Treatments > Factors that Influence Treatment Decisions and Timing

Last update: 08/27/2010

TOPICS
Factors | When? | Which? | Goal of Treatment?

Big Picture Questions	Rank Your Treatment Priorities
Factors that determine treatment timing and approach	FDA Treatment Flow Chart for Indolent NHL
Considerations at relapse,  guidelines from patients	Treatment Resources
Background on treatment: goals | types | outcomes | interventions	Would a clinical trial be appropriate for me?  Questions for your doctor PDF
Questions for your Doctor	Watch & Wait - considerations for and against

TOPIC SEARCH: PubMed | Medscape

There are many factors that influence treatments decisions, particularly for patients with indolent lymphomas.  It's an ongoing and complex process, which involves understanding the risks of the disease, as well as assessing the potential risks and benefits of numerous treatment options.  ...   (discussion continued below)

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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.

Disease Characteristics	Basis of Treatment Decisions	Patient Characteristics
Type of lymphoma (cell type)  and it's expected natural history Grade: indolent, intermediate, aggressive Stage: localized or widespread? High or low-risk clinical behavior? Growth rate? Discordant - growing faster in one location than another?   Emerging in new locations?   Sensitivity to initial therapies?   Causing symptoms?  serious or mild? predictive of need to treat? Suggests high-risk disease? See FLIPI for a system of estimating  risk in follicular lymphoma   Previously treated or untreated? Types and toxicities of prior treatments Response of lymphoma to  treatments and treatment types?   Sensitivity to initial therapy Complete Response?   Partial Response?   Stable Progressing during treatment? Response to subsequent therapies Location of tumors Near vital organs?  Bone marrow involvement? Affecting appearance or social confidence? Bone marrow function (blood counts) Monitoring schedule for accurate assessment of disease status?	Goal of treatment:   a) Durable remission (potential to cure?)   versus   b)  Management - treat minimally as needed IMPORTANT: the most appropriate goal of therapy can be based on both Disease and Patient Characteristics, and not necessarily on patient preferences alone.   Strength of evidence for available therapies? Best Practice (standard of care)?   Large controlled randomized trials?   Long follow up?   Findings reproduced by different groups? Balancing potential benefits versus  risks (short and long term)    Proven to improve survival?   Can burn treatment bridges?   Fast acting? How different physicians may interpret the same data Physician biases when Best Practice is not established Treating physician is a lymphoma specialist or general oncologist? Treating physician is aware of clinical trials and willing to consider referral to clinical  trials? Treating physician can administer the full range of therapies? RIT?, Stem Cell Transplant? Clinical Trials? Large cancer center, versus community center Patient-physician communications Availability of tissue to determine eligibility for targeted therapy?	Age (chronological and physiological) Performance Blood counts Comorbidities (secondary conditions)?  Kidney (renal) and Liver (hepatic) function?   Diabetes? Heart condition? HIV/AIDS, Hepatitis, Autoimmune? Preferences/temperament Tolerance for risk? Note: Even inaction has risk; and depending on the circumstances, under-treating or delaying treatment can be higher risk than administering aggressive or immediate treatment. Prefers treatment that are easy to administer and least disruptive to normal life? Prefers treatment with curative potential? Will report symptoms  honestly and on a timely basis? Our biases, beliefs, and fears. Quality of life considerations:   significance of loss of hair,  fatigue, anxiety ... Life Circumstances Informed about disease, therapies and risks? Financial limitations? Insurance   Limited/ none? co-payment issues? Supportive care at home? Ability to travel? Responsibilities and duties to others: Employment  Family, children

GOAL OF TREATMENT

Job one: What is the most appropriate goal of treatment. 

Durable remission with potential  to cure?
versus Management - treat minimally as needed

Often the treatment goal is based on: 

1. risk of the disease - based on pathology results and clinical behavior FLIPI
   (rate of growth, sensitivity to treatments used so far)  
    

2. age - being young sometimes favoring, or allowing for, more aggressive approaches to therapy
    

3. strength of the data* that supports the goal of the treatment for your clinical setting: 
    
   a) the type of lymphoma (MALT, Follicular, MCL...)
    
   b) grade - indolent (slow growing/stable), or aggressive 
    
   c) stage - areas of involvement and tumor burden 
      (nodal, localized, extranodal, degree of bone marrow involvement), 
    
   d) treatment history and sensitivity to prior treatment types and duration of response to prior therapy (Complete response?  PR (partial response?), Progression during treatment?)
    
   * Note: Response to a biologic, such as Rituxan, may not predict response to chemotherapy, and vice versa.
    
   e) your performance and immune status, comorbidities (secondary conditions) 
    
   * Strength of Data:  Is best practice established?
       Proven superior in comparative studies? ... Large controlled randomized trials?
       Long follow up?  
       Reproduced by different groups? 
       

Virtually every treatment approach has potential tradeoffs:  

An aggressive therapy might give a better chance for a complete and more durable remission (or cure), but can have greater toxicities in the short or long term.  

However, if you take smaller risks with each treatment (less aggressive therapy), you may need to treat more often (depending on the clinical behavior of the lymphoma) and therefore the cumulative risk could be the same or greater with what seems to be the safer  protocol.

... And even avoiding or delaying therapy has potential risks.

So there's no avoiding risks, we just exchange one kind for another. 

This is not to suggest that any choice is as good as another in all clinical circumstances, only that in some instances a definitive best choice will not exist. And we will need the help of our doctors to sort this out.

The Challenge of indolent disease: 

There is no standard approach. No best practice. Each case is unique. It can remain dormant for many years, or progress and behave aggressively.  Typically, indolent lymphomas are sensitive to initial therapies. 

It takes time to get reliable answers from clinical trials, because survival is long for indolent lymphomas, and the clinical course of individual patients is variable.  

"Ultimately, it may well be that the optimal treatment will be determined
by patient clinical and biological characteristics." ~ Dr. Bruce Cheson. Advances in the Treatment of Non-Hodgkin's Lymphoma - Dr. Cheson  Medscape

Can indolent lymphomas be cured?  
 
Only a minority of patients with advanced stage indolent lymphomas may be cured, but emerging data suggests that the proportion could be increasing.  
 
See Can we Cure Indolent Lymphomas?

WHEN TO TREAT?

Watch & wait (observation until symptomatic) became the standard approach for indolent lymphomas because studies (circa 1979) indicated that early interventions with combination therapies did not provide a survival advantage.   

"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." Watchful waiting is still common practice today. 

Click here for more detail on Watchful Waiting and Monitoring Lymphomas

Q: How long before I need treatment for indolent lymphoma?

The Time to initial treatment can vary significantly. For follicular lymphoma "a substantial proportion of patients may never require treatment."  Source: Follicular lymphoma: a historical overview, Koen Van Besien & Harry Schouten. Feb 2007

In one study "the median (middle) 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).  Source: No initial therapy for stage III and IV non-Hodgkin's lymphomas of favorable histologic types, Source: PMID: 369420  Also see related related PubMed articles  PubMed 

Q: What are the signs and symptoms that may indicated when to treat indolent lymphomas?

	Symptoms (fatigue, pain, fevers...)
	Threatened end-organ function (enlarged node obstructing bowel)
	Cytopenia secondary to lymphoma (low blood counts)
	Bulky disease - according to the GELF criteria: nodal or extra-nodal mass (except spleen) > 7cm in its greater diameter 2
	Steady progression
	Patient preference
	Elevated serum LDH or B2-microglobulin
	involvement of multiple nodal sites (each with a diameter greater than 3  cm) 2
	symptomatic splenic enlargement 2
	compressive syndrome 2
	pleural/peritoneal effusion 2   Sources: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf 1 PRIMA study: 2 http://prima. gela.org/ studydoc/ 1_ETUDE/PRIMA_ Protocol_ Version4. 0_Finalnonsurlig ne.pdf

See also: GELF criteria for need to treat.

Q: Is  indolent lymphoma ever treated early?

Yes.  Stage I and II (localized) indolent lymphoma are typically treated at diagnosis with curative intent with localized radiotherapy. The cure rate is about 50% according to some reports. 

See for many published studies on this question: www.lymphomation.org

NOTE: You may want to ask your oncologist about use of PET and a bone marrow biopsy to confirm that the lymphoma is truly localized. "PET may be useful in confirming limited disease in the few patients with early stage I disease, because these patients may be treated with local radiation." Source jnm.snmjournals.org 

Q: What about managing lymphoma with herbs and alternative therapies?

It's easy to be seduced by testimonials made by individuals and groups claiming that natural life style changes can change the course of the disease, but, unfortunately, there is no clinical evidence to support these claims.  

See for details: When lay persons give medical advice & The Problem with Testimonials

SELECTION OF TREATMENT?

The good first step is to decide on the most appropriate goal of treatment ...

Is it to manage the disease by treating minimally as needed? 

or to achieve a durable remission with combination therapy?

Note: Selecting the goal of treatment and the protocol should be done in consultation with your oncologist, because he or she is a medical professional and has first-hand clinical information about your diagnosis, health status, treatment history, and the clinical behavior of the lymphoma. 

Getting a second opinion from a *lymphoma specialist* is strongly recommended. 

General community oncologists may not be up-to-date on the latest approaches to treating the many subtypes of lymphomas. Lymphoma specialists will also be aware of investigational approaches that have promise, such as new doses or combinations of proven therapies. Most general oncologists will encourage you to seek a second opinion about treatment and adopt the advise given by the specialist.

Overview of Common Treatment Options for indolent lymphomas
 

	Watchful Waiting (W&W)   Judge clinical behavior and avoid treatment before it's needed. Some patients with indolent lymphomas (a minority) never need treatment.
	Intent to manage (first line)   Rituxan x 4, or Rituxan x 8 (extended dosing study) Single agent alkylators (Chlorambucil or Cyclophosphamide) or steroids
	Intent to manage (second line and subsequent therapy)   Rituxan x 4, or Rituxan x 8 (extended dosing) Single agent alkylators (Chlorambucil or Cyclophosphamide) Oral low dose combination chemotherapy, such as PEP-C
	Intent to induce durable remission (first line for localized disease)   localized radiotherapy (stage I or stage II)
	Intent to induce durable remission (first or second line)   Rituxan-based Chemo (R = Rituxan)          CHOP-R, CVP-R, F-R, , FND-R Rituxan-based chemo, followed by extended dosing (maintenance) Rituxan Radioimmunotherapy (RIT) as single agent (study) RIT following combination chemotherapy (study)
	Intent to induce durable remission (second line and subsequent therapy)   Autologous stem cell rescue  Allogeneic stem cell transplant Radioimmunotherapy

Main source: NCCN Clinical Practice Guidelines in Oncology™ Non-Hodgkin's Lymphoma, 2008 http://www.nccn.org/professionals/physician_gls/PDF/nhl. pdf  (requires free registration)

 

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Factors that my influence selection of treatment

Factors that influence treatment timing and type - when the goal is management:
 

	Is a fast treatment response necessary?
	Is there a promising investigational or approved therapy with minimal expected side effects - to  try when treatment is not needed?
	How the therapy under consideration might complement or compromise subsequent  treatment options or eligibility for subsequent treatment protocols.
	The short - or long-term toxicity of the treatment under consideration.
	Tumor burden and disease locations.
	Other factors that determine your eligibility for treatments

Factors that influence treatment selection - when the goal is a durable remission :
 

	The disease - and treatment-specific data from well-designed studies that support the use of a treatment for your setting;
	The treatment-related risks compared to other treatments appropriate to this goal;
	Your age, general health, and tolerance for risk;
	Tumor burden and disease location;
	You have a family member who is a good match and is willing to donate stem cells;
	Other factors that determine your eligibility for treatments

Other factors that influence treatment timing and type:
 

	The disease - and treatment-specific data from well-designed studies that support the use  of a treatment for your setting;
	Your physician's areas of expertise and possible biases;
	If your physician works with investigational therapies;
	What your insurance carrier will pay for;
	The questions you ask, how well you communicate your treatment goals and symptoms,  and how informed you are about the disease and the available treatments.
	Other factors that may determine your eligibility for treatments: We recommend that you take an inventory of these items (that describe your treatment setting) to help the doctors you consult to more easily identify appropriate treatment protocols.    Diagnosis - lymphoma subtype (including phenotype markers, such as CD20, CD19, etc.)  Treatment history - specific prior therapies or treatment types - may be required, or may exclude you Bone marrow involvement with lymphoma (greater than 25% bilaterally for Bexxar/Zevalin)  Bone marrow (Hematopoietic) function - measured by Hemoglobin, Lymphocytes, Platelets,  Neutrophils   Co-morbidities - other conditions, such as heart (cardiovascular) disease, HIV, Hepatitis B/C,  and other infections  Kidney (Renal) function - measured by Creatinine Liver (Hepatic) function - measured by Bilirubin, AST and ALT  Lungs (Pulmonary) function - measured by a variety of tests or observation  Neurological - such as history of seizures, CNS involvement   Patient characteristics - age, gender, life expectancy, pregnancy, etc.  Performance status - as measured by performance standards

Resources  

1. The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on 761 cases. Leuk Lymphoma. 2003 Nov; 44(11): 1911-7. PMID: 14738142 | Related articles 

2. Grade 3 and anthracycline-containing [such as CHOP] treatments 
   Commentary from Experts  PAL 
    
   Meet the Professors - a provocative discussion among experts regarding first 
   treatment options for advanced follicular lymphoma  meettheprofessors.com  | PDF

3. Controversies in Follicular Lymphoma: "Who, What, When, Where, and Why?"  
   
   Myron S. Czuczman Hematology 2006:303-310. Abstract | Full Text | PDF

4. Webcast: Attacking NHL Early   

5. Follicular lymphoma: chemotherapy and/or antibodies?
   
   Michele Ghielmini  Oncolog Institute of Southern Switzerland  www.bloodjournal.org

6. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma.
   
   J Clin Oncol. 2002 Oct 15;20(20):4261-7. PMID: 12377971 | Related articles 

7. Leonard, John, MD  * (Highly recommended) 
   
   Making Decisions about Treatment for NHL LLS PDF (8/9/05)

8. NCCN Practice Guidelines in Oncology (NHL) – v.1.2008  
   http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf 

9. Approaches to treating non-Hodgkin's Lymphoma:
   
   Dr Leonard  nhlupdate  |  Dr Coleman  nhlupdate  |  Dr Zelenetz nhlupdate
   
   Dr. Cheson  nhlupdate |  Dr Czuczman  nhlupdate.com |  Dr Armitage  nhlupdate.com
   
   Audio files for patients: John Leonard, Mitchell Smith, Brad Kahl  nhlupdate.com

10. High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When? -  Journal of Clinical Oncology, Vol 21, Issue 21 (November), 2003: 3894-3896  www.jco.org 

11. Background Information on Non-Hodgkin's Lymphoma, FDA  PDF  | PDF-Help

12. Cancer Treatment: Determining the Best Long-Term Plan for You  PDF file - Maloney, Cha | PDF Help

13. Conventional Treatments of indolent NHL,  Cheson / Zelenitz  Transcript or  Webcast |  WebCast-help 

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

15. "Thin" Decisions  Patient perspective on consulting experts and making treatment decisions

16. Treatments of NHL (flowcharts) - MDACC  PDF | PDF-Help

17. NCCN Clinical Practice Guidelines in Oncology™ Non-Hodgkin's Lymphoma, 2008 http://www.nccn.org/professionals/physician_gls/PDF/nhl. pdf 

18. Indolent, Stage I and Contiguous Stage II Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov

19. Indolent, Recurrent Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov

20. Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov 

21. How I treat indolent lymphoma  bloodjournal.hematologylibrary.org

    Dr. John G. Gribben  Institute of Cancer, Barts and The London, Queen Mary School of Medicine, London, United Kingdom

22. Indolent, Recurrent Adult Non-Hodgkin’s Lymphoma ~ Best Practice  Cancer.gov

23. Dan L. Longo, MD, Scientific Director
    National Institute on Aging Baltimore, Maryland 

    Follicular Lymphoma: Expanding Therapeutic Options  Cancernetwork.com

24. Aiming at a Curative Strategy for Follicular Lymphoma caonline.amcancersoc.org  
    Maurizio Bendandi,MD, PhD   http://caonline.amcancersoc.org:80/cgi/reprint/58/5/305?eaf  

25. R-CHOP versus R-CVP in the treatment of follicular lymphoma: a meta-analysis and critical appraisal of current literature  pubmedcentral.nih.gov

Also see Expert Review Articles and Interviews

* Considerations for the younger patient with indolent lymphoma:  

The goal of aggressive therapy is to get a durable response, and a possible cure. It may be that the aggressive approach is more reasonable for the young patient, especially if it's determined that you have high-risk disease. 

First, initial treatment provides the best opportunity to succeed - there is less tumor burden, and your health and the disease have not been affected adversely by prior treatments. For example, cancer cells can adapt from multiple exposures to single agent treatments, which can lead to more resistant disease later on.

Second, younger persons can often rebound better from the toxicities of strong treatment - and therefore may not be harmed as much long term, even if the treatment fails to meet the goal. And if you fail to realize a durable remission, you will have learned early that you have high risk disease and can adapt the clinical plan accordingly.

Finally, if the treatment succeeds, you may improve survival significantly - which is especially important to young patients who will reach survival expectations when still young. (Current estimates for survival ranging from 7 to 18 years for follicular lymphoma, depending in part on the age of the population.)   

* Considerations for the elderly or Infirm patient with indolent lymphoma:  

Rituxan, and single agent chemotherapy for management.

Radioimmunotherapy may be considered instead of combination chemotherapy.

 

In conclusion, when first diagnosed with indolent lymphoma ... 

... we suggest the following: 

1. Try to objectively identify the risks of the disease by tests and close observation
   
   (How fast the lymphoma progresses or how well it responds to initial management treatments).  

2. Become informed about the disease and its treatments. 

3. Consult respected experts to discuss the risks and benefits of all standard treatments, 
   and promising investigational options. 

4. Communicate your priorities and fears to your doctors. 

5. Honestly report symptoms to your doctor.

6. Consult with a specialist to determine the most appropriate goal of treatment - and the approach and timing that best fit the goal.

7. Also ask about the impact of the protocol under consideration on future treatment options.

Conflict of Interest in Medical Decision-making?

Sometimes.  But rarely is it unethical.  See for details: PAL

Why should patients consult outside experts and become informed?  
 
Even trained oncologists can have conflicts of interest, biases, or gaps in knowledge - especially if he or she does not specialize in lymphomas. 

Investigators may have an intellectual bias about an investigational therapy they are testing.  A community doctor might have a bias in favor of what is easiest to administer.  

An HMO physician may prescribe what is least expensive. Another doctor might be influenced, unconsciously or not, by sales promotions from the drug industry.  

Patients expressing their desire to continue working without interruption may influence a busy physician to prescribe what meets the immediate needs, without fully discussing possible negative long-term implications of that treatment decision ...   

Still another reason to seek a second opinion is that it sets up a kind of peer review, which is likely to be an incentive for your local community doctor to be more focused on your care and the decision process. The good community doctor will encourage a second opinion by experts, and will be willing to carry out the recommendations, when possible ... or send you elsewhere when not.

We suggest that you avoid the following:  

1. Start a treatment without first consulting at least one lymphoma expert - unless symptoms or clear dangers indicate a strong need to treat, and you are comfortable with the rationale. 

2. Base your treatment decision on the outcomes of other patients. Keep in mind that each lymphoma and patient can be unique.

3. Believe conspiracy theories used to promote unorthodox therapies. Consider that these theories require the complicity of multiple scientists, doctors, and regulators - who also get cancer and whose loved ones, spouses, parents, grandparents and children also get cancer.   

Strive to be objective: see Evaluating Medical Claims and Data.

Rank Your Treatment Priorities

Rank Your 
Treatment Priorities

Using the items on the right, create a list of your treatment priorities, most important first. 
(The current order is random.)

When it's time to treat, this ranking list may help you decide on the treatment that's best for you. 

These priorities are primarily for indolent (slow growing) lymphoma.

Return to top

 The treatment:

	is most likely to improve symptoms and get a response
	offers a chance for a cure
	has the least risk of death
	has the least long term after effects - secondary cancers, arthritis, fatigue, mental confusion, immune suppression
	does not preclude the use of other promising treatments in the future
	has the least short-term toxicity
	is easy to administer and is least disruptive to normal life.

Big Picture Questions 
 
... when it's time to make a treatment decision

Big Picture Questions

Good questions to ask your doctor when reviewing treatments

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When it comes time to make a treatment decision, Dr. Maloney at the October 2002 Education Forum sponsored by LRF offered the following rational  guidelines. 

	What is the goal of the treatment?   The goal of treatment could be the following: chance for a cure or long term disease-free response, management with low toxicity, need to shrink a tumor that is causing problems etc.  (See Rank Your Priorities, above.))
	What are the outcome data for the treatment?   Complete Response (CR) rate, Partial Response (PR) rate, duration of Response, etc.
	What toxicity and/or risks are associated with the treatment? (Long-term and short-term toxicity, mortality rate, etc.)    How does the toxicity compare with other treatment options, that may also be appropriate to the goal of treatment?
	Can I still use standard treatments if this treatment doesn't work?   Using specific chemotherapy agents might make it difficult or impossible to harvest stem cells for a transplant, for example.
	Does this treatment preclude the use of promising investigational treatments in the future?

First treatment as Assessment - A Boxing Analogy

One way to look at watchful waiting is as an assessment period. Like what prize fighters do in the early rounds as they circle one another. That is, it's a time to size up the opponent to determine how to proceed. Is my opponent fast or slow? Do I need to take a chance early, or is he so docile that I need not take any risks at all?  
Similarly, the response to first treatment, like a probing jab, is also part of the assessment. It provides clues about how to proceed. Is my opponent strong or weak, susceptible to damage,  or is he hard as nails?

(But be aware that lack of sensitivity to Rituxan does not predict sensitivity to chemotherapy, and probably vice versa, because they these agents have completely different mechanisms of action. So a single agent chemotherapy might be tried after a round of Rituxan, for example, as part of assessment and hopefully it will be a successful action as well.) 

If both types of probing treatments fail to provide a significant benefit, it may be time to plan for tougher later rounds, such as by harvesting stem cells when the circumstance allows.  It may also be to time to consider taking risks in order to try to eliminate, instead of manage, your opponent. 

As always, timing's important - that is, when to expend your limited resources. You may want to wait for signs that your opponent is weak, or induce weakness by sequencing your offensive efforts with different combinations. 

But you also need to rest and recover in order to prepare for later rounds. So watchful waiting can be a time to take proactive action to build and improve your general health and performance. 

Finally, when you are young and in good health it might be reasonable to start aggressively because being young and fit you may be better able to recover for the later rounds if needed.  In general starting aggressively, early, can be the best opportunity to win the fight outright, or improve your chances in the later rounds if you achieve  a durable remission. But this does not mean that you execute the plan before the opponent makes the first move ... is clearly on the offensive. 

~ KarlS