Interestingly, in UptoDate, there is no mention of the use of hormone ablation either as a neoadjuvant or alternative to surgery. And no comparison between hormone ablation vs. surgery.

Here is the info about doing nothing vs. surgery:

" In the PIVOT trial, 731 men with T1-T2NxM0 prostate cancer were randomly assigned to radical prostatectomy or observation [3]. Men assigned to observation were offered palliative therapy for symptomatic or metastatic progression. At a median follow-up of 10 years, there was no statistically significant improvement in overall survival with radical prostatectomy, the primary endpoint of the trial (hazard ratio for death 0.88, 95% CI 0.71-1.08). By the end of the study there was a 2.9 percent lower overall mortality in the radical prostatectomy group compared with those managed with observation (47.0 versus 49.9 percent). There was a statistically nonsignificant decrease in mortality due to prostate cancer or treatment (HR 0.63, 95% CI 0.36-1.09). However, there was a statistically significant decrease in the incidence of bone metastases (4.7 versus 10.6 percent, HR 0.40, 95% CI 0.22-0.70). Whether additional differences will become evident with longer follow-up is uncertain."

http://www.uptodate.com/contents/radical-prostatectomy-for-localized-prostate-cancer?source=search_result&search=prostate+cancer+and+surgery&selectedTitle=1~150

Here is an interesting portion from a recent publication:

3.2. Androgen Deprivation Therapy (ADT) in Combination with RadiotherapyArguably, combination therapy with radiation and long-term androgen deprivation therapy (ADT) has been one of the most important modifications to modern clinical practice for prostate cancer. The rationale of the combined approach is that the addition of ADT is believed to slow progression of the tumor by eliminating the hormonal stimulus that drives cancer cell proliferation [32]. Furthermore, in vivo animal models have shown that the combined effect of ADT and radiotherapy increases overall cell kill and diminishes growth velocity of the surviving cancer cells [33, 34]. Several agents, such as luteinizing hormone-releasing hormone (LHRH) analogs and nonsteroidal antiandrogens have been used to exploit the sensitivity of prostate cancer to hormonal suppression. Of note, surgical (bilateral orchiectomy) and medical castration are of equal efficacy and using multiple methods of androgen blockade does not confer an additive benefit for nonmetastatic patients [35]. Several prospective studies have demonstrated that the combination of radiotherapy and long-term androgen suppression improves disease control and survival, compared with either treatment alone for men with adverse risk factors. A prospective phase III trial, EORTC 22863, enrolled 415 men randomized to either radiotherapy alone or radiotherapy plus three years of LHRH analog (goserelin) to assess the additive effect long-term ADT in locally advanced patients. The study reported an increase in both disease-free and overall survival in the combination therapy group. Furthermore, the 10-year results of this study found no increase in cardiovascular toxicity in addition to the survival benefit [36–38]. In 2009, a prospective randomized study by Widmark et al. involving 875 high-risk patients (stage T3, PSA < 70 ng/mL) receiving ADT monotherapy (total androgen blockade for 3 months followed by continuous flutamide 250 mg) or ADT with radiotherapy also demonstrated a survival benefit with a minimal yet acceptable increase in side effects in the combination therapy cohort [39]. Similar findings were reported by D’Amico et al. in 2008, who reported an overall survival benefit in high-risk patients receiving combination therapy, despite a shorter course of ADT treatment than the aforementioned studies [40]. The optimal duration of ADT has been a controversial topic, and several studies have examined whether or not the long-term side effects of ADT outweigh the clinical benefits. It is understood that the incidence of side effects correlates with the duration of ADT treatment. Long-term complications associated with ADT are both real and severe, ranging from osteoporosis with risk of pathologic fracture, metabolic dysfunction including development of diabetes as well as cardiovascular disease with potential for fatal myocardial infarction [41, 42]. In 2009, Bolla et al. reported the results of the prospective EORTC 22961 trial randomizing 885 men with T2c-T4, N0 disease, in order to assess whether short-term ADT (6 months) was able to achieve the same survival benefits that had previously been reported with long-term ADT (≥2 years) while simultaneously reducing exposure to hormonal therapy. The 5-year overall mortality rate was 19.0% and 15.2% for short-term and long-term ADT, respectively; demonstrating that short-term ADT in conjunction with radiotherapy is inferior with regards to overall survival [43]. Furthermore, RTOG 9202, a large phase III trial of 1554 patients with T2c-T4 non-metastatic high-risk disease, reported that long-term ADT with radiotherapy is superior to short-term ADT with regards to disease-free survival, risk of distant metastasis, local progression and incidence of biochemical failure; however, no difference in overall survival was observed. A criticism of this study by Horwitz and colleagues is that it was not sufficiently powered to assess for overall survival. Upon subset analysis of 337 patients with a Gleason score 8–10 a benefit in overall survival was seen in the long-term ADT cohort [44]. A Canadian multicenter phase III trial examining short-versus long-term neoadjuvant ADT in combination with radiotherapy found that increasing the duration of neoadjuvant ADT from 3 to 8 months conferred a significant disease-free survival benefit among high-risk patients (42% versus 71% 5-year disease-free survival rate) [45]. While the duration of ADT has definitively demonstrated an effect on patient survival, the sequencing (adjuvant, concurrent, neoadjuvant) of when ADT is administered in relation to radiotherapy does not appear to affect outcomes in men with high-risk prostate cancer [46–48].In summary, the current standard of care for high-risk and locally advanced disease is EBRT in conjunction with long-term ADT; specifically, a 3D-CRT or IMRT radiation therapy technique to a dose of 75–80 Gy in conjunction with long-term ADT in a neoadjuvant, concurrent, or adjuvant setting for approximately 2-3 years. Generally, high-risk patients are usually not considered for treatment with brachytherapy; however, certain clinical scenarios may warrant the use of brachytherapy boost in combination with EBRT, with consideration of short-term ADT [49]. Additionally, a surgical approach may be considered for selected high-risk-patients, although, it is a seemingly less popular approach due to the invasive nature in comparison to EBRT as well as the distinct set of complications which surgery poses; including perioperative mortality, long-term sexual dysfunction, and urinary incontinence. Additionally, the high likelihood that postoperative radiotherapy will be required potentially exposes patients to toxicities of both surgery and radiotherapy.

http://ww.hindawi.com/journals/au/2012/641689/

Dear Fatih:

THE ISSUE OF ACTIVE SURVEILLANCE/WATHCFUL WAITING IN PROSTATE CANCER

This is, once again, a great and highly vital question from my colleague and good friend Fatih Uckun!

I have reviewed this issue most recently as of this year's beginning, and when you asked me to share this question with you, I updated my findings as of date of this posting [22 May 2013], but given the length and complexity of the full review, I present below a - hopefully - more accessible but I think not materially less valuable - 10-point summary of my findings and conclusions, which I hope will stimulate further discussion and debate here, on one of the most subtle but critical outstanding issues in current prostate cancer clinical practice/

1. The Current Indeterminacy of Active Surveillance / Watchful Waiting

The optimal management of clinically localized prostate cancer has not been determined and no broad consensus has emerged even as of date of this writing (may 2013), due in large part to the paucity of RCT data robustly comparing the efficacy and harm across primary treatment options, especially surgery versus its absence or deferral (and I hasten to note here something often overlooked in this heated (if not overheated) debate: that despite the urological and urosexual adverse events of surgical and other interventions, nonetheless not only was patient satisfaction with all selected treatments was high, but over 90% indicated they would make the same treatment decision again, with the clear majority being either delighted or pleased with their treatment decision [1]).

2. Level I Evidence: Trouble in Paradise

Restricting ourselves to high-quality data (prospective RCT), a survival benefit for surgery compared with watchful waiting was demonstrated in the randomized SPCG-4 trial [2] from Scandinavia, where at a median of 12.8 yr of follow-up, the relative risk of death from prostate cancer among men assigned to surgery was 0.62, that is a roughly 40% relative reduction, and most noteworthy, although the benefit was confined to men

Dear Constantine,

What is your professional considered opinion regarding androgen deprivation therapy in non-metastatic prostate cancer patients. For many patients who refused surgery, a 3-6 month Lupron therapy (monthly Depot injections x 3 months), followed by IMRT has been quite effective in providing >10y progression-free survival in my experience. I am also aware that some continue their patients on Casodex even after external beam radiation therapy. Others use extended Lupron/Casodex therapy for patients who refuse both surgery and radiation therapy.

Best

Fatih

Dear Fatih:

Fabulous question! And I am largely in agreement with you on a significant potential benefit (although I do not advocate duration of ADT shorter than 4 months; see below), but let me expand on that to enrich the specifics and allow to unfold some principles of ADT deployment, since the precise answer is disease-dependent.

Note that I differentiate low-risk non-metastatic disease from advanced non-metastatic disease, the latter which includes:

(1) clinically localized intermediate-risk (T2b/c disease, Gleason score 7 or a PSA level of 10–20 ng ml−1) and high-risk disease (clinically localized T3a tumors, a Gleason score between 8 and 10 or a PSA level of >20 ng ml−1), these two categories (intermediate + high risk) spanning up to T3a disease, and

(2) non-metastatic locally advanced disease (that is, Stage T3b/4).

Indisputably, the addition of ADT to primary radiation therapy (RT) not only benefits local control and PFS, but also improves survival in both intermediate- and high-risk patients with localized disease and in patients with locally advanced disease, support by a number of RCTs (including the Dana-Farber/D'Amico Trial [D'Amico et al., JAMA 2004] and the RTOG) 94-08 Trial [Jones et al., N Engl J Med 2011] in which the post hoc subgroup analysis found benefit only in intermediate-risk patients, with no benefit in low-risk ones), but in low-risk disease, androgen deprivation therapy (ADT) fails to improve survival, but is plausibly harmful.

In addition, in high-risk and locally advanced disease several large randomized trials have demonstrated a survival advantage with the addition of a GnRH agonist to radiation (including the EORTC 22863 Trial [Bolla et al., N Engl J Med 1997; Bolla et al., Lancet 2002]; the RTOG 85-31 Trial [Pilepich et al., Int J Radiat Oncol Biol Phys 2005]; the RTOG 9202 Trial [Horwitz et al. J Clin Oncol 2008]; and the EORTC 22961 Trial [Bolla et al., N Engl J Med 2009].

What the Evidence Supports: Six Principles of ADT

On the survival endpoint therefore, I would conclude from my systematic review and critical appraisal that the aggregated evidence strongly warrants these evidence-based principles of ADT deployment:

(1) The use of 4 to 6 months of ADT (that is, a GnRH agonist with or without anti-androgen) for localized intermediate-risk prostate cancer patients undergoing definitive RT.

(2) The use of 24 to 36 months of ADT (GnRH agonist w/wo anti-androgen) for both (a) localized high-risk prostate cancer patients and (b) locally advanced prostate cancer undergoing primary RT.

(3) Duration of ADT shorter than 4 months should be avoided: the large AU/NZ Trans-Tasman Radiation Oncology Group 96.01 Trial Trial [Denham et al., Lancet Oncol 2011] evaluated RT alone against RT with either 3 or 6 months duration of ADT for localized and locally advanced prostate cancer (median follow-up 10.6 years, and with 84% high-risk patients), observing significant benefits of decreased distant progression, prostate cancer-specific mortality and all-cause mortality for 6 month ADT duration compared to RT alone, in contrast to three months of ADT which showed absolutely no benefit on any of these survival endpoints. In addition the RTOG 9202 Trial [Horwitz et al. J Clin Oncol 2008] compared 4 months vs. 28 months of ADT, where a subgroup analyses revealed an OS benefit with longer duration of therapy (Gleason scores of 8–10 (5-year OS 81% vs. 71%), and resulted in improvements in local and distant control as well as rates of biochemical progression. Indeed, the EORTC 22961 Trial [Bolla et al., N Engl J Med 2009] found that RT plus ADT for 6 months was associated with inferior survival compared with RT plus ADT for 3 years, in locally advanced prostate cancer.

(4) But a rigorous assessment of benefit/harm is required in recognition of established long-term toxicities associated with, but underestimated for, ADT, and that for at-risk populations (such as those with frank and significant risk factors for metabolic syndrome, cardiovascular and osteoporotic disease) the balance be weighted against harm.

(5) There appears to be systematic bias in the literature on ADT: a review [Phillips et al., Int J Clin Pract. 2012] of 155 peer-reviewed articles on ADT found (a) that the vast majority of articles failed to acknowledge many more stressful adverse events associated with ADT (for both patients and their partners); (b) AEs of LHRH agonists were frequently minimized; and (c) alternatives to LHRH agonists for ADT were rarely acknowledged.

(6) In the special case of non-metastatic biochemical recurrence, although the RTOG 9601 Trial [Shipley et al., J Clin Oncol 2011] found that the addition of 24 months of daily bicalutamide (Casodex) during and after RT significantly improved freedom from progression, and reduced incidence of metastatic disease, a survival benefit has yet to emerge, and the data to date is lacking in direct evidence that this strategy delays either the onset of radiographically evident metastases, or improves survival, and this absence of prospective support in the non-metastatic biochemical recurrence disease context suggest that deployment, given the still incompletely understood and disconcertingly wide (and underestimated) spectrum of adverse events, is premature.

Best regards, and thanks for always enriching these discussions!

Dear Constantine,

Thank you very much for this very detailed response. I agree with your assessments and conclusions. Most of the patients I treated also received a 6+ month ADT. A few of the of the younger patients did not want to have extended issues with erectile dysfunction. By the way, Cialis was highly effective in supporting their recovery to their perceived "normalcy".

There has been some concern voived via blogs that extended ADT may contribute to development of a "dementia-like" clinical picture, which is partially reversable. Any thoughts on that ?

Kind regards and very best

Fatih

Dear Constantine,

Am I correct in my assumption that you would also use a bisphosphonate like like Zometa when you elect to use ADT in your prostate cancer patients.

Dear Fatih:

Good questions all. I take them up below:

Management of Some Adverse Events from Prostate Cancer Androgen Deprivation Therapy (ADT)

1. PDE-5 Inhibitors for ADT-induced Sexual Dysfunctions

Oral phosphodiesterase type 5 (PDE5) inhibitors are considered the standard of care especially in patients who received nerve-sparing RP and should be instituted as soon as possible to protect and prevent corporal endothelial and smooth muscle damage. But there are three cautions:

(1) In RTOG 0215 Trial [Bruner et al., J Sex Med. 2011], the first randomized, double-blinded (cross-over) trial of a phosphodiesterase Type 5 (PDE-5) inhibitor in the treatment of ADT-induced erectile dysfunction, treatment-specific response occurred - and benefit was modest - in as few as 21% of patients, effectively leaving 4 out of 5 patients without relief.

(2) Furthermore this landmark trial was short term: 24 weeks of which in only 12 was there active therapy. The more recent long-term randomized, double-blind, placebo-controlled Australian trial [Ilic et al., J Med Imaging Radiat Oncol. 2013] of the same agent (sildenafil) taken for 6 moths, with a 2-year follow-up, there was no difference in erectile function scores between the two groups (active and placebo) throughout the treatment period, concluding that although regular use of sildenafil may improve short-term sexual function, there was no evidence of long-term erectile function for patients while on medication.

(3) we still lack any significant consensus on the exact timing, on the dosing, and on the optimal duration of PDE-5 inhibitors (and given their known equi-efficacy, application is across the entire class), nor its potential impact in other forms of prostate cancer treatment modalities including non-nerve-sparing RP.

At this time, with no evidence of long-term benefit and equivocal data of efficacy in the short-term, with - at best - the vast majority of patients failing to achieve significant relief even at a modest level, we must conclude that prostate oncology is largely failing to provide clinically relevant remediation of many of the most QoL-compromising adverse events of ADT, whose total benefit-harm ratio is as yet to achieve a clearly favorable balance.

Some Hope

I will add a small but non-trivial ray of hope here in a procedure I have been advocating for some while both in this and in the general treatment context of erectile dysfunction, and although I use pharmaceutical-grade RYR (red yeast rice) standardized at no less than 10 mg monocolins component instead of the statin atorvastatin (Lipitor), the principle is the same and I have been able to match and exceed benefit obtained in trial data: the approach is to use a statin to improve response to a PDE-5 inhibitor (sildenafil) for remediating erectile dysfunction in patients initially irresponsive to PDE-5 inhibition [El-Sisi et al., Int J Impot Res. 2013]. Nonetheless, we need new solutions to capture still larger proportions of patients, some of which are slowly beginning to be researched.

ADT-Induced Cognitive Compromise

Data on cognitive decline, namely decline of memory and neurocognitive function, during ADT is to date inconsistent, although provisional evidence suggests the likelihood of a non-trivial problem especially as to spatial memory. One prospective Australian study utilized interval neurocognitive battery testing men (n=50) treated with ADT, finding that 48% demonstrated decline in one cognitive task, and 14% in two or more tasks at one year [Salminen et al., Br J Cancer2003.], but against this a different prospective trial (n=244) failed to demonstrate any evidence of neurocognitive function decline after ADT use for 12 months [Alibhai et al., J Clin Oncol 2010]. But the methodological quality of the aggregate literature on this issue I found to be of largely poor quality, beset by problems of low sample size and inadequate controls, and indeed there is no differentiation of intrinsic versus reactive cognitive decline, if any: it is not impossible I would suggest that some of the many adverse effects of androgen ablation therapy including vasomotor dysfunction, fatigue and anemia, and possibly other cardiometabolic side effects, may themselves contribute indirectly to the impairment of cognition.

Thus need is the execution of a large-scale, methodologically robust randomized trial of prostate cancer patients randomized to ADT versus to watchful waiting, with planned analysis of metrics of cognitive decline and dysfunction. A trial close - but only close - to this, with some limitations, has just reported findings, the Polish ADT-QoL Trial [Wiechno et al., Psychooncology. 2013] where it was observed that there were no statistically significant differences between patients on ADT (n=88) and those without ADT (n=61) in cognitive function. This is still small, but the assignment to ADT and no-ADT is a requisite protocol; what is most lacking is standardized metrics, where here patient rated themselves.

Finally, although to date no active intervention has shown significantly beneficial (data on estrogen is wholly inconsistent), nonetheless on a case observation level (n=180), I find improvement in any observed and reported cognitive compromise by virtue of aggressively addressing and remediating fatigue and anemia, adding consistent strength and aerobic training, and if necessary, supplementation with standardized ginsenosides (from Ginseng), standardized rosavins and salidrosides (from Rhodiola) and HD (high-dose) EGCG (a CAM intervention of some value in the "chemo-brain" of breast cancer therapies). For fatigue and chemo-brain in particular I have successfully used, across over a dozen malignancies LD-guarana (low-dose: negligible amounts of caffeine) based on the recent randomized, double-blinded, crossover clinical trial (Oliveira Campos et al., J Altern Complement Med. 2011) which demonstrated that guarana favorably remedied cancer-induced or chemotherapy-induced fatigue, with no significant increase in cardiovascular events, and no worsening sleep quality, nor any induction of anxiety or depression. Furthermore, these findings have been robustly confirmed in a meta-analysis of three clinical trials (Giglio et al. TANG, 2011) which found that guarana was an effective, inexpensive, and nontoxic alternative for the short-term treatment of fatigue (patients were breast cancer).

Bone Interventions in Prostate Cancer

Correct Fatih I would favor zoledronic acid (Zometa, Reclast) by a modest margin, although I can also countenance (besides Zometa) either alendronate (Fosamax) or risedronate (Actonel) but not ibandronate (Boniva) nor denosumab. Although denosumab and toremifene remain backup options, denosumab to date has shown a reduction in vertebral fractures but non-vertebral fractures, especially hip fractures, are the most critical ones, with higher mortality than many malignancies themselves (including breast and prostate cancer). Thus a bisphosphonate should be integrated within a program of optimal vitamin D (Alibhai and colleagues [Osteoporos Int. 2013] have recently shown benefit in remediating BMD and fracture risk induced from ADT), and a regular regimen of physical activity that includes both aerobic and strength/resistance training.

Kind regards

Constantine

Dear Constantine,

A couple of remarks/thoughts:

1. In regards to sexual dysfunction: After ADT x 6 months followed by IMRT, use of androgen patches (72 h every 2 weeks x 2 months) for short-term elevation of testesteron level along with the use of Cialis (not Viagra which absolutely does not work in these patients) had a fantastic effect. After about 2 months, there is no need for androgen patches.

2. In regards to chemotherapy-induced fatigue, leukovorin 25 mg po QID can have a dramatic effect in some patients when used alone or with L-glutamine. By the way, we saw some benefit in non-cancer patient populations with chronic fatigue as well : http://www.ncbi.nlm.nih.gov/pubmed/16889122

3. The EGCG info is interesting; does it have anything to do with its effects on ER/UPR pathway.

Best

Fatih

Dear Fatih:

Tadalafil PDE-5 Inhibition Therapy for Erectile Dysfunction

Thanks for the tips and personal experience, especially on tadalafil (Cialis) because to date there has been no evidence of efficacy in ADT-induced sexual dysfunctions, for the excellent reason, not of any demonstrable failure, but rather because it has never in fact been tested in that context at all. There is a randomized Phase II trial of it but only in post-radiotherapy prostate cancer patients, not patients on androgen deprivation therapy (ADT) which several lines of evidence show to compromise the normal expected response to PDE-5 inhibitors (the failure to test it in the ADT context may have been secondary to early concerns of cardiac safety but other than avoidance of coadministration with nitrates, alpha-blockers and antihypertensives, a rapid review I undertook of cardiosafety data was in fact reassuring). Therefore the protocol you outline and the success you've had with it in post-ADT PC patients appears worthy of further exploration, with one proviso that I suspect you are already aware of: I am not sanguine about the use of testosterone in a prostate cancer context where it is contraindicated by numerous guidelines including the current Endocrine Society Guidelines. There is unequivocal evidence that testosterone can stimulate growth and aggravate symptoms in men both with locally advanced and with metastatic prostate cancer. However, patients deemed successfully treated for prostate cancer in the context of subsequent to radical prostatectomy, and then consequently diagnosed with hypogonadism can be candidates for limited short-term testosterone therapies but if and only if after a prudent interval that confirms no clinical or laboratory evidence of residual disease.

Folinic Acid/FA (Leucovorin/LCV) for Oncologic Fatigue

This too is intriguing and suggests further exploration. There appears to be no data directly on the use of FA/LCV in oncotherapy-induced fatigue; and the excellent study you undertook was in the special context of CFS (chronic fatigue syndrome) where all patients had prior Epstein-Barr Virus (EBV) exposure and 72% even had reactivated EBV exposure, so extrapolation is limited, but I hasten to add not rendered implausible. That's because you nonetheless appear to be on to something here if the data you cite is confirmed (of a fatigue-remediating benefit from folinic acid in the oncologic context of vinca alkaloids and, most intriguingly, in that of the anti-folate agent MTX (methotrexate)). Given this oncologic connection and the findings of your article, I am rather surprised that this promising potential intervention hasn't as far as I am aware been pursued further for oncotherapy-induced fatigue, something of a missed opportunity, like that of tadalafil, above, for erectile dysfunction secondary to ADT, certainly plausible in properly cardio-safety selected populations.

ECGC

We have little evidence to that effect although it remains plausible. Rather, in the vast literature, anti-fatigue protection was most highly correlated with the lowered levels of lipid peroxidation and restoration of reduced glutathione levels in the brains, elevating the activity of oxygen radical species-metabolizing enzymes, especially SOD, glutathione peroxidase and catalase, strongly suggesting the pivotal role of oxidative stress in the pathophysiology of CFS, with the ability to decrease inflammation via decreasing the levels of TNF-a (tumor necrosis factor-alpha) and TGF-b (tissue growth factor-beta), as well as IL-6 and IL-8 (via attenuation of extracellular signal-regulated kinase and NFk-b (nuclear factor kappa-B) in human mast cell line-1 cells), and with a potential contribution from its metal-chelating capabilities (neutralizing ferric iron to form redox-inactive iron, hence protecting cells against iron-mediated oxidative damage).

Thanks again for the highly stimulating ideas and discussion!

Kind regards

Constantine

Dear Constantine

After external beam RT, and a 6 month ADT, those patients have undetectable PSA and free PSA levels. The testosterone level would be detectable just for a very short time. But remember that level is a level the patient will live with rest of his life anyway and despite presence of native testosterone we don't use lifelong ADT. I would not use injections of testosterone.

Many physicians think leukovorin is a chemo agent and indeed some insurance companies list it as chemo because of its concomitant use with 5 FU or concecutive use with MTX. Just FYI, it was because the subjective favorable effects in cancer patients, why my internist colleague tried it in non cancer patients. As you know folinic acid has better CNS penetration and yields higher tetrahydrofolate levels than frolic acid. So in patients with peripheral neuropathy and fatigue it appeared to have favorable effects. But you need to get a cheap source.

My experience with leukovorin goes back to mid 1980s when a young woman with a PNET of brain stem developed debilitating fatigue and neuropathy after the 8 in 1 protocol, (unable to walk, play piano, climb up the stairs or button up her shirt). Leukovorin worked like a miracle. She had a completevrecovery within 10 days. I tried to present the case to my senior colleagues Mark Nesbit and BJ Kennedy, without telling anything about the leukovorin or the outcome, they both suggested the use of leukovorin. Apparently it has been used by the people who established the disciplines of pediatric oncology and medical oncology.

I thought you would like to know the context

Dear Fatih:

Fascinating!!! Thanks much.

Kind regards

Constantine

Dear Constantine

Just FYI. Many of the patients were also using L Glutamine. So it was not a single agent intervention

Dear Fatih:

Understood - but still remains thought-provoking given how few interventions have achieved significant benefit.

Thanks again!

Constantine

Dear Constantine,

In regards to leukovorin, it seemed to be necessary to start with 4x/day doseing (25 mg/dose), but after 2-3 months it did not seem necessary to continue this schedule and one can reduce it to twice daily dosing.

In regards to "extreme fatigue" in cancer patients, I would like to mention a few additional items:

1. Elderly non-prostate cancer male patients (e.g. NSCLC) may benefit from Testesteron depot IM injections if they have evidence of low testesteron levels and no cardiovascular contraindications

2. When fatigue is also associated with loss of appetite and decreased food intake which in turn makes the fatigue worse, low dose Dexamethasone (2 mg orally 1x/day in the morning (along with Ranitidine 75 mg at night) has been very effective. Many such patients appear to have a poor adrenal gland function based on laboratory assessments. You cannot do this in patients with diabetes of course.

3. When patients develop extreme fatigue after cranial radiation, one should consider somnolence syndrome. In such patients, high dose Decadron for 3 days (20 mg 2x/day x 3 days) can result in significant improvement.

4. Calory intake seems to be important for elderly - protein shakes can be beneficial.

Very best

Fatih

Dear Fatih,

The best way to fight fatigue is increased physical activity! (it doesn't make sense, right?....but it is true). If you have fatigue, get off your butt :)

Most cancer patients are depressed. Depression leads to perception of fatigue.

Depression is associated with inflammation. One can reduce depression (and inflammation) through diet and exercise as well as other methods (meditation, yoga, music, walking in nature,..)

I prefer dietary and behavioral interventions rather than pharmacologic...

Warm regards,

Omer