Diffuse Large B-Cell Lymphoma

Diffuse Large B-Cell Lymphoma
Treatment policy prepared by
Dr. Kevin Imrie, Dr. Mary Doherty & Dr. Robert MacKenzie
Policy Revised July 2001
Major changes:
Classification of Management of Localized Disease
Addition of Rituximab to CHOP in the Elderly
1. Introduction
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma
in the WHO classification, accounting for 31% of all lymphomas [1]. This entity
consists of cases that would have been classified as diffuse large cell lymphoma
(Subtype G) and immunoblastic lymphoma (Subtype H) in the working formulation
[2]. The terms, intermediate grade and DLBCL are not completely synonymous
however, as intermediate grade in the working formulation includes lymphomas of T-
cell origin as well as diffuse small cleaved cell lymphoma (Subtype E).
2. Diagnosis
The diagnosis of DLBCL is dependent on an adequate biopsy specimen (preferable
open surgical biopsy) with immunohistochemistry. Diffuse large B-cell lymphomas
are composed of large cells (at least twice the size of small lymphocytes), which
mark for B-cell markers such as CD19 and 20. The entity should be distinguished
from peripheral T-cell lymphoma, anaplastic large cell lymphoma (CD 30 positive)
and primary mediastinal B-cell lymphoma with sclerosis [2].
3. Baseline Investigations
The following investigations are indicated for most patients with DLBCL:
• CBC, differential, blood film
• Serum electrolytes and creatinine
• Liver function tests
• Serum LDH
• Serum uric acid
• HIV serology
• Chest x-ray
• CT chest, abdomen, pelvis
• Unilateral bone marrow biopsy
• Total body gallium scan
Patients who will be managed with palliative intent may have more limited
staging investigations with a focus on identification of disease that is likely to
require symptomatic management.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 1/14

CSF Analysis
A lumbar puncture to evaluate leptomeningeal involvement with lymphoma should
be performed in patients with:
• Bone marrow involvement
• Testicular lymphoma
• HIV positivity
• Paraspinal, sinus or vertebral involvement
• Multifocal bone involvement
• Elevated LDH and > 1 extra nodal sites
• Unexplained neurologic symptoms
Samples should be sent for cell count, protein and 5-10cc should be sent for
cytologic examination.
Gallium Scan
A total body gallium scan should be performed in all patients being treated with
curative intent, particularly those who would be considered for salvage therapy and
stem cell transplantation if not in complete remission after initial therapy.
HIV Serology
B-cell lymphoma is the most common malignancy associated with HIV infection. As
HIV lymphoma is treated differently and risk factor assessment is imperfect in
identifying HIV positive patients, most patients with DLBCL should undergo HIV
serology testing at diagnosis. If serology testing is not planned, patients should be
asked in detail regarding risk factors, including blood transfusion, intravenous drug
use and sexual contact with persons who may have been at risk for HIV.
Cardiac Assessment
A cardiac assessment should be performed in all patients potentially eligible for
anthracycline-based chemotherapy (such as CHOP). MUGA scan or 2Dechocardiogram
should be performed in all patients with a history of:
• Age > 60
• Hypertension
• Congestive heart failure
• Peripheral vascular disease
• Cerebrovascular disease
• Angina
• Cardiac arrythmia
• Myocardial infarction
2/14

Diffuse Large B-Cell Lymphoma
4. Staging
Patients with DLBCL should be staged according to both the Ann Arbor and IPI
staging systems [3].
Ann Arbor Stage
The Ann Arbor staging system continues to be in use in DLBCL. This system
provides limited prognostic information, but is of use in determining patients eligible
for treatment with combined modality therapy. All patients should have an Ann Arbor
stage assigned.
Stage Definition
I
II
III
IV
Involvement of a single lymph node region or a single extranodal
site.
Involvement of two or more lymph nodes on the same side of the
diaphragm or localized involvement of an extra lymphatic organ or
site and one or more lymph nodes on the same side of the
diaphragm.
Involvement of lymph node regions on both sides of the diaphragm
that may also be accompanied by involvement of the spleen or by
localized involvement of an extra lymphatic organ or site or both.
Diffuse or disseminated involvement of one or more extra lymphatic
organs or tissues, with or without associated lymph node
involvement.
The absence or presence of fever > 38.5°C, drenching night sweats, and/or
unexplained weight loss of 10 percent or more body weight in the six months
preceding admission are to be denoted in all cases by the suffix A or B respectively.
The International Prognostic Factor Index
The International Prognostic Factor Index (IPI) provides more precise and
reproducible prognostic information than the Ann Arbor stage, but does not
distinguish patients eligible for combined modality therapy for localized disease [4].
The IPI stage is dependent on five prognostic factors: Age, Ann Arbor stage,
Performance status, LDH and number of extranodal sites.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 3/14

Development of a Prognostic Factor Model: The International Index and Age-Adjusted Index
Risk Group
Risk
Factors
Distribution
of cases
CR
Rate (%)
RFS OF CRs (%) Survival (%)
2-yr 5-yr 2-yr 5-yr
Rate Rate Rate Rate
A. International Index (patients of all ages)
Low (L)
0, 1
Low-intermediate (LI) 2
High-intermediate (HI) 3
High (H)
4, 5
35
27
22
16
87
67
55
44
79
66
59
58
70
50
49
40
84
66
54
34
73
51
43
26
B. Age-adjusted Index Applied to Patients ≤ 60 yrs of Age
Low (L)
Low-intermediate (LI)
High-intermediate (HI)
High (H)
0
1
2
3
22
32
32
14
92
78
57
36
88
74
62
61
86
66
53
58
90
79
59
37
83
69
46
32
C. Age-Adjusted Index Applied to Patients > 60 yrs of Age
Low (L)
Low-intermediate (LI)
High-intermediate (HI)
High (H)
0
1
2
3
18
31
35
16
91
71
56
36
75
64
60
47
Adapted from information appearing in The New England Journal of Medicine.
46
45
41
37
80
68
48
31
56
44
37
21
Clinical Characteristics of Patients ≤ and >60 Years of Age
≤60 yrs (%) >60 yrs (%)
Advanced stage (III/IV)
Elevated serum LDH
Non-ambulatory performance status (2-4)
> 1 Extranodal disease site
64
41
19
30
68
39
19
30
5. Management of Localized Disease
General Recommendations
Patients presenting with localized (stage I-II) DLBCL generally have a good
prognosis. Combined modality therapy in most series is associated with less
cardiac toxicity and longer survival [5]. Most patients with stage I-IIA DLBCL
should receive combined modality therapy. Such patients should be seen in
consultation by a radiation oncologist early in order to plan radiotherapy soon
after completion of chemotherapy. Three cycles of CHOP (Appendix B)
should be administered at 3 weekly intervals Response will be assessed by
CT scan 3-4 weeks after the third cycle. Patients in CR/CRU after
chemotherapy will receive 3000 cGy in 15 fractions. Patients who have had a
reduction in tumor mass > 50% (PR) and have a residual abnormality < 5cm
will receive involved field XRT to 3000 cGy in 15 fractions with a boost of 600
cGy in 3 fractions to residual disease. Patients who have not achieved at
least a PR or who have residual bulk > 5cm will receive 3 further CHOP and
will be re-staged after 6 cycles with a plan to proceed to radiation with doses
described above.
4/14

Diffuse Large B-Cell Lymphoma
Radiation alone: Favorable outcome has been reported for patients under age
65, stage IA DLBCL with bulk < 2.5cm [6]. Outcome is poor for patients with bulk >
2.5cm and those over age 65. Therapy with radiation alone can be considered for
patients under 65 with stage IA disease with bulk < 2.5cm, as well as patients with
localized disease who are felt to be at high risk from anthracycline-based
chemotherapy. Such patients should receive 3000 cGy in 15 fractions to the volume
of presumed microscopic disease and a boost of 600 cGy in 3 fractions to the
involved volume.
Certain specific sites such as bone, breast, CNS, gastric, small bowel, testis
and thyroid require special considerations.
Bone: Patients with localized (monostotic) bone lymphoma have a very favorable
prognosis with long term survival of > 90% [7]. Surgery should be limited to biopsy
only; where possible patients should undergo MRI of the involved area to delineate
extent of involvement. Patients should receive 4-6 cycles of CHOP followed by
radiation. Radiation should be given to whole bone or to area defined by MRI if
available. 3600 cGy should be administered in 18 fractions with a boost to 4400 cGy
in 22 fractions to unresected gross disease, if present. Radiation alone can be
considered for patients with monostotic bone lymphoma who are at high-risk from
anthracycline-based chemotherapy as many series report 5-year survival rates of
40-60% with radiation alone. Patients with multiple bony sites (polyostotic) are at
higher risk and should receive 6 cycles of CHOP followed by irradiation of areas of
bulk disease using the above fractionation schemes.
Breast: Patients with lymphoma of the breast should undergo excisional biopsy.
Mastectomy and axillary lymph node dissection are not required [8, 9]. Patients with
stage IEA disease and bulk < 3cm have a favorable prognosis and can be treated
with post-op radiation to the breast, axilla and supraclavicular fossa to a dose of
3000 cGy in 15 fractions with a boost of 600 cGy in 3 fractions to the site of bulk.
Survival rates of > 80% is expected in all age groups. Patients with stage IEA & bulk
> 3cm as well as stage IIEA should receive 3 cycles of CHOP and radiation to
breast, axilla and supraclavicular fossa to a dose of 3000 cGy in 15 fractions.
CNS: Primary CNS lymphoma is rare, accounting for < 3% of all intracranial
neoplasms [10]. It is clinically quite distinct from other aggressive histology
lymphomas in that it pursues a locally aggressive course, but does not tend to
disseminate. Although radiation treatment results in complete radiologic (CT)
response in 80% of patients, median survivals are up to 2 years with the majority of
patients relapsing locally despite doses of 6000 cGy in 30-33 fractions. In addition, it
is relatively unresponsive to standard anthracycline-based chemotherapy regimens
such as CHOP. The best published survival rates are from an institutional study of
combined modality therapy with high dose methotrexate chemotherapy and whole
brain irradiation to 4000 cGy plus a boost of 1440 cGy [11]. This form of treatment is
effective at delaying recurrence, but is associated with the potential for severe
delayed brain injury.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 5/14

The current recommended management in our centre is the use of high-dose
chemotherapy with high-dose methotrexate, vincristine and procarbazine without
radiation. If the patient is unfit for chemotherapy, whole brain radiation 2000 cGy in 5
fractions should be given if the intent is palliative or 5000 cGy in 25 fractions if the
intent is aggressive and patient is under age 70. If the patient has previously
received chemotherapy, the recommended dose is 3600 cGy in 20 fractions.
Gastric: Gastric lymphoma is typically diagnosed by endoscopic biopsy. Gastric
resection is not mandatory and should be reserved for patients with hemorrhage,
ulceration or extensive transmural involvement [12]. Patients with localized disease
(stage IAE and stage IIAE) should receive 3 cycles of CHOP and radiation to the
gastric bed and regional nodes to a dose of 3000 cGy in 15 fractions [13]. Patients
with advanced disease should receive 6 cycles of CHOP. Radiation can be
considered for initial bulk or residual disease [14].
For patients who have been surgically staged (i.e. who have undergone partial or
total gastrectomy), radiation alone to the gastric bed and regional lymph nodes is
recommended to a dose of 2500 cGy in 20 fractions. Ten-year survival rates are
reported to be > 80%. For patients who have not been surgically staged and are unfit
for chemotherapy, consider whole abdominal radiation (2500 cGy in 20 fractions)
with a boost to any identifiable areas of gross disease of 1000-1500 cGy in 5-8
fractions. Five-year survivals of 71% are reported.
Small Bowel: Surgical resection is initially undertaken as patients usually present
with acute abdominal problems. Patients will subsequently be treated with 6 cycles
of CHOP.
Testis: Patients with testicular lymphoma should undergo high inguinal
orchiectomy [15]. CT scan of the brain and lumbar puncture should be performed if
stage > 1 [16]. Patients with stage IE – IIE should receive 3 cycles of CHOP plus
radiation to the scrotum (3000/15 cGy). Patients with stage IIIE and IV should
receive 6 cycles of CHOP plus scrotal irradiation. CNS prophylaxis is not routinely
offered.
Thyroid: Patients should undergo an open biopsy for diagnosis [17]. Patients with
stage IAE disease and postoperative tumor bulk < 3cm should receive radiation
alone (3600 cGy in 18 fractions) [18]. Patients with more advanced disease should
receive 3 cycles of CHOP and local irradiation. Radiation is given as a modified
upper mantle to thyroid bed, nodes of the neck and superior mediastinum.
6/14

Diffuse Large B-Cell Lymphoma
6. Management of Advanced Stage Disease
Age < 60: Most patients under age 60 should receive chemotherapy alone. CHOP
is as effective as any other studied regimen and is associated with less toxicity than
most second or third generation regimens [19]. Patients will be scheduled to
receive six cycles of CHOP at 3-week intervals (Appendix B). Response will be
assessed clinically at each cycle and by CT scan after the 3 rd – 4 th cycle. Patients
progressing on therapy or who fail to achieve a 50% reduction in disease bulk after
the 3 rd – 4 th cycle of chemotherapy will be considered refractory to therapy and
should be considered for salvage therapy (Section 7, page 10) [20]. At the
completion of the 6 th cycle of treatment patients will be completely re-staged
including bone marrow and/or lumber puncture if initially positive.
Age > 60: Elderly patients with DLBCL do substantially worse than those under
age 60 yrs. The lower response rate to therapy appears to relate to both a more
aggressive behavior, as well as increased difficulty delivering treatment.
Two approaches have been used to improve outcome in older patients. One
strategy has been to aggressively maintain or increase dose intensity using growth
factor support, while a second approach has been to attenuate doses of therapy to
limit toxicity [21]. The strategy of dose reduction has been associated with less
toxicity, but also shorter survival [26]. (See CCO-EBR 6-7)
Preliminary results of a multicenter randomized trial comparing CHOP to CHOP +
Rituximab in patients aged 60–80 with previously untreated DLBCL. Response
rate, progression-free survival and survival were all superior in the CHOP-
Rituximab arm with a 15% one year survival benefit [30]. Recent data suggest a
similar benefit if G-CSF is used to decrease cycle interval from 3 weeks to 2 weeks
[31].
[New]
Patients aged > 60 who are being treated with curative intent should receive full
dose CHOP + Rituximab (Appendix B); supported by growth factors if indicated
(Growth Factor Support, page 8).
High Risk Patients
Results of treatment with CHOP in patients with high-risk disease according to the
IPI are sub-optimal. Response rates are as low as 44% for the high-risk category
with a 2-year survival of only 34% [4, 21]. These patients are ideal candidates for
new experimental therapy, such as transplantation and biologic therapy. At present,
however, such patients should be treated with CHOP in the absence of clinical trials.
Patients not felt to be candidates for curative treatment should be treated
conservatively including radiation or palliative chemotherapy as appropriate.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 7/14

Dose Modification of CHOP
The intent is to deliver full dose chemotherapy for all patients; however, dose
modification may be needed for selected patients. Doses will not be modified for
advanced age alone. Patients with hematologic impairment due to marrow
involvement with lymphoma should also receive full dose therapy, potentially with
growth factor support (see Growth Factor Support below). Patients with
cytopenias due to other reasons should be treated with caution. Patients with
hepatic dysfunction may require modification of adriamycin and vincristine doses.
Those with bilirubin levels of > 50 should not receive either agent, while those with
bilirubin levels of 20-50 should have 50% dose reduction. Patients with significant
peripheral neuropathy, and those at risk due to diabetes, alcoholism, or other factors
should receive vincristine with caution, but will not routinely be dose-reduced.
Growth Factor Support
The DSG believes that dose intensity is important in patients receiving CHOP with
curative intent [22]. G-CSF will not be initiated at the time of the first cycle of
treatment. Patients who develop febrile neutropenia with any cycle of treatment, as
well as those who have a neutrophil count below 1.5 prior to cycle 2-6 of treatment
should be started on G-CSF for all remaining cycles. Dose delays and reductions
should be kept to a minimum.
CCO EBR 12-2
Antibiotic Prophylaxis
Antibiotic prophylaxis is not routinely indicated for patients undergoing CHOP. It can
be considered for selected patients, but must be weighed against the potential
development of antibiotic resistance, as well as increased difficulty using outpatient
therapy for febrile neutropenia.
Assessment of Response
Responses are classified according to the Cheson criteria (Appendix C). A
complete response (CR) requires complete disappearance of detectable clinical and
radiologic evidence of disease and disappearance of all disease-related symptoms
and normalization of biochemical abnormalities. A CRU involves > 75% reduction in
lymph node masses with a normal or indeterminate bone marrow.
Responses will be felt to be incomplete if the above criteria are not met. Wherever
possible, a biopsy should be performed to confirm incomplete response.
8/14

Diffuse Large B-Cell Lymphoma
Management of Incomplete Responders
Patients who progress while on therapy or who fail to achieve a complete response
do poorly [20]. Patients who are potentially eligible for intensive therapy and stem
cell transplantation should begin salvage chemotherapy with DHAP (Appendix B)
[23]. Patients who are not transplant candidates should be managed palliatively.
Involved field radiation should be considered in such patients with persistent disease
that can readily be encompassed in a radiation field. Aggressive salvage
chemotherapy alone is not considered curative in this setting, and as such the
palliative benefit of such treatment must be weighed against the heavy toxicity of
such regimens. Substantial palliative benefit can often be obtained with less toxicity
with less aggressive palliative regimens (such as oral VP-16 + prednisone
[Appendix B]).
Radiotherapy (CR or Good PR)
Involved field radiation (3000 cGy/15 for CR, 3600 cGy/18 for PR) should be
considered upon completion of chemotherapy for patients with bulky disease at
presentation (>10cm) if local relapse would compromise organ function (such as
spinal cord, cauda equina, biliary tree or ureter).
Incomplete Response
Involved field radiation can offer significant palliative benefit in patients not eligible
for high dose therapy. Dose and fractionation may vary depending on site and
volume to be treated.
Follow Up
10–50% of patients with DLBCL who enter remission will relapse, usually within the
first 12–18 months. Patients who achieve a CR should be followed every 3-4 months
for the first 2 years and every 6-12 months thereafter. Assessment should consist of:
• History & Physical
• CBC & differential
• Liver function tests
• Serum LDH
Patients in PR may need more frequent follow up.
Imaging
Routine surveillance imaging is an inefficient means of identifying relapse. Imaging
should be performed in patients with symptoms suggestive of relapse or in selected
patients felt to be at high risk of recurrence.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 9/14

7. Management of Relapsed Disease
Patients with DLBCL who relapse after anthracycline-based chemotherapy have a
short survival [24]. The main prognostic factor is duration of first complete response.
There is compelling evidence that autologous stem cell transplantation (ASCT)
improves survival in patients with chemosensitive relapse. For this reason, ASCT
should be recommended to patients of younger age (< 65) with good performance
status and no limiting co-morbid medical problems. Patients should be referred to a
transplant center early for assessment.
Many salvage chemotherapy combinations have been developed to get patients to
transplant in this disease (DHAP, ESHAP, MINIBEAM and MIME) [25]. These
regimens share many features such as the absence of anthracycline, agents such
as VP-16, cis-platinum and cytosine arabinoside. These regimens are associated
with response rates of 25– 40%. There is no compelling evidence that any of these
regimens is superior to any other. Currently the NCIC is conducting a phase II trial of
gemcitabine, dexamethasone and cisplatin (NCIC LY.10). For patients not eligible
for this study DHAP is relatively well tolerated without extensive need for inpatient
care. In our center, DHAP will be given for first line salvage therapy for all patients
(Appendix B). Two cycles will be given at 4-6 week intervals as hematologic
recovery allows. Patients must have a response to chemotherapy in order to
proceed to transplant. If no response is seen to first line salvage, alternate regimens
can be considered, but the response rate is low and responses are often short-lived.
Palliative therapy should be considered in this case. Involved field radiation should
be considered for patients with localized relapse in whom stem cell transplantation is
not possible.
In addition, radiation may be offered in selected patients undergoing high-dose
therapy to treat areas of initial bulk or residual disease. Such treatment should be
discussed with the transplant team and may take place before or after high-dose
therapy.
8. Special Considerations
Lymphoma in the Elderly
Patients with localized disease should be treated according to Section 5 (Page 4).
Elderly patients with DLBCL do substantially worse than those under age 65. The
lower response rate to therapy appears to relate to both a more aggressive behavior
as well as increased difficulty delivering treatment.
CCO EBR 6-7
Two approaches have been used to improve outcome in older patients. One strategy
has been to aggressively maintain or increase dose intensity using growth factor
support, while a second approach has been to attenuate doses of therapy to limit
toxicity [21]. The strategy of dose reduction has been associated with less toxicity,
but also shorter survival [26].
10/14

Diffuse Large B-Cell Lymphoma
Patients over the age of 65 years of age who are being treated with curative intent
should receive full dose CHOP supported by growth factors if indicated (Growth
Factor Support, page 8). Dose modification, or cessation of curative therapy and
consideration of radiotherapy should be considered if chemotherapy toxicity of
therapy is excessive. In some cases, patients may be treated with palliative rather
than curative intent. Such an approach may be warranted due to major limiting comorbid
medical problems or may reflect patient wishes.
Prophylaxis and Treatment of Leptomeningeal Lymphoma
CNS relapse is relatively common in DLBCL and is uniformly associated with short
survival [27]. Factors that predict a higher likelihood of CNS relapse are extranodal
involvement (especially blood, bone marrow, testicular, sinus orbits), high LDH,
stage IV disease, epidural lymphoma. All patients with such risk factors should have
CSF sampled by LP with 10cc sent for cytology. Prophylaxis with intrathecal
methotrexate is ineffective. Patients with known leptomeningeal disease should
undergo spinal MRI to identify focal deposits, which can be treated with radiation.
Patients with known CNS involvement (leptomeningeal or intraparenchymal) should
receive CHOMP (Appendix B). Patients with evidence of gross disease on MRI
scan or CT Scan of the neural axis should be treated with involved field
radiotherapy.
Management of HIV Lymphoma
Patients with HIV associated lymphoma have an aggressive course and tend to
experience more treatment toxicity. There is some evidence to suggest that
attenuated dose chemotherapy is less toxic than full dose chemotherapy and
associated with longer survivals.
a. Primary CNS Lymphoma
HIV positive patients with primary CNS lymphoma and good performance status
should undergo whole brain radiation (2000 cGy/5). Those with poor performance
status should be treated palliatively [28].
b. Other Sites
Patients with nodal or visceral involvement with lymphoma should be considered for
aggressive systemic treatment. In the absence of a clinical trial, patients with good
performance and early HIV infection status should be treated with full dose CHOP
and 6 intrathecal treatments with Ara-C (50mg via LP or ommaya reservoir) [29].
Patients with more advanced HIV status, but with reasonable performance should
receive half dose CHOP with intrathecal therapy. Patients with poor performance
status should be treated palliatively. All patients should receive septra prophylaxis,
where possible antiretroviral therapy should be continued.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 11/14

9. References
1. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s
lymphomas: Clinical features of the major subtypes. J Clin Oncol. 1998
Aug;16(8):2780-95.
2. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of
lymphoid neoplasms: A proposal from the International Lymphoma Study group.
Blood. 1994 Sep 1;84(5):1361-92.
3. Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on
Hodgkin’s Disease Staging Classification. Cancer Res. 1971 Nov;31(11):1860-1.
4. [Authors not listed] A predictive model for aggressive non-Hodgkin’s Lymphoma.
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J
Med. 1993 Sep 30;329(14):987-94.
5. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with
chemotherapy plus radiotherapy for localized intermediate and high-grade non-
Hodgkin’s lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6.
6. Sutcliffe SB, Gospodarowicz MK, Bush RS, Brown TC, et al. Role of radiation
therapy in localized non-Hodgkin’s lymphoma. Radiother Oncol. 1985
Nov;4(3):211-23.
7. Ferreri AJ, Reni M, Ceresoli GL, Villa E. Therapeutic management with
adriamycin-containing chemotherapy and radiotherapy of monostotic and
polystotic primary non-Hodgkin’s lymphoma of bone in adults. Cancer Invest.
1998;16(8):554-61.
8. Dixon JM, Lumsden AB, Krajewski A, Elton RA, Anderson TJ. Primary
Lymphoma of the Breast. Br J Surg. 1987 Mar;74(3):214-6.
9. Liu FF, Clark RM. Primary lymphoma of the breast. Clin Radiol. 1986
Nov;37(6):567-70.
10. Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Int Med.
1993 Dec 1;119(11):1093-104.
11. DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for
primary CNS lymphoma. J Clin Oncol. 1992 Apr;10(4):635-43.
12. Ersnt M, Stein H, Ludwig D, et al. Surgical therapy of gastrointestinal
lymphomas. Eur J Surg Oncol. 1996 Apr;22(2):177-81.
13. Gospodarowicz M, Sutcliffe S, Clark RM, Dembo AJ, Patterson BJ, et al.
Outcome analysis of localized gastrointestinal lymphoma treated with surgery
and postoperative irradiation. Int J Radiat Oncol Biol Phys. 1990 Dec;19(6):1351-
5.
12/14

Diffuse Large B-Cell Lymphoma
14. Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the gastrointestinal
tract. Semin Oncol. 1999 Jun;26(3):324-37.
15. Touroutoglou N, Dimopoulos MA, Younes A, et al. Testicular lymphoma: late
relapses and poor outcome despite doxorubicin-based therapy. J Clin Oncol.
1995 Jun;’13(6):1361-7.
16. Connors JM, Klimo P, Voss N, Fairey RN & Jackson S. Testicular lymphoma:
improved outcome with early brief hemotherapy. J Clin Oncol. 1988
May;6(5):776-81.
17. Logue JP, Hale RJ, Stewart AL, Duthie MB and Bannerjee SS. Primary
malignant lymphoma of the thyroid: a clinicopathological analysis. Int J Radiat
Oncol Biol Phys. 1992;22(5):929-33.
18. Tsang RW, Gospodarowicz MK, Sutcliffe SB, Sturgeon JF, Panzarella T,
Patterson BJ. Non-Hodgkin’s lymphoma of the thyroid gland: prognostic factors
and treatment outcome. The Princess Margaret Hospital Lymphoma Group. Int J
Radiat Oncol Biol Phys. 1993 Oct 20;27(3):599-604.
19. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen
(CHOP) with three intensive chemotherapy regimens for advanced non-
Hodgkin’s lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6.
20. Haw R, Sawka CA, Franssen E, Berinstein NL. Significance of a partial or slow
response to front-line chemotherapy in the management of intermediate-grade or
high-grade non-Hodgkin’s lymphoma: a literature review. J Clin Oncol. 1994
May;12(5):1074-84.
21. Shipp MA. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has
“high-risk” disease? Blood. 1994 Mar 1;83(5):1165-73.
22. Rusthoven J, Bramwell V, Stephenson B. Use of granulocyte colony-stimulating
factor (G-CSF) in patients receiving myelosuppressive chemotherapy for the
treatment of cancer. Provincial Systemic Treatment Disease Site Group. Cancer
Prev Control. 1998 Aug;2(4):179-90.
23. Martelli M, Vignetti M, Zinzani PL, et al. High-dose chemotherapy followed by
autologous bone marrow transplantation versus dexamethasone, cisplatin, and
cytarabine in aggressive non-Hodgkin’s lymphoma with partial response to frontline
chemotherapy: a prospective randomized Italian multicenter study. J Clin
Oncol. 1996 Feb;14(2):534-42.
24. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow
transplantation as compared with salvage chemotherapy in relapses of
chemotherapy sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995 Dec
7;333(23):1540-5.
Toronto-Sunnybrook Regional Cancer Centre
Hematology Site Group - Treatment Policies 13/14

25. Shipp MA, Mauch PM, Harris NL. Non-Hodgkin’s lymphomas. In Cancer
Principles and Practices in Oncology 5 th Ed. DeVirta VT, Hellman S, Rosenberg
SA ed. Philadelphia Lippincolt, 1997.
1. Tirelli U, Errante D, Van Glabbeke M, et al. CHOP is the standard regimen in
patients with ≥ 70 years of age with intermediate-grade and high-grade non-
Hodgkin’s lymphoma: results of a randomized study of the European
Organization for Research and Treatment of Cancer Lymphoma Cooperative
Study Group. J Clin Oncol. 1998 Jan;16(1):27-34.
27. van Besien K, Ha CS, Murphy S, et al. Risk factors, treatment and outcome of
central nervous system recurrence in adults with intermediate-grade and
immunoblastic lymphoma. Blood. 1998 Feb 15;91(4):1178-84.
28. Flinn IW, Ambinder RF. AIDS primary central nervous system lymphoma. Curr
Opin Oncol. 1996 Sep;8(5):373-6.
29. Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared with standard-dose
m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human
immunodeficiency virus infection. National Institute of Allergy and Infectious
Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 Jun 5;336(23):1641-8.
30. Coiffer B, Lepage E, Herbrecht R, et al. Mabthera (Rituximab) plus CHOP is
superior to CHOP alone in elderly patients with diffuse large B-cell lymphoma:
Interim results of a randomized Gela Trial. Blood 96 (suppl 1): 950a, 2000.
31. Pfreundschuh M, Trümper L, Kloess M, et al. 2-weekly CHOP (CHOP-14): the
new standard regimen for patients with aggressive non-Hodgkin’s lymphoma
(NHL) >60 years of age. Blood. 2001. Vol. 98, No. 11:725a (Abstract #3027).
14/14