|LETTER TO THE EDITOR
|Year : 2012 | Volume
| Issue : 2 | Page : 326-329
Psychostimulants for chemotherapy induced cognitive changes in cancer, Ockham's razor, anyone?
Department of Radiation Oncology, Dr. Balabhai Nanavati Hospital, S.V. Road, Vile Parle (W), Mumbai-400 056, India
|Date of Web Publication||26-Jul-2012|
ACRO, Department of Radiation Oncology, Clinical Neurosciences Division, Dr. Balabhai Nanavati Hospital, S.V. Road, Vile Parle (W), Mumbai - 400 056
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Dutta V. Psychostimulants for chemotherapy induced cognitive changes in cancer, Ockham's razor, anyone?. J Can Res Ther 2012;8:326-9
I welcome and would like to thank the authors for their views on the review, ''Chemotherapy, neurotoxicity and cognitive changes in breast cancer' (July-September 2011 issue of this journal)'. "The neurobiological basis of anti-cancer therapy induced cognitive dysfunction and the promising pharmacological modalities against the same." (Revannasiddaiah S., Gupta M., Seam R., Gupta M.) 
One is often left in a quandary when involved in a field such as this, when interventions that are therapeutically intended can be both relieving and debilitating at the same time. These things are indubitably linked together and keep clouting the other's presence, which is why the neurotoxic effects of cancer therapies are steering research into a direction that could be more anodynic. Pharmacotherapy and non-pharmacotherapy are both being attempted, but the latter seems to be more at the receiving end for not summing up to the exactitudeness of routine science. The pathogenesis of cognitive impairment associated with chemotherapy (CT) is still at large. So far, we have been able to ascertain that there are adverse neurotoxic effects that directly influence and can trigger oxidative stress, have severe hormonal implications, and are responsible for creating an extensive cytokine environment involving cell death and associated cognitive dysfunction and fatigue. ,,, However, the trigger is often multifactorial, as each one's genetic constitution may allow, or sometimes even elevate the likelihood of exacerbating these neurocognitive symptoms. 
The authors in their views opined that, "Cognitive changes after therapy for breast cancer can arise from the neurological toxicities of therapy as well as of a result of psychological stresses (of cancer diagnosis and the uncertainties of outcomes). It would be improper to blame all of the symptoms of therapy-induced cognitive impairment upon chemotherapy alone. Therapy in breast cancer can include a combination of surgery, chemotherapy, radiotherapy, and hormonal manipulation."
In the review, the psychological stressors attached to the diagnosis of cancer and its coping was accounted in detail.
The unmet consensus of the effects of neurotoxicity and speculations that surround the methodological reservations from each and every related field were also clearly cited, "Extensive literature now surrounds this domain, with most research speculating about the quantitative aspects of the phenomenon. While inquiring, unavoidable methodological reservations accompany each practitioner from their chosen field of expertise. This inevitably clouds the full appreciation of the problem since most of its contributory aspects then cannot be adeptly linked."
"Self-reported problems of cognitive decline are intricately linked with psychological stress, fatigue, and anxiety related to the diagnosis of breast cancer. , So, most times these perceived symptoms outweigh what can actually be assessed neuropsychologically". ,
"While studying the long-term toxicity effects on cognition and other functions, it becomes important to first examine the relation between the patient's subjective perception of her cognitive loss and the objective scores received through neuropsychological testing. Most studies have shown a positive correlation between the two but when controlled for depression, anxiety, and fatigue, the correlation often weakened". 
Poeppelreuter et al., in their study  examined this trend between self-reported cognitive loss / deficits and objective scores on learning and memory in 119 breast cancer (BC) patients, where a significant relation was found between the two, but when controlled for an affective variable, the correlation weakened.  Bender et al.,  incorporated a similar design in 31 early stage BC patients, who were also on hormonal therapy. Here too the affective variables were controlled, following which a similar correlation was found, as in the previous study.
In fact, direct dose-dependent effects of CT too were studied. , Ahles et al.,  confirmed that more cycles of CT were associated with poorer neuropsychological test scores. Apart from scoring less on the neuropsychological performance index, the group on a higher dose also reported having more problems on the self-rating questionnaire (Squire Memory Self-Rating Questionnaire). Schagen and colleagues  in fact incorporated a longitudinal design, where different CT regimens were studied, and found that the effects of a high dose of carboplatin, thiotepa, and cyclophosphamide (CTC) had a detrimental effect on the neurocognitive performance on this group of 28 women when compared with their age-matched controls, whereas, no difference was found between the group that was on cyclophosphamide, epirubicin, fluorouracil (CEF) and the one without any CT regimen. However, because the use of tamoxifen was not controlled, its influence on the cognitive functions could not be ascertained. This was clearly mentioned in the article, "The study also had several limitations; the use of tamoxifen was not controlled, all the patients on CT were also on tamoxifen, whereas, the no-CT group was not. So, the influence of tamoxifen on cognitive functions could not be clearly determined. Moreover, both the high-dose CTC group and the standard dose CEF group showed a difference in their cognitive test performance; this itself confounds the test results as it cannot be solely attributed to either the CT regimen or the use of tamoxifen, or the combination of both."
Some studies have shown that there are no cognitive changes after the use of adjuvant CT or tamoxifen for as long as six months, but the plausibility of patients rating themselves as cognitively impaired in self-rating questionnaires are higher than healthy controls, post six months. 
The authors had also remarked that, "The recent emergence of evidence in favor of a neurochemical basis for 'chemo-brain' indicates that psychological measures such as counseling and cognitive behavioral therapy may not be effective in countering the neurobiological changes." Randomized Controlled Trials (RCT's) conducted with pharmacological agents were rendered, were more effective in countering cancer-related fatigue and 'chemo fog,' and were touted as 'being unequivocally better than non-pharmacological measures'.
Psychostimulants, like methylphenidate, structurally linked to amphetamines, are known to increase alertness, attention, and vigilance. In a review,  seven open-label clinical trials were studied where methylphenidate was used for the treatment of cancer-related fatigue (CRF), although the fatigue levels improved, , the effects were not dissimilar from those of a placebo drug used in a double-blind study.  In another placebo-controlled trial with cancer patients dexmethylphenidate showed improvements in fatigue. 
In another randomized double-blind study that was placebo-controlled, women with breast cancer were administered d-methylphenidate, where its effectiveness on fatigue and cognitive deficits were assessed. All the patients underwent neuropsychological testing at the baseline, at the end of their CT, and at the ?6 month follow-up. Patients also self-evaluated themselves on their quality of life and fatigue. Here too, the findings failed to suggest that d-MPH, combined with adjuvant chemotherapy could improve the quality of life or fatigue. 
Very few randomized, placebo-controlled clinical trials have been successfully carried out to assess the efficacy of psychostimulants in patients with cancer-related fatigue. Most studies so far have been theoretically driven and given the debilitating side-effects of these psychostimulants like nausea, anxiety, irritability, insomnia, severe mood swings, anorexia, and tachycardia, their side effects far outweigh their benefits.
Modafinil, a central nervous system (CNS) stimulant was used in two open-label studies, where its efficacy on fatigue was observed. , Adverse effects like headache, infection, nausea, heightened anxiety, and insomnia were the common symptoms. More RCT's were recommended, to evaluate its effectiveness on chronic renal failure (CRF) in patients who were already on CT and those who had completed CT and radiotherapy. 
So far, no effective intervention has been developed to counter the effects of CT-associated neurocognitive deficits.  Randomized controlled trials have assessed the use of methyphenidate and erythropoietin, but without any promising results.  Unless we are able to decipher the underlying mechanisms of how these chemotherapeutic regimens work, no one particular intervention can prove itself to be more beneficial than the other. Current consideration is given to alleviating symptoms of depression and anxiety with pharmacological agents, which come with their own baggage of adverse side effects. Moreover, as most of the studies implicate a frontostriatal dysfunction as far as cognitive symptoms of attention and concentration, verbal learning, and memory are concerned, ,, it would be naïve to recommend psychostimulants like methylphenidate and CNS stimulants like modafinil to effectively counter such deficits, without any compensatory cognitive rehabilitative strategies. No published research has yet seen the effect of cognitive rehabilitation programs on cancer survivors, although its effectiveness is well known in the treatment of other patient groups. ,
One needs to exert caution when recommending these psychostimulants and CNS stimulants to ease off symptomatic cognitive clouding and fatigue. Compensatory mechanisms involving cognitive rehabilitation strategies should be a part of the therapy, along with cognitive behavior therapy (CBT), to counter cognitive symptoms and fatigue. CBT is a behavior modification therapy and its use was never intended for cognitive rehabilitation. Compensatory cognitive strategies that are used post a traumatic injury to the brain and the dementias are made more efficacious by a conscious volitional effort, in contrast to the passive diction of psychopharmacotherapy. Moreover, the unique biochemistry of each patient combined with a dose of a stringent CT regimen, along with these psychotropic drugs, can only be more damaging, as the side effects of these medications cannot and must not be obviated.
As different etiologies and contributing factors are involved in the cognitive symptoms and fatigue related to cancer, the approach required is often extensive and cannot be replicated with each individual. Some of the most scrupulously designed clinical trials have involved the epoetin alfa and darbepoetin alfa; whereas, psychostimulants and CNS stimulants have shown little promise in open-label prospective studies, with negative findings in randomized placebo-controlled designs. The potential benefits along with the associated side effects of the different classes of medication must be correctly assessed. 
In another study,  patients received paroxetine, a selective serotonin reuptake inhibitor, to treat their cancer-related cognitive dysfunction, and reported improvement in attention and memory, when compared to controls receiving placebo. However, affective factors like anxiety and depression, as confounding factors, were not considered, despite drug administration during the acute phase of chemotherapy. Besides, side effects like drowsiness, dizziness, nausea, anxiety, insomnia, constipation, diarrhea, and increased sweating were well known. The authors here recommended long-term studies with a follow-up period of six-to-twelve months after the completion of cancer treatment.
Post-cancer fatigue research has been in the forefront in recent years, but not many effective interventions have been found; so far results appear to be mixed and insufficient, with exercise being potentiated as beneficiary by some. , Effects of yoga  and acupuncture  too have been examined, but without any conclusive benefits or follow-up.
A study done by Gielissen et al.,  (2006), showed the beneficial effects of CBT for fatigue in cancer survivors. Long-term efficacy of CBT in these patients was assessed after completion of therapy and in the follow-up period of one to four years. Recuperation of fatigue severity, functional impairment, and psychological well-being after CBT remained steady even during the follow-up phase. The authors opined that CBT for post-cancer fatigue was useful in treating psychosomatic stress and eased fatigue; an effect that was seen even two years following the completion of CBT. An earlier randomized controlled trial by the same authors showed similar benefits. 
Cognitive behavior therapy, along with hypnosis, has also been examined in radiotherapy-related fatigue in breast cancer patients, and was effectual in both controlling and averting fatigue. 
If we were to consider taking the patient's account seriously, it ought to perhaps impel us into considering that she may want to exert her own volitional will before bending into accepting what may only be putatively therapeutic. In this case, the redundancy of needless agents floating in the market compels us to this principle of Ockham's razor, which is edged in this pointlessness of doing with so many things, when the same can also be done with very little!
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