results(Impact Of ILRT, subgroup analyses)

Fig: PFS and OS according to receipt of RT in patients with bulky disease (a and b)


Fig: PFS and OS according to receipt of RT in patients with with elevated serum LDH (c and d)

• 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


• 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)

• 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)

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


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)

ECOG 1484 • Median age: 59• % stage II: 68%• % bulky: 31%• N=399, CR=215


Horning et al. JCO, 2004


ECOG 1484 8 CHOP plus RT vs no RTDFS at 6 years 73% with RT vs 56% without RT (P = .05)

Horning et al. JCO, 2004


(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

• 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



• 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


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


Murray et al, Clin Onc 2015

• 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


Murray et al, Clin Onc 2015

• 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


Verhappen et al, Radiotherapy and Oncology Oct 2013


Verhappen et al, Radiotherapy and Oncology Oct 2013

• 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)


Yu et al, IJROBP 2010

• 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

• 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

• 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

limited stage dlbcl role of radiotherapy

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