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Treatments > Factors that may determine timing and approach 

Last update: 11/30/2009

TOPICS
Treatment Factors | Factors specific to indolent NHL | Factors that influence treatment selection 
  FDA Diagram of Frontline Treatment Strategy for Indolent NHL

Recommended 
Background info:
Current Therapies in the Treatment of Non-Hodgkin's Lymphoma: Chemotherapy - Richard I. Fisher, MD - Medscape  (free login req.)

We believe that shared decision making is important, especially when there is no standard of care and the type of lymphoma you have has an indolent (slow progressing) course. 

Time to treatment following diagnosis: ... 

  1. 44 non-protocol patients, followed since 1963, in whom initial treatment was withheld until required to evaluate the pace of disease and the necessity of treatment; and 

  2. 112 previously untreated patients who have participated in prospectively randomized clinical trials since 1971. 

For all 44 "deferred" patients, the median time before requiring treatment was 31 months, and there have been 19 patients who have not yet required therapy for periods of 3 to 104 months. 

The median actuarial survival for all 44 patients was 121 months (~10 years). 

At 4 years, the actuarial survival of the 44 patients with deferred treatment is 77.3%, compared with 83.2% for the 112 protocol patients (P = 0.60). 

(0.60 is not statistically significant)

Careful observation without initiation of therapy is an appropriate option in the management of patients with relatively asymptomatic advanced non-Hodgkin's lymphomas of favorable histologic types."

Source: PMID: 369420

Also see related PubMed articles on deferring treatment - PubMed 

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Uncharted approach to managing indolent NHL:

Lay Commentary:

Can treating early with combinations of biologics and immune-based therapies improve both survival and quality of life?

Can this approach delay the need for cytotoxic therapies significantly, or perhaps indefinitely, for a significant number of patients?

Unfortunately, we're not likely to find the answer to these questions -- mainly because of how our drug evaluation system works and the nature of indolent NHL.

It's a catch 22: Using biologics and immune-based therapies prior to chemotherapy is plausible, and preliminary data with the frontline use of Rituxan shows it has potential, however, it's more difficult to prove clinical benefit in this setting, mainly because the clinical course of untreated indolent NHL is so variable.

Because of this, drug sponsors don't often test new drugs in this setting, especially therapies that will have modest effects as single agents, and despite the reasonable expectation that this approach will have more potential in chemo-naive pts. -- and there is less expected risk to patients.

Instead, almost all new treatments for indolent NHL are evaluated in previously treated patients. 

Why?

Because drug sponsors know that these patients have a more predictable time to progression, presumably because the disease has come to a point that it once needed to be treated, and probably because of the side effects of cytotoxic therapies received -- suppression and damage to immunity, additional DNA hits to surviving malignant cells ...

We need to ask the NCI, investigators, and drug sponsors to be brave and design studies of this type. It may well be what's needed to make significant progress against both indolent and aggressive lymphomas.

Factors that may determine treatment timing and approach:  

When the goal of treatment is cure, treatments are initiated early:
 
  • all aggressive NHL at any stage (combination chemotherapies)
  • some indolent localized, stage I/ II, lymphomas (radiotherapies)

NOTE: There is some evidence that some individuals with stage III/IV indolent lymphomas may have improved survival and possible cures with experimental combination therapies, but most data shows no benefit to early initiation of treatment in this setting.

Additional factors that help to determine when to start treatment are the characteristics of the lymphoma at diagnosis as determined by the pathology report, it's actual clinical behavior, and other factors. Here's a breakdown:

  • Cell type and pattern and how this might predict the expected clinical course and response to treatment:
     
    • if the cell type or pattern predicts the NHL will typically grow rapidly and will be resistant to standard therapies, you might consider more aggressive approaches or investigational therapies. 
       
  • Grade - how fast or slow the NHL is likely to progress:
     
    • Aggressive NHL is treated early and aggressively; the goal is cure.
       
    • Slow growing indolent NHL has no standard approach as described below.
       
  • Stage - how widespread the lymphoma. See more below.

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Timing factors specific to indolent (slow growing) NHL:

  • Stage -- how widespread the lymphoma is:
     
    • Yes. For localized stage I/ II indolent NHL, radiotherapy may be used shortly after diagnosis, and the goal is cure.
        
    • No. For advanced stage III/IV, treatment is often deferred until the patient is symptomatic, but other approaches may be appropriate. Deferring treatment is called watch and wait. Individuals with indolent NHL can have many years without the need for treatment. 
       
      See sidebar for one report's findings of the average time to treatment for follicular and small lymphocytic types after diagnosis. 

      NOTE: It's common for b-cell lymphomas to be diagnosed at stage IV, and with bone marrow involvement. Patients typically respond well to initial treatments and bone marrow involvement is reversible.
       

  • Clinical behavior as determined by observation, imaging and other tests.
     
    • Pathology reports can only estimate your clinical course.
       
    • Indolent NHL can have long periods of stability and sometimes spontaneous regressions.
       
    • Some lymphomas diagnosed as indolent are clinically aggressive.
       
  • Overall tumor burden and/or areas of bulky disease. 
     
    • It might be important to treat before a tumor becomes "bulky"  (a lymph nodes greater than 10 cm.) in order to optimize treatment results.
       
  • Areas of involvement:
     
    • The location of the tumors can often determine when treatment is needed, not just the tumor burden -- such as evidence of real or threatened organ dysfunction.
       
  • Symptoms and how it affects your quality of life.
     
  • Your age and treatment priorities.
     
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Factors that influence treatment selection for NHL:

There is no apparent standard treatment for indolent follicular lymphomas. 

See
Summary of factors that can influence the
timing and choice of therapy


Illustrates the complexity of treatment decisions - and how they can interact; and how each case and lymphoma can be unique, thus treatments may need to be tailored accordingly.

Management approaches (treat minimally, only as needed):

Rationale: Use relatively low-toxic therapies to control or regress disease on an as-need basis. Choose therapies that are least likely to compromise effectiveness of subsequent treatments. So far, this approach is at least as good as aggressive frontline approaches for indolent NHL, and perhaps better. [1] Reserve aggressive combination therapies (CHOP) for a time when transformation occurs.  (About 25% to 35% of patients exhibit transformation by 10 years. [1]

Possible caveats:  Over time the disease is likely to become more wide spread, more heterogeneous (variable), and could develop mutations that make it more aggressive and/or resistant to treatment. 

Common Approaches:

  • Watchful waiting until symptoms, marked progression, or when approaching bulky disease. 
     
  • Manage with mild single-agent treatments first, such as Chlorambucil, applied only when needed. 
     
  • Initial frontline use of Rituxan (experimental)
     
  • Re-treatment with single-agent or combination therapies, or Rituxan as needed.
     
  • Treat refractory disease with Zevalin, and in the near future, Bexxar.
     
  • Vaccines have been tried experimentally.
     
  • Many additional options are available in clinical trials.
    Also see Uncharted Approaches, in the side bar.

NOTE: When the NHL does not respond to initial treatments (it usually does), strong aggressive therapies may be more appropriate, and the goal of treatment might switch to cure, or obtaining a durable complete response.

Aggressive approaches:

Rationale: Essential for individuals with aggressive or transformed disease. Combine and/or sequence effective therapies in established or new ways -- or with new agents -- in order to maximize response and  effectiveness. Your best chance for a cure is to treat early while the malignant clones are more homogeneous, less wide spread, and of fewer number.  This approach might be more appropriate experimentally for individuals with indolent NHL who are young have a higher tolerance for risk; and for individuals with clinically aggressive indolent NHL that's refractory to initial mild treatments. 

Possible caveats: Increased toxicities. May increase risks of secondary cancers, although this risk is often low. Increased chance of treatment-related mortality for some approaches. For indolent NHL, there is no definitive proof that aggressive treatments can improve overall survival. But always, you must weigh the treatment-associated risks against the risks of particular type of lymphoma that your are dealing with.

Some Common Approaches:

  • Combination chemotherapy with Rituxan for CD20 positive types.
     
  • Radiotherapy, which may cure if treated when in stage I or II.  
    Consolidation with chemotherapy and/or Rituxan might be considered.
     
  • Combination chemotherapy, sequenced with vaccines (experimental) 
     
  • Combination chemotherapy, sequenced with Zevalin/Bexxar (experimental)
     
  • Aggressive combination chemotherapy, followed by a stem cell transplant. (Experimental for indolent NHL.)
     
  • Milder combination chemotherapy, followed by a mini transplant. (Experimental)
     

[1] - Horning S, Rosenberg S: The natural history of initially untreated low-grade non-Hodgkins lymphomas. N Engl J Med 311:1471-1475, 1984.)

See also:
Factors that determine timing and approach | FDA Flow Chart for Frontline Indolent NHL Questions for your Doctor | Treatment Decisions | Watch & Wait

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Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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