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Natural History - treated and untreated
The "natural history" of a lymphoma refers to the expected clinical course of the disease if it is untreated. Along with the availability of effective treatments, the natural history provides the context that guides the most appropriate timing and approach to treatment. For example, a type of lymphoma with a very short natural history would require prompt and effective therapy - with curative intent; while a less aggressive type might be observed and treated (managed) as needed with less aggressive therapy.
So when to treat follicular lymphoma, and with what therapy, is individualized based on the clinical behavior of the lymphoma (including sensitivity to initial therapy) - such as if it is causing symptoms and if it is growing steadily, remaining stable, or even regressing spontaneously - but it is also based on patient characteristics - such as one's age and fitness or if there are any secondary medical conditions. At this time, in large part because of the variable natural history of follicular lymphoma - there is no gold standard treatment that applies to all patients. However, this is not meant to suggest that all approaches to treatment are equally appropriate for each clinical circumstance. For example, if the behavior of a follicular lymphoma becomes aggressive it will often be best to treat it accordingly.
IncidenceFollicular non-Hodgkin's Lymphoma (NHL) is a very common type lymphoma, approximately 30% of all cases. There are about 61,000 new cases of NHL diagnosed annually. Therefore, there are approximately 18,300 new cases of follicular NHL diagnosed annually. Follicular lymphomas account for 70% of indolent (slow growing) lymphomas. Diagnosis of follicular lymphoma in children is very rare (emedicine.medscape.com). The mean age at diagnosis is about 60 to 65 years. DiagnosisTo diagnose a lymphoma, a biopsy must be performed by the surgical removal (resection) of a lymph node. A fine needle aspiration may be performed if a lymph node is not accessible, but this is not considered a definitive way to determine the diagnosis. A series of tests will then be performed on the sample to determine the characteristics of the cells. If a malignancy is determined, these discovered characteristics will allow your doctors to recommend appropriate treatments to use when needed. Resources:
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Staging tests:
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Physical exam:
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Labs and tests:
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Treatment, age and gender specific:
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Staging refers to the how widespread the disease is. Imaging tests (CT MRI, PET) and bone marrow biopsies are commonly done to estimate this. See Staging for more detail.
Value of PET imaging in Follicular Lymphoma: Discussion http://www.medscape.com/viewarticle/583796_4
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fatigue (anemia) |
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loss of appetite |
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feeling of fullness or discomfort due to enlarged liver or spleen |
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enlarged lymph nodes - painless swelling in the neck, armpit or groin - often in more than one group |
Other symptoms may include night sweats, unexplained high temperatures and weight loss. These are known as B symptoms.
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The variable natural history
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Prognostic Indicators |
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FLIPI Follicular Lymphoma International Prognostic Index |
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NEW 2012, Shuangge , Associate Professor of Biostatistics, Yale University: Risk factors for the etiology and prognosis of follicular lymphoma |
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Clinical Oncology News 2013:
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NCCN Guidelines for Follicular Lymphoma - Patient friendlier |
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Clinical Features, Prognosis and Treatment of Follicular Lymphoma
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PET imaging response after rituximab-containing induction therapy in follicular lymphoma predictor of OS http://bit.ly/2c9vrYa |
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Cancer: Racial differences in presentation and management of follicular non-Hodgkin lymphoma in the US
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Rev. Bras. Hematol. Hemoter. São Paulo 2012: Follicular lymphoma - treatment and prognostic factors |
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Early stage - Strahlentherapie Und Onkologie: Radiotherapy in stage I-III follicular non-Hodgkin lymphoma: Retrospective analysis of a series of 50 patients
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Video - Dr. Kahl interview: Results of the RESORT Trial for Follicular Lymphoma:
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Indolent - Oncology Times: Bendamustine + rituximab offers new standard first-line treatment option for lymphoma |
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Follicular - ASH 2011: CHOP + Rituxan versus CHOP - Bexxar |
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Management of Follicular Lymphoma in the Up-Front and Relapsed Settings http://bit.ly/mjsYzy
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Novel Agents for Follicular Lymphoma Lymphoma:
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Treatment Approaches for Follicular Lymphoma Continue to Evolve -- An Interview with Dr. Andre Goy http://bit.ly/fbfIfm
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Aiming at a Curative Strategy for Follicular Lymphoma caonline.amcancersoc.org Maurizio Bendandi,MD, PhD
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Evolving Paradigms in Follicular Lymphoma: Re-Evaluating Prognostic Factors and Challenging Treatment Dogmas molecularonc.comCara A. Rosenbaum, MD
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Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology – v.1.2006 nccn.org pdf |
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Low grade Lymphoma asheducationbook.org /2004 full text |
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Follicular NHL, overview
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Follicular NHL, technical
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"The cells of follicle center lymphomas are derived from the germinal center cells of the normal lymph node. This category in the Working Formulation encompasses three different tumor types:
Most common cell-size subtype of follicular lymphoma. An indolent (slow growing) lymphoma.
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PubMed abstracts for: Review | Therapy | Diagnosis |
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PubMed abstracts for: Review | Therapy | Diagnosis |
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follicular predominantly small-cleaved (generally slower growing) |
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follicular mixed small-cleaved and large-cell, and |
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follicular predominantly large-cell (generally faster growing). |
In the Kiel classification, these tumors are included within the centroblastic/centrocytic and follicular centroblastic classifications."
source: cancernetworkExtranodal Follicular Lymphoma - a Retrospective Review and Comparison with Localized Nodal Follicular Lymphoma. Session Type: Poster Session 529-I - ASH 2004 | Terms of Use
It's common to find a mix of cell-sizes in the diagnosis of follicular lymphoma.
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About - full text ncbi.nlm.nih.gov |
" Two signatures [in follicular lymphomas] -- one which indicated poor prognosis, the other good--had strong synergy and together predicted survival better than any other model tested.
Unexpectedly, both came from nonmalignant immune cells infiltrating the tumors. The good prognosis signature genes reflect a mixture of immune cells that is dominated by T cells. T cells react to specific threats to the body's health. In contrast, the poor prognosis signature genes reflect a different group of immune cells dominated by macrophages and/or dendritic cells--which react to nonspecific threats--rather than T cells. http://www.cancer.gov/Also see Host/tumor interaction and the microenvironment
See more on each subtype below.
As tumor classification systems evolve, research using older systems may show different results than newer systems. As insights into genetic and molecular aspects of tumors are discovered it is hoped that treatment strategies more tailored to an individual's tumor will be identified. This will take research and will be facilitated by participation in research trials.
- Anjou NHL-info
TOPIC SEARCH: Scholar | PubMed
Grade 3 (large cell) Follicular lymphomas make up only a minority of all Follicular lymphomas. Follicular Large cell lymphomas may have a more aggressive clinical behavior, and therefore treatments may be initiated early with intend to cure or induce durable remissions.
Grade 3 confusion?
NCCN GUIDELINES for grade 3: "Follicular lymphoma, grade 3 is an area of controversy. The distinction between follicular grade 3a and 3b has not been shown to have clinical significance to date.
Follicular lymphoma grade 3 is commonly treated according to NCCN guidelines for DLBCL (BCEL-1). Any area of diffuse large B-cell lymphoma (DLBCL) in a follicular lymphoma of any grade should be diagnosed and treated as a DLBCL." - April 2011
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2017: Survival outcomes for various treatment modalities in advanced-stage grade 3 follicular lymphoma (FL3):
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Compiled abstracts: Follicular grade 3 lymphoma |
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A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival bloodjournal.hematologylibrary.org
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Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas, May 2008 http://www.haematologica.org/cgi/content/full/93/7/1033 |
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Non-Hodgkins Lymphomas Clinical Practice Guidelines in Oncology – v.1.2006 nccn.org professionals pdf |
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Low-Grade Lymphoma, Hematology 2004 asheducationbooksJane N. Winter, Randy D. Gascoyne and Koen Van Besien |
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Cytologic subtypes of grade 3 follicular lymphoma bloodjournal.hematologylibrary.org
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Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Ann Oncol. 2006 Jun;17(6):920-7. Epub 2006 Mar 8. PMID: 16524969 Full text |
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Follicular Lymphoma grade 3B. A separate entity? dissertations.ub.rug.nl
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Natural history of follicular grade 3 non-Hodgkin's lymphoma. Bierman PJ. Curr Opin Oncol. 2007 Sep;19(5):433-7. Review |
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A Clinicopathologic Evaluation of Follicular Lymphoma Grade 3A Versus Grade 3B Reveals No Survival Differences http://findarticles.com
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A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood. 2003 Mar 15;101(6):2363-7. Epub 2002 Nov 07. PMID: 12424193 full text | related abstracts |
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PubMed abstracts for Large cell follicular:
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Follicular Large Cell Lymphoma: An Aggressive Lymphoma That Often Presents With Favorable Prognostic Features bloodjournal.org |
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Grade 3 and anthracycline-containing treatments [such as CHOP]
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Sometimes follicular lymphomas are first diagnosed in the skin (present there), or spread to the skin later on. When lymphomas that normally present in the lymphatic system moves to other areas it is called extranodal disease. Spreading to the skin is not necessarily considered a negative prognostic indicator.
Also see Extranodal lymphomas
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Follicular Center Cell Lymphomas of the Skin thedoctorsdoctor.com |
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Cutaneous follicle center lymphoma: a clinicopathologic study of 19 cases. Mod Pathol. 2001 Sep;14(9):828-35. PMID: 11557777 PubMed |
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Cutaneous presentation of follicular lymphomas.
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Factors that determine treatment timing and approach:
The characteristics of the lymphoma at diagnosis as determined by the pathology report, and it's actual clinical behavior, and other factors determine the type of treatment and the timing of treatment you and your doctor will consider.
The good news is that lymphomas are often sensitive and responsive to treatments. Aggressive lymphoma are often cured, and indolent (slow growing) lymphomas are often managed effectively. Importantly, recent advances in the understanding of lymphoma has led to effective new therapies and better therapies are certain to follow.
For indolent lymphomas, treatment is often deferred until the patient becomes symptomatic. For aggressive lymphomas treatment is typically initiated early with intent to cure.
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See Factors that influence treatment selection and timing - PAL |
Radiation therapy for FL
"should be used in patients with stage I disease, although this represents a minority of cases of follicular lymphoma.
Radiation therapy also can be used to treat localized or bulky lymphadenopathy that is causing obstruction or when a more urgent response is desired to relieve obstruction.
Radiation therapy usually is tolerated well and, in many instances, can spare the patient the need for additional chemotherapy. The radiation oncologist is also involved in the care of patients receiving radioimmunotherapy."
Source: emedicine.medscape.com
"Advanced Follicular lymphoma (FL) is considered challenging to cure with standard therapies ... As a result, the selection, timing, and sequencing of available therapies have been a matter of continuing debate. " (Olin, et al nih.gov )
There is no apparent standard treatment for indolent follicular lymphomas.
Current practices include:
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Watchful waiting until symptoms, marked progression, or transformation occurs, |
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Management with single agent chemotherapy and/or Rituxan when needed. |
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Numerous Investigational therapies. See below. |
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Aggressive early treatments with combination therapies for high-risk disease, such as when the lymphoma is resistant to initial treatments. |
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Radioimmunotherapy, with Zevalin or Bexxar |
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Stem cell transplants, ablative and mini (non-ablative). |
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Radiotherapy, which may cure if treated when in stage I or II |
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TOPIC SEARCH: PubMed: Review | Therapies
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NEW NCCN Guidelines for Follicular Lymphoma - Patient friendlier |
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Adult Non-Hodgkin’s Lymphoma ~ Best Practice Cancer.gov |
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Radiation for stage I or stage II with curative intent, and management (See Sidebar) |
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Considerations at Relapse PAL |
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Treatment decisions - factors that determine PAL |
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Watchful waiting PAL |
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Elderly ~ treatments for PAL |
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Refractory (resistant to treatment) resource page PAL |
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Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma
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FL - Oncologist, 2009: Role of Hematopoietic Stem Cell Transplant in the Management of Follicular Lymphoma
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FL - Medscape Education: The Role of Hematopoietic Stem Cell Transplant in Follicular Lymphoma
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Role of Stem Cell transplant in Follicular lymphoma,
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Transformed disease PAL |
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R-CHOP v. R-CVP in the treatment of follicular lymphoma: a meta-analysis |
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Novel Agents for Follicular Lymphoma, Dec 2010
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Follicular Lymphoma: Emerging Therapeutic Strategies: Therapy for Untreated FL http://bit.ly/a18BZW
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R-CHOP versus R-CVP in the treatment of follicular lymphoma: a meta-analysis and critical appraisal of current literature pubmedcentral.nih.gov |
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Aiming at a Curative Strategy for Follicular Lymphoma caonline.amcancersoc.org
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Cure for fNHL? Radiolabeled and Native Antibodies and the Prospect of Cure of Follicular Lymphoma theoncologist.alphamedpress.org
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Cure word used: Mini-BMT: follicular Non-Hodgkin's Lymphoma Cure? www.webmd.com83% in Complete Remission 5 to 9 Years After Mini-BMT for Follicular Lymphoma |
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Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy ~ Ranjana Advani, Saul A. Rosenberg, Sandra J. Horning 2004 - full text article jco.org |
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Treatment of Non-Hodgkin's Lymphoma: Next Steps - Medscape.com 2004 (free login req.) Review of progress for Follicular, SLL, Diffuse Large Cell, and Mantle Cell. |
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Follicular Lymphoma, Treatment Policy - Dr. Louise Bordeleau PDF | PDF-Help |
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Treatment overview PAL |
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Untreated |
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Relapsed |
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Excluding transplant |
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And by Type of Agent |
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Technical: Atlas of Genetics and Cytogenetics in Oncology and Haematology - Follicular lymphoma http://bit.ly/8LTric |
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Molecular pathways in follicular lymphoma nature.com pdf
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Survival Improving for Patients with Stage IV Follicular Lymphoma cancerconsultants.com
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Bcl-2 negative: Follicular center cell lymphoma with the t(14;18) translocation in which the rearranged BCL-2 gene is silent. Leukemia. 1993 Nov;7(11):1834-9.
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Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte.
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Clinicopathologic correlations of genomic gains and losses in follicular lymphoma.
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Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities Eric Jonasch, Frank G. Haluska Massachusetts General Hospital, Boston, Massachusetts, USA alphamedpress.org |
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Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: results of a large controlled clinical trial. Eur J Haematol. 2002 Mar;68(3):144-9. PMID: 12068794 PubMed |
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High-Dose Therapy for Follicular Lymphoma Oncology Arnold Freedman, MD, Jonathan W. Friedberg, MD , and John Gribben, MD, PhD Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts |
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Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B.
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New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma. J Clin Oncol. 2005 Oct 17; PMID: 16230674 | Related articles |