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By Alan Cocchetto, NCF Medical Director

From Winter 2012-2013 Forum

With the National CFIDS Foundation identifying internalized radionuclides as the key factor in the development of CFIDS/ME in its own patient cohort, this knowledge opened the door to examine radiation-induced fatigue or more formally what is commonly referred to as cancer-related fatigue (CRF).

What is cancer-related fatigue and how is it defined? Cancer-related fatigue is a highly prevalent condition in cancer patients at all stages [1,2].

It is a most distressing symptom that substantially impairs quality of life (QoL) and physical and emotional functioning. It disrupts daily activities and has a substantial economic impact. It is characterized by persistent tiredness disproportionate to activity and an increased need to rest; a sustained sense of exhaustion that cannot be completely relieved by rest; as well as diminished energy, mental capacity, and psychological status.

Typically the causes of CRF have generally been poorly understood while research lags far behind research activities on other cancer-related topics. Factors that contribute to its development include cancer type and cancer treatment; length of time after treatment; other medications; anemia; sleep disorders; nutrition problems; pain; activity level; and psychosocial factors. CRF can persist for years and is also common in disease-free cancer patients.

Though fatigue has not been typically regarded as a risk factor for cancer relapse, one study had identified fatigue, as part of a biological model, as a significant predictor of recurrence-free survival in breast cancer patients while emotional function remained a significant predictor of overall survival [3]. These are interesting findings in light of what we have learned about the CFIDS/ME disease process.

The table below is a draft of the ICD-10 criteria for CRF:

Fatigue Table

A1 Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level

A2 Complaints of generalized weakness or limb heaviness

A3 Diminished concentration or attention

A4 Decreased motivation or interest to engage in usual activities

A5 Insomnia or hypersomnia

A6 Experience of sleep as unrefreshing or nonrestorative

A7 Perceived need to struggle to overcome inactivity

A8 Marked emotional reactivity (e.g., sadness, frustration, or irritability) to feeling fatigued

A9 Difficulty completing daily tasks attributed to feeling fatigued

A10 Perceived problems with short-term memory

A11 Postexertional malaise lasting several hours

B The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

C There is evidence from the history, physical examination or laboratory findings that the symptoms are a consequence of cancer or cancer therapy

D The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium

* NOTE: CRF is diagnosed when six (or more) of the symptoms above have been present everyday or nearly every day during the same two-week period in the past month, and at least one of the symptoms is significant fatigue (A1).

In another study, the findings for CRF were just as interesting as those above. Of 379 patients with a prior history with chemotherapy, seventy-six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis [4]. Ninety-one percent of those who experienced fatigue reported that it prevented a “normal” life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest and/or relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations. The conclusion from this study was that “CRF is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.”

You may be thinking right about now “Sure, this describes my CFIDS/ME but what can be done to influence this horrible fatigue so as to improve my overall QoL?” Well, there is new research being done at the National Institutes of Health that appears to be right on target! Scientists working at the NIH have recently identified the upregulation of alphasynuclein, associated with radiation treatment, as a key identifier of CRF [5].

This represents an important neuroinflammatory mechanism seen in other neurodegenerative diseases. Normally an unstructured soluble protein, alpha-synuclein can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. These disorders are known as synucleinopathies [6]. Drugs that target alpha-synuclein should prove to be useful in CRF. However, in the NCF’s review of the literature, two publications jumped out at us [7,8].

Generally, the drugs used for CRF included many that have been used for CFIDS/ME. Some of the CRF treatments that were mentioned included hematopoietics, corticosteroids, psychostimulants, as well as L-carnitine, modafinil, bupropion, and selective serotonin reuptake inhibitors such as paroxetine, just to name a few. One other therapy for CRF that looks very promising is Thyrotropin-Releasing Hormone or TRH [9,10]. TRH administration was associated with significant improvement in fatigue level and was associated with a positive impact on QoL! This information is covered in more detail in the “Just Ask” column in this Forum.

Fortunately for the NCF, we found one publication that compared CRF and CFS [11]. Titled “The experience of cancer-related fatigue and chronic fatigue syndrome: a qualitative and comparative study,” this study aimed to better understand the manifestations of CRF in women treated for breast cancer and to compare them with those of women diagnosed with CFS. The results revealed a similar core set of symptoms featuring fatigue, neurocognitive difficulties and mood disturbances. Women with CFS reported additional symptoms including musculoskeletal pain and influenza-like manifestations. Both groups suffered disabling behavioral consequences of the symptom complex. The study concluded that “Qualitatively, CRF appears closely related to CFS.”


  1. Mistletoe treatment in cancer-related fatigue: a case report; Wode K, Schneider T, Lundberg I, Kienle GS; Cases J. 2009 Jan 22;2(1):77
  2. Cancer-Related Fatigue Facts; The Leukemia & Lymphoma Society;*
  3. Psychological distress and fatigue predicted recurrence and survival in primary breast cancer patients; Groenvold M, Petersen MA, Idler E, Bjorner JB, Fayers PM, Mouridsen HT; Breast Cancer Res Treat. 2007 Oct;105(2):209-19
  4. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition; Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, Johnson DH, Miaskowski C, Scherr SL, Portenoy RK, Vogelzang NJ;Oncologist 2000;5(5):353-60
  5. Upregulation of alpha-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways; Saligan LN, Hsiao CP, Wang D, Wang XM, John LS, Kaushal A, Citrin D, Barb JJ, Munson PJ, Dionne RA; Brain Behav Immun. 2012 Sep 26. pii: S0889-1591(12)00436-9
  6. Wikipedia;
  7. Cancer-related fatigue: a practical review; Campos MP, Hassan BJ, Riechelmann R, Del Giglio A; Ann Oncol. 2011 Jun;22(6):1273-9
  8. Pharmacologic treatment of cancer-related fatigue; Carroll JK, Kohli S, Mustian KM, Roscoe JA, Morrow GR; Oncologist. 2007;12 Suppl 1:43-51
  9. Thyrotropin-releasing hormone as a treatment for cancer-related fatigue: a randomized controlled study; Kamath J, Feinn R, Winokur A; Support Care Cancer. 2012 Aug;20(8):1745-53
  10. Thyrotropin-releasing hormone can relieve cancer related fatigue: hypothesis and preliminary observations; Kamath J, Yarbrough GG, Prange AJ Jr, Winokur A; J Int Med Res. 2009 Jul-Aug;37(4):1152-7
  11. The experience of cancer-related fatigue and chronic fatigue syndrome: a qualitative and comparative study; Bennett B, Goldstein D, Friedlander M, Hickie I, Lloyd A; J Pain Symptom Manage. 2007 Aug;34(2):126-35*

[Ed. Note: Two of the above references are offered to our membership, #2 and #11.]

The National CFIDS Foundation * 103 Aletha Rd, Needham Ma 02492 *(781) 449-3535 Fax (781) 449-8606