DCA and Cancer: Non-Hodgkin’s lymphoma cured in 4 months (Case presentation)

Today we would like to present you our first article based on Dichloroacetate usage benefits as described in case series. This writing will focus on a middle aged man who managed to cure his IV stage Non-Hodgin lymphoma with the use of DCA.

But first – let’s briefly remember some important aspects of this cancer and Sodium dichloroacetate.

Non-Hodgkin lymphoma is a type of cancer that begins in the body‘s immune system cells – T or B lymphocytes. The main histological difference between this malignancy and an other similar illness, the Hodgkin disease, is that the latter cancer has Reed-Sternberg cells present in biopsies. Hodgkin lymphoma is a lot rarer between the two diseases. Besides that, it is also one of the most successfully treated cancers today – 5-year survival rate is about 90 %. (Ref.)

Often one of the first considerably important symptoms of Non-Hodgkin lymphoma is enlarged non-painful lymph nodes. The other signs of the disease include fever, loss of weight, fatigue, cough, shortness of breath and night sweats. This cancer is first suspected when the associated symptoms appear (especially the painless swelling in the lymph nodes) or by accidentally discovering abnormal blood test results. Then the person has to get his blood checked for further analysis.

Above all, computed tomography scans and biopsies play a major role in determining the final diagnosis and the best possible choice of treatment for such patient.

Non-Hodgkin Lymphoma Hodgkin lymphoma
 Symptoms Non-painful lymph node swelling, night sweats, weight loss, fever, fatigue, cough, shortness of breath
 Diagnosis Confirmed via a biopsy of an abnormal lymph node, bone marrow or suspected tumor tissue
 Occurrence More common (6th most widespread cancer in the world) Less common (about ten times fewer cases than Non-Hodgkin lymphoma
 Age groups 45 years and older 15 – 24 years old or 60 years and older
 Treatment Mostly chemotherapy
(R-CHOP chemo regimen)
I or II stage – radiotherapy, ± chemotherapy
III or IV stage – always chemotherapy
(ABVD chemo regimen)
 Prognosis Depends on the type,
recovery is less frequent than in Hodgkin lymphoma
One of the most treatable cancers

Did you know that Non-Hodgkin lymphoma is a quite common cancer ?

Non-Hodgkin lymphoma accounts for 4 % of all new cancer cases. About 20 men and women of 100 000 develop this disease annually.
In 2014 there were about 660 000 people in America who were living with this diagnosis. (Ref.)

The numbers of new Non-Hodgkin lymphoma cases are increasing every year. However, this could be because the diagnostic capabilities of such diseases are getting better. (Ref.)

Non-Hodgkin Lymphoma symphoms and risk factors I DCA and Cancer


A lot of cancers, including Non-Hodgkin lymphoma, are treated with chemotherapy which can help achieve full remission (cured cancer).

Unfortunately, treatment with such medications can result in uncomfortable adverse reactions and long-term health problems. Sometimes the malignancy can relapse (come back) and you have to take chemo drugs all over again.

Not surprisingly, this can be a couple of reasons why people seek alternative cancer therapies by themselves or with the help of other specialists.
One of such alternative treatment choices is Sodium dichloroacetate. Before the idea that this drug could be used to help someone with oncological illnesses, the substance has been used for several decades as a medication for children suffering from congenital mitochondrial diseases.

DCA pharmacokinetics, pharmacodynamics and side effects were studied and discovered long before the accidental findings that this medication could be useful for treating cancer. (Ref.1), (Ref.2)

But how does DCA work ? To put it simply, the most important thing that you should know about the mechanism is that the drug inhibits an important enzyme for cancer – pyruvate dehydrogenase kinase. This leads to various changes in tumor cells.

Firstly, the Warburg effect is diminished. This resumes normal cellular respiration from aerobic glycolysis and lowers elevated intracellular acidity. Secondly, dichloroacetate promotes selective cancer cell apoptosis (cell death) which means that it stops tumor growth and shrinks their volume. Last but not least, DCA can even lower the risk of metastasis. (Ref.)

These sound like great accomplishments considering the fact that the risk of side effects is significantly lower when you take DCA with a couple of other food supplements.

If, however, the adverse reactions do show up – they‘re mostly mild and do not cause much discomfort. These issues are entirely reversible and go away in a couple of days when you stop taking dichloroacetate. (Ref.)

So, this appears to be a promising alternative cancer treatment. And it‘s already helping people who are dealing with oncological diseases. (Ref.1), (Ref.2)

We believe that it could help even more people. That is why we would like to present a case in which a currently 52 year old man cured his cancer.

He had IV stage Non-Hodgkin follicular lymphoma, which was completely resolved as a result of self-medication with DCA (Sodium dichloroacetate).

Non-Hodgkin Lymhpoma I Before and after DCA treatment

The person was at the age of 46 when he started feeling strange. In the last 5 months he lost a lot of weight (50 pounds), had constant fever and drenching night sweats. On top of that, he had enlarged cervical lymph nodes that extended all the way from the top of his neck to the collarbone.

Finally, the man decided to wait no more and got his health checked. The results of a computed tomography scan concluded that there were pathologic lymph nodes in his head, neck, chest, abdomen and pelvis. This was poor news.

Once the male had biopsies taken from his bone marrow and lymph nodes, the diagnosis became clear – he had IV stage Non-Hodgkin follicular lymphoma.

Shortly afterwards the doctors gave him six cycles of R-CHOP chemotherapy (rituximab,cyclophosphamidedoxorubicin,vincristine and prednisolone).

The chemo treatment took several intense months. When he once again had a CT scan performed, the doctors confirmed that he was clear from cancer. He had achieved his first remission (his tumors disappeared).

The man resumed to his former way of life, continued his ordinary daily activities and regularly performed health checks at the physician‘s office. For a year he was completely healthy.

However, after some time the fever, coughing and night sweats came back. Not only that, but he had also lost 11 pounds in two weeks.

Non-Hodgkin Lymphoma I DCA usage protocol for cancerThe male went straight to the doctors and after a couple of diagnostic procedures he received bad news.

He had enlarged lymph nodes on the right side of his head and neck. The cancer was back.

When the man received offers to repeat the treatment, he refused, claiming that chemotherapy and its side effects, especially nausea and vomiting, made him extremely upset and that he would rather avoid the experience.

As a result of his situation, he started searching for alternative cancer treatments that could improve his condition.

Shortly, he learned about DCA, bought this substance online and began treating himself.

His every day ‘‘DCA protocol“ consisted of:
• 1 000 mg Sodium dichloroacetate,
• Vitamin B1 500 mg,
• Alpha-Lipoic acid 1200 mg,
• Green tea leaf extract (Jarrow) 500 mg,
• 10 oz of  Mountain Dew (he would mix it with DCA and drink it afterwards).

The man took this regimen every day. These were the results:

✓ After two weeks his fever, night sweats, fatigue and weight loss started to improve.
✓ After a month of taking DCA his enlarged lymph nodes started to shrink. Two months later no lymph nodes were palpable.
✓ After 71 days of the regimen his symptoms disappeared completely. He recovered his sense of well-being, was full of energy, regained normal appetite and was once again able to have good quality sleep.

Eventually, something astonishing happened. There were no remaining signs of cancer left in his body. This was confirmed by a PET scan at 2008 December (4 months after he had begun his DCA therapy).

All of the previous tumor was gone. The man was cured from Non-Hodgkin lymphoma cancer.

Last time they contacted this person who beat cancer was at the end of 2012. Then he claimed that he still takes 1 000 mg of DCA three times a week together with Thiamine and Alpha-Lipoic acid for prophylaxis.

The 52 year old man feels great. He enjoys his life and works full-time. The last PET scan did not detect any cancerous tissues and cells in the body. Aside from his slightly elevated triglyceride and cholesterol levels, all of his blood tests are normal (the fat and cholesterol are probably higher due to other reasons).

Non-Hodgkin Lymphoma I Before and After DCA treatment PET scan

We prepared this case for presentation based on voluntary medical document distribution to the researchers.

Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models


Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.

Keywords: tumor metabolism, DCA, 17O MRS, hyperpolarized 13C-MRI, 18F-FDG PET


Warburg metabolism (enhanced glycolysis in the presence of oxygen) is a common feature of several malignant tumors and is associated with cancer aggressiveness, invasiveness and poor prognosis []. Because of this high glycolytic rate in various cancers, targeting glucose metabolism is presented as an attractive anticancer approach endowed with a high specificity and limited undesirable side effects []. Indeed, conventional treatments rely on the rapid proliferation process present in cancer cells but also in healthy cells. Treatments targeting glycolytic metabolism should instead specifically alter metabolic adaptations that support the Warburg malignant phenotype, adaptations that are not shared by normal cells. To support drug development and assessment in clinical trials, there is a critical need for dedicated criteria evaluating tumor response to these emerging therapies. Moreover, for new cytostatic agents targeting tumor metabolism, the use of conventional anatomical imaging techniques is not optimal for treatment response assessment [] and only functional and molecular imaging techniques may offer the possibility of an early assessment of the tumor response [].

Recently, we have investigated the effects of dichloroacetate (DCA) in tumor cell lines presenting different metabolic profiles []. DCA is a promising molecule that promotes glucose oxidation over glycolysis by inhibiting the mitochondrial pyruvate dehydrogenase kinase (PDK) and has successfully reached clinical trials []. We found that 5 mM DCA was more effective in glycolytic-phenotype cancer cells, where reduction in cell proliferation was mediated by a reactivation of mitochondrial function and a decrease in glycolytic and pentose phosphate pathway fluxes. Our data suggested that DCA may benefit to patients with highly glycolytic tumors. Therefore, the objective of the present study was to assess the effect of DCA in these prototypical tumor models in vivo, namely the glycolytic MDA-MB-231 human breast cancer model and the oxidative SiHa human cervical cancer model. For this purpose, we used a multi-modality molecular imaging approach using several pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy (17O MRS), glucose uptake, evaluated by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and pyruvate transformation into lactate, measured during hyperpolarized 13C-magnetic resonance imaging (hyperpolarized 13C-MRI), were monitored before and after DCA treatment in tumor bearing mice. Surprisingly, in vivo models did not recapitulate the previously observed in vitro behavior.


To assess the impact of DCA treatment on the metabolism of the models in vivo, oxygen consumption (Figure ​(Figure1),1), glucose uptake (Figure ​(Figure2)2) and lactate flux (Figure ​(Figure3)3) were measured in MDA-MB-231 and SiHa tumors before and 24 hours after DCA treatment.


Figure 1

Effect of dichloroacetate on tumor oxygen consumption in vivo

Tumor H217O signal from representative MDA-MB-231 tumors A. and SiHa tumors B. acquired before, during and after a 2 min inhalation period of the 17O2gas. H217O signal is expressed as relative to the mean baseline signal before 17O2delivery. 17O2 metabolismis not modified by DCA treatment. C. Comparison of the rate of H217O signal after 17O2 delivery in tumors pre and post-treatment. Data are expressed as means ± SEM. Paired tests were two-sided.


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Figure 2

Effect of dichloroacetate on tumor glucose uptake in vivo

Representative 18F-FDG PET images showing MDA-MB-231 A-B. and SiHa C-D.tumor-bearing mouse imaged before and 24 hours after DCA treatment. Tumors are indicated by thin arrows. 18F-FDG uptake is expressed in %ID/g. Images were normalized. DCA does not alter 18F-FDG uptake in MDA-MB-231 and SiHa tumors. E. Comparison of 18F-FDG uptake before and after treatment. Data are expressed as means ± SEM. Paired tests were two-sided.


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Figure 3

Effect of dichloroacetate on tumor lactate production in vivo

Tumor lactate and pyruvate peak intensities after i.v. injection of hyperpolarized 1-13C pyruvate from representative MDA-MB-231 tumors A-B. and SiHa tumors C-D. Lactate production, measured by the Lac/Pyr ratio, in MDA-MB-231 and SiHa tumors before and after treatment E. Data are expressed as means ± SEM. Paired tests were two-sided.

In Figure ​Figure1,1, tumor H217O spectra are presented for representative MDA-MB-231 (Figure ​(Figure1A)1A) and SiHa tumors (Figure ​(Figure1B)1B) during 17O MRS experiments. The results were highly reproducible under the same conditions tested. The evolution of H217O signal, demonstrating the 17O2 metabolism in tumors, was similar before and after DCA treatment in MDA-MB-231 tumors (Figure ​(Figure1A)1A) and in SiHa tumors (Figure ​(Figure1B).1B). In both tumors models, we found that DCA treatment did not majorly impact oxygen consumption, as assessed by the rate of increase in H217O signal (Figure ​(Figure1C).1C). MDA-MB-231 tumors exhibited a slope of 1.02 10-3 ± 0.16 10-3 s-1and 0.91 10-3 ± 0.09 10-3 s-1 before and after treatment respectively (n=5, P=0.5366). For SiHa tumors, the slopes were 0.85 10-3 ± 0.14 10-3 s-1 under baseline condition and 0.79 10-3 ± 0.11 10-3 s-1 post-treatment (n =5, P=0.2892).

18F-FDG uptake (%ID/g) measured in both tumor models under baseline and post-treatment conditions are presented in Figure ​Figure2.2. In both tumor models, we found that DCA treatment did not lead to a significant change in the uptake of 18F-FDG (Figure 2A-2D), assessing a limited impact of DCA on glucose uptake (Figure ​(Figure2E).2E). %ID/g measured on PET images (mean ± SEM) were 1.88 ± 0.12 under baseline condition and 1.78 ± 0.11 after treatment for MDA-MB-231 tumors (n=7, P=0.2120) and 1.79 ± 0.21 under baseline condition and 1.89 ± 0.19 after treatment for SiHa tumors (n=7, P=0.0813).

The influence of DCA treatment on pyruvate transformation into lactate was measured after hyperpolarized 1-13C pyruvate injection during hyperpolarized 13C-MRS studies (Figure ​(Figure3).3). Representative pyruvate and lactate peak intensities over time of MDA-MB-231 tumors and SiHa tumors captured before and 24 hours after DCA treatment are shown in Figure 3A-3D. Lactate production was reduced after DCA treatment only in SiHa tumors (Figure ​(Figure3E).3E). Lactate/pyruvate ratio (Lac/Pyr) shifted from 0.55 ± 0.05 to 0.48 ± 0.04 in MDA-MB-231 tumors (n=7, P=0.3105) and from 0.82 ± 0.05 to 0.63 ± 0.07 in SiHa tumors (n=7, P=0.0348).

We also evaluated the magnitude of response to the treatment by measuring the variation within the above biomarkers between baseline and post-treatment conditions (Figure ​(Figure4).4). No differences in oxygen consumption and lactate flux measurements were observed between MDA-MB-231 and SiHa tumors during the treatment (P>0.05) (Figure 4A, 4C). Only a small but significant difference in behavior was observed for 18F-FDG uptake measurements (P=0.0240) (Figure ​(Figure4B).4B). MDA-MB-231 tumors decreased their 18F-FDG uptake after treatment (n=7, -5.4 ± 3.5 %) compared to SiHa tumors (n=7, +6.7 ± 3.1 %).


Figure 4

DCA does not significantly influence the metabolism of glycolytic tumors compared to oxidative tumors, as assessed by 17O2 metabolism A., 18F-FDG uptake B. and pyruvate transformation into lactate C. measurements in vivo

The magnitude of response to dichloroacetate (variation) is identical in both models, only a small difference in behavior is observed for 18F-FDG uptake. Data are expressed as means ± SEM. Unpaired tests were two-sided.


In this study, the impact of DCA on tumors presenting different metabolic profiles was evaluated using molecular imaging in vivo. Recent findings identified that DCA preferentially impairs glycolytic cells compared to oxidative cells. The purpose of the present study was to establish the relevance of these findings in vivo using the same prototypical tumor models as in our in vitro study [], namely the MDA-MB-231 human breast cancer model reported as glycolytic [] and the SiHa human cervical cancer model documented as oxidative []. The dose and administration scheme were selected based on previous reports attesting the efficacy of DCA in tumors [].

In vitro, we previously identified clear effects of DCA treatment on oxygen consumption, glucose consumption and lactate uptake in glycolytic MDA-MB-231 human breast cancer cells. On the other hand, the metabolic activity of oxidative SiHa human cervical cancer cells was not altered by DCA treatment. Using a multi-modality imaging project, we were not able to recapitulate these findings in vivo. Pre-treatment, MDA-MB-231 and SiHa tumors exhibit the same metabolic profile. As MDA-MB-231 and SiHa tumors were previously described as hypoxic under baseline condition [], we highlighted here that both tumor models exhibit a glycolytic phenotype under anaerobic condition. Post-treatment, glycolytic MDA-MB-231 tumors do not appear more impacted than oxidative SiHa tumors (Figure 1-4). Also, some marginal metabolic changes were identified such as a significant decreased lactate production in SiHa tumors (Figure ​(Figure3E)3E) or a decreased 18F-FDG uptake in MDA-MB-231 tumors (Figure ​(Figure4B).4B). Together, those findings did not highlight a clear metabolic shift in MDA-MB-231 tumors or in SiHa tumors treated with DCA during 24 hours (Supplementary Figure S1). This inability to observe any treatment response in vivo could not be attributed to any differences in growth rate between the tumor models under study (Supplementary Figure S2). Also, the measurement repeatability was formerly established using the same tumor models []. Our study demonstrated that the tumor metabolic response to DCA was dramatically different between in vitro and in vivo conditions.

Because of its good tolerability and safety, DCA has been universally exploited to lower lactate levels in acquired or congenital forms of lactic acidosis []. In 2007, Bonnet and colleagues investigated the effects of DCA in cancer and discovered that DCA was promoting apoptosis in vitro and decreasing tumor growth in vivo []. Since then, this orally available and cheap molecule has been further investigated in vitro, in vivo and successfully reached clinical trials. The first data available from the clinical trials indicate that DCA appears to be efficient in adults in solid and brain tumors []. However, no firm conclusions stand out in advanced non-small cell lung cancer []. In another recent study of Feuerecker and co-workers, promotion of tumor growth was even observed after DCA treatment in neuroblastoma tumors []. These studies indicate that response to DCA treatment may drastically vary among tumor types.

The redirection of glucose metabolism from glycolysis to oxidation leading to the inhibition of proliferation and the induction of caspase-mediated apoptosis was initially proposed as the generic mechanism of action of DCA. In a recent phase I study in patients with advanced solid tumors, decreased 18F-FDG uptake was observed after DCA therapy, supporting the use of 18F-FDG uptake as a potential biomarker of response to DCA []. Also, hyperpolarized 13C-pyruvate MRI has already been used in several preclinical studies to monitor DCA effect in solid tumors [], but also in cardiac [] and brain studies []. In the present study, 18F-FDG uptake was unchanged after DCA treatment (Figure ​(Figure2E).2E). This suggests that DCA treatment does not impair glucose uptake and phosphorylation but could potentially impact downstream transformation of glucose. However, no effects on bicarbonate production were detected that could demonstrate changes in energy metabolism from glycolysis to oxidative phosphorylation (Supplementary Figure S3). Recent findings suggested that DCA may also act by other mechanisms. While a possible disruption of the balance between fatty acid β-oxidation and glucose oxidation has already been suggested as an additional mechanism involved in the overall effects of DCA in vivo (as reviewed by []), PDK inhibitors may potentially induce other compensatory mechanisms that could limit the impact of such drugs on global tumor metabolism. The anti-cancer effects of DCA appear to rely on multiple mechanisms depending on the drug concentration, drug administration scheme [] and cell type []. Also, a change in PDK isoform expression between in vitro and in vivo model could also greatly influence the effect of DCA on tumor metabolism in vivo. Indeed, oncogene regulation and tumor microenvironment, like extracellular acidosis, can affect PDK isoform expression [], possibly leading to the expression of a PDK isoform less sensitive to DCA effects. Our findings are consistent with a recent study highlighting that tumor microenvironment could be as important as the (epi) genetic profile to shape the tumor phenotype []. Further investigations using relevant isogenic cell clones with ability to form tumors in vivo should be considered to determine the effects of DCA on energy metabolism in vivo.

In conclusion, our multi-modality imaging study identified major discordances between in vitro and in vivo metabolic responses to DCA treatment, in cancer models presenting distinct metabolic profiles. Results suggest preferring implanted tumors and spontaneous cancer models to study DCA treatment within the milieu of the tumor microenvironment. Overall, further investigations are required to elucidate the impact of different tumor microenvironments on metabolic effects of DCA and its impact for clinical use.


Cell culture

MDA-MB-231 (human breast cancer) and SiHa (human cervix squamous cell carcinoma) cell lines (American Type Culture Collection [ATCC]), were routinely cultured in Dulbecco’s modified Eagle’s medium containing 4.5g/l glucose supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin.

Animal housing

Animal studies were undertaken in accordance with Belgian and the Université catholique de Louvain ethical committee regulations (agreements number UCL/2010/MD/001 and UCL/2014/MD/026). Hyperpolarized 13C-MRI experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animal Resources (National Research Council, 1996) and approved by the National Cancer Institute (NCI) Animal Care and Use Committee.

Tumor implantation and animal experiments

A total of 107 MDA-MB-231 cells or 107 SiHa cells, amplified in vitro, were collected by trypsinization, washed three times with Hanks balanced salt solution and resuspended in 200 μL of a 1:1 mixture of Matrigel (BD Biosciences) and Hanks balanced salt solution. For 17O MRS and PET scan experiments, the tumor cells were inoculated subcutaneously into the hind thigh of nude NMRI female mice (Janvier Le Genest-Saint-Isle, France). For hyperpolarized 13C-MRI experiments, the tumor cells were inoculated subcutaneously into the hind thigh of athymic nude female mice (Frederick Cancer Research Center, Animal Production, Frederick, MD, USA). The experiments were performed when tumors reached 7 mm (at this tumor size, necrosis was less than 5% as characterized by Hematoxylin Eosin staining).

To assess the effects of DCA on tumor metabolism using biomarkers, all animals have undergone imaging before and after treatment, with one day between each measurement. Dichloroacetate sodium (Sigma-Aldrich) was administered intraperitoneally (200 mg/kg) after baseline measurements to the mouse. Another dose was given 24 hours after the first dose injection. Post-treatment measurements were initiated 1 hour after treatment administration. This administration scheme is consistent with previous studies attesting the effects of DCA in tumors using hyperpolarized 13C-MRI []. The imaging protocol is summarized in Figure ​Figure55.


Figure 5

Experimental protocol

Mice were anesthetized by isoflurane inhalation (Forene, Abbot, England) mixed with air in a continuous flow (2 L/min). Animals were warmed (approximately 35°C) throughout the anesthesia period.

17O MRS experiments

For oxygen consumption experiments, 17O MRS was performed on an 11.7 T (Bruker, Biospec) controlled by Paravision 6.0 (Bruker, Ettlingen, Germany). Experiments were carried out using a 1H/17O Bruker surface coil system positioned over the tumor mass. Anatomical images were firstly acquired using a T2-weighted axial turbo RARE sequence (TR = 2500ms; TE = 30ms; rare factor = 8; NA = 2; FOV = 25x25mm2; resolution: 98 x 98 μm2; 1 mm slice thickness). 17O MRS measurements were carried out using a nonlocalized, single-pulse sequence (TR = 16.5 ms; NA = 600; repetition: 120; Tacq = 20 min; Acq BW = 5000 Hz; FA = 20°). For 17O MRS sequence, the 90° reference pulse was optimized previously on natural abundance H217O samples.

To measure tumor oxygen consumption during the 17O2 delivery, a total of 120 17O-spectra were collected in about 20 min, before, during and after a 2 min inhalation period of the 17O2 mixture. The integrals of the H217O peaks over time were measured using a home-made program written in Matlab (The MathWorks Inc., Natick, MA, USA). H217O signal was then expressed as relative to the mean baseline signal before 17O2 delivery. The mean signal of the final steady state (sfinal) during the post-inhalation period was calculated between 1100 and 1200 s. We considered that the steady state was reached when the signal stood between sfinal ± 5 % of signal variation. The slope during the linear incorporation phase was measured between 600 sec and the time point when steady state was reached.

PET/CT imaging

Whole-body PET imaging was performed on a dedicated small-animal PET scanner (Mosaic, Philips Medical Systems, Cleveland, USA) with a spatial resolution of 2.5 mm (FWHM). The PET scans were followed by whole-body acquisitions using a helical CT scanner (NanoSPECT/CT Small Animal Imager, Bioscan Inc., DC, USA). For each breathing condition, anesthetized mice were injected 120 μl intraperitoneally with 11.1-14.8 MBq of 18F-FDG (Betaplus Pharma, Brussels, Belgium). A 10 min transmission scan was first obtained in a single mode using a 370 MBq 137Cs source for attenuation correction. A 10 min static PET acquisition was then performed after a 60 min resting period. After the correction with attenuation factors obtained from the transmission scan, images were reconstructed using a fully 3D iterative algorithm (3D-RAMLA) in a 128 x 128 x 120 matrix, with a voxel size of 1 mm3. After PET acquisition, anesthetized animals were transferred on the same bed from the PET scanner to the CT scanner (x-ray tube voltage: 55 kVp; number of projections: 180; exposure time 1000 ms) for anatomical reference. The CT projections were reconstructed with a voxel size of 0.221 x 0.221 x 0.221 mm3. Regions of Interest (ROIs) were delineated on PET images using PMOD software (PMOD™, version 3.403, PMOD technologies Ltd, Zurich, Switzerland). 2D ROIs were established on consecutive transversal slices using a 50% isocontour tool (ROI including the pixel values larger than 50% of the maximum pixel) that semi-automatically defined a 3D Volume of Interest (VOI) around the tissue of interest. To avoid overestimation of the uptake within the VOI, PET/CT fused images where used to discriminate hot pixels coming from the neighboring tissues like urinary bladder. Using the mean uptake within this VOI, the global tracer uptake was assessed in tumors and expressed as percentage of injected dose per gram of tissue (%ID/g).

Hyperpolarized 13C-MRI studies

1-13C pyruvic acid (30 μL), containing 15 mM OXO63 and 2.5 mM gadolinium chelate ProHance (Bracco Diagnostics, Milano, Italy), was hyperpolarized at 3.35T and 1.4K using the Hypersense DNP polarizer (Oxford Instruments, Abingdon, UK) according to the manufacturer’s instructions. After 60-90 min, the hyperpolarized sample was rapidly dissolved in 4.5 mL of a superheated alkaline buffer that consisted of 50 mM Tris(hydroxymethyl)aminomethane, 75 mM NaOH, and 100 mg/L ethylenediaminetetraacetic acid. The hyperpolarized 1-13C pyruvate solution (96 mM) was intravenously injected through a catheter placed in the tail vein of the mouse (12 μL/g body weight). Hyperpolarized 13C MRI studies were performed on a 3T scanner (MR Solutions, Guildford, UK) using a home-built 13C solenoid leg coil. After the rapid injection of hyperpolarized 1-13C pyruvate, spectra were acquired every second for 240 seconds using a single pulse sequence. Data were analyzed in a model free approach using the lactate/pyruvate ratio, calculated from the areas under the curves of the 1-13C lactate peak and the 1-13C pyruvate peak [].

Statistical analysis

Analysis was performed using the GraphPad Prism 7 software. Results are expressed as means value of parameter ± SEM. All statistical tests were two-sided. Paired t-test was used to compare mean changes between groups (baseline vs. post-treatment) for each tumor model, and unpaired t-test was used to compare mean changes between the two tumor models. Results with P < 0.05 (*), <0.01 (**), or <0.001 (***) were considered to be statistically significant.

Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

  • M. Dunbar
  • S. Coats
  • L. Shroads
  • Langaee
  • Lew
  • R. Forder
  • J. Shuster
  • A. Wagner
  • W. Stacpoole


Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. DesignWe conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four-week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

Frequently Asked Questions

Is DCA natural?

DCA is a synthetic drug, but it is a very simple compound similar to a chemical combination of salt and vinegar. It works against cancer in a natural way (by triggering natural cell suicide).

Is DCA safe?

DCA has been used in humans to treat a rare disease called “congenital lactic acidosis” and found to have some mild to moderate side effects. Our experience so far suggests that DCA is safe to use in cancer patients under close medical supervision. Some animal studies show that DCA can itself cause liver cancer. These studies used doses which are much higher than what would be prescribed for cancer treatment. Also, no human study has every demonstrated liver tumour formation because of DCA therapy. We have observed that DCA can have 2 main categories of side effects.

Nerve injury in the hands and feet (“peripheral neuropathy”). Neuropathy typically takes several weeks to months to develop and is reversible if it is caught early. In the existing literature, neuropathy from DCA has always been shown to be reversible. We use vitamin B1 (benfotiamine or thiamine), acetyl L-carnitine and R alpha lipoic acid to prevent and reduce the severity of peripheral neuropathy. These medicines can be given orally or intravenously depending on the degree of neuropathy. Published data clearly demonstrates all of these medicines can help chemo and/or diabetic neuropathy, and our own extensive experience confirms that these supplements are effective for DCA neuropathy as well.

Sedation, confusion, hallucinations, memory problems, mood changes, hand tremors. These side effects are temporary and appear to be dose-dependent and age-dependent. This finding is consistent with existing human research on DCA that we have reviewed. We use benfotiamine (a type of vitamin B1), acetyl Lcarnitine and R alpha lipoic acid to prevent/reduce these side effects.

Heartburn, nausea, vomiting, indigestion. These side effects may occur with DCA, and we prescribe a “proton pump inhibitor” antacid medication (e.g. pantoprazole) as needed to treat them.

Other Side Effects:
Some patients experience pain at the sites of their tumour(s) within the first few days of starting DCA. This may be an indicator of the effectiveness of DCA. About 1-2% of patients have mild liver toxicity (increase in liver enzymes noted without symptoms). We have not observed any drop in blood cell counts due to bone marrow toxicity, or any other significant organ toxicity. Note that leukemia patients may see a drop in their high white blood cell count, indicating destruction of the cancerous white cells.

Most side effects reported so far have been mild or moderate. Patients experiencing moderate side effects are usually taken off DCA as a precaution. Most side effects typically resolve within days after stopping DCA. Neuropathy can take weeks or months to resolve, and is reversible.

TLS (Tumour Lysis Syndrome)

This is a condition in which a large number of tumour cells are rapidly killed, causing a sudden release of the contents of the dead cells into the bloodstream. It can result in abnormal heart rhythms, salt imbalance in the blood and kidney failure. A detailed reference article can be found here. TLS occurs most commonly in patients with a large mass of tumour cells in the body who receive chemotherapy, especially with lymphomas or acute leukemia. In theory, DCA should not cause TLS because it kills cancer cell naturally by apoptosis. We have not had a single case of TLS in our patients treated with DCA alone. Since DCA can enhance the effect of chemotherapy in certain cases, it may be more likely to occur if DCA is combined with chemotherapy (especially without medical supervision). We have noticed that intravenous DCA can work more quickly than oral DCA in some cases, so there is theoretically more risk of TLS if i.v. DCA is combined with other therapies such as chemo. We have observed one cases of TLS when i.v. DCA was combined with cannabis oil.

DCA and Renal Failure

DCA is not toxic to the kidneys. DCA can safely be used in patients with moderately severe renal failure based on our experience.

DCA and Heart Failure

DCA is safe to use in patients with heart failure. DCA improves the pumping efficiency of the heart without increasing oxygen demand. As a result, it can improve heart failure or angina.

DCA and Heart Rhythm Disturbance

DCA shortens the QT interval which is an electrical measurement of the heart determined by ECG. Combination with drugs that prolong the QT interval is therefore unlikely to cause abnormal heart rhythms. Rather, DCA may prevent abnormal heart rhythms.

DCA and Liver Failure / Jaundice

DCA is metabolized by the liver, so dose adjustment is needed for patients with liver failure. Also, a difference cycles may be needed. Intravenous DCA is likely safer than oral DCA for patients in liver failure.

DCA and Diabetes

Diabetics may notice a slight improvement in blood glucose control. Diabetes medications generally do not have to be changed, but blood glucose monitoring will determine if adjustment is required.

DCA-Drug Interactions

We have observed that drugs that can cause confusion or hallucinations have a potential to interact with DCA.

This may include cannabinoids, benzodiazepines and other CNS drugs, especially if they are already causing some neurological side effects. Patients on stable doses of opiate pain medications or benzodiazepines who are not having side effects from these drugs rarely have such issues.

DCA and Caffeine

We have received a large number of inquiries about caffeine following some anecdotal reports of enhanced DCA effect with excessive tea/caffeine intake. After conducting a limited review of our DCA patients, we have noted that a few patients with high tea/caffeine consumption (> 10 cups per day) have shown no response to DCA. Also, many patients who have shown an excellent response to DCA do not take tea/coffee or caffeine or take it in minimal amounts.

There are a number of potential harmful effects of consuming high doses of caffeine including increased likelihood of seizures in brain tumour patients, abnormal heart rhythms, anxiety, and insomnia. Even though there is new data to show that intravenous high dose caffeine can enhance chemotherapy, the potential for caffeine to enhance DCA therapy is unverified. We are presently recommending against the use of high dose caffeine, unless it is done with medical supervision. Patients should use moderation with consumption of caffeinated drinks and check with their own doctor, naturopath or dietician for specific advice.

DCA and Chemotherapy

For the first time in North America, Medicor and AccuTheranostics (previously known as ORT) began conducting ChemoFit tests with DCA and chemo combined (2008). Eligible patients were able to have a sample of their own tumor analyzed to see if combinations of DCA and chemo were effective, and if they worked better than chemo or DCA alone. The accuracy of the ChemoFit test ranges from 85-95%.

We have already had some exciting results showing that DCA can, in some cases, dramatically enhance the cancer-killing effects of chemo, rarely to the point of cure (estimated 0.5% chance of cure). However, there is a possibility that DCA can interfere with chemo as well. This is similar to single agent chemo being better than combination chemo for some patients. Published lab research now confirms our findings.

If you are a patient who is thinking of combining DCA and chemotherapy, we recommend you contact Dr.
Bradford or Dr. Thakur at AccuTheranostics for information.

The best time for a ChemoFit test to be done is at the time of cancer surgery. If you have already had surgery, but you have an accessible tumour, it can be biopsied by your surgeon for the ChemoFit test. Malignant ascites fluid samples and malignant pleural effusion samples can now be tested with ChemoFit, eliminating the need for a biopsy in some patients. If you are not able to have the ChemoFit test, a treatment plan can be developed to safely combine DCA with most chemotherapy drugs with minimal risk of interference (depending on the chemotherapy schedule).

What is the status of DCA clinical trials?

The first phase 2 clinical trial of DCA in glioblastoma was completed but was not published as a trial, possibly because the DCA doses were too high and resulted in many patients dropping out (our opinion, actual reason not disclosed by the authors).

Several DCA clinical trials have been conducted. These can be reviewed here.

Even though we have seen clear evidence of DCA’s effectiveness in several types of cancer, Medicor physicians believe that it is necessary for formal clinical trials to be conducted. DCA is different from other drugs that undergo clinical trials because it is not a “new” drug. It has already been used for decades in humans and has a relatively safe profile. This means that the trials may take less time but may still take years. Many cancer patients cannot wait this length of time. We are hopeful that information obtained from our experiences with DCA will supplement clinical trials and help patients and the medical community.

There is a publication that says DCA increases the growth of colon cancer. Is that correct?

There is a publication which reports that DCA enhances the survival of colon cancer cells. This paper is flawed because the researchers looked at the effects of DCA on cancer cells with a complete absence of oxygen (anoxia). While hypoxia (low oxygen) may be common in tumours, anoxia (complete lack of oxygen) is not a normal situation. In very rapidly growing tumours, there will be areas of anoxia, however colon cancer generally does not behave that way. In summary, we believe our clinical findings from treating actual patients are more meaningful than this lab study done under artificial conditions. DCA (both oral and intravenous) can be an effective treatment for colon cancer based on our extensive clinical experience. DCA can cause symptom improvement, tumour shrinkage, tumour stability, or reduction in the colon cancer blood marker CEA.

Do I Qualify for DCA Treatment?

Patients with a documented diagnosis of cancer (any type) under the following categories qualify for treatment:

  • failed conventional, scientifically proven treatments
  • told by their doctor that there is no safe or effective treatment for their cancer
  • waiting to start conventional treatment, and would like to do something in the interim
  • treated for cancer, and would like to prevent recurrence (where no proven recurrence prevention is available)
  • receiving therapy which has a poor chance of success and would like to strengthen their treatment
  • reviewed conventional therapies with the oncologist (or other specialist) and declined them voluntarily after fully understanding the risks and benefits

How is DCA administered?

DCA is currently available in 4 formulations: cream, oral liquid, oral capsules, intravenous. Oral DCA can be taken at home.

Use of Oral Dichloroacetate for Palliation of Leg Pain Arising from Metastatic Poorly Differentiated Carcinoma: A Case Report


Dichloroacetate sodium (DCA) is a nonproprietary drug currently used for treatment of inherited mitochondrial diseases. It was discovered in 2007 that DCA promotes human cancer cell death by a novel mechanism. Soon after this discovery, physicians began using DCA off-label for cancer treatment in a palliative setting. A case report is presented of a 71-year-old male with poorly differentiated carcinoma of unknown primary metastatic to the right leg and liver who achieved excellent palliation of leg pain by using oral DCA after failing conventional therapy.


Dichloroacetate sodium (DCA) is a nonproprietary drug currently approved in Ontario, Canada for treatment of inherited mitochondrial diseases.1 It was discovered in 2007 by Bonnet et al. that DCA promotes human cancer cell death by a novel mechanism of inhibition of aerobic glycolysis and apoptosis induction.2 Soon after this discovery we began using DCA off-label in our cancer clinic3 for treatment of patients who had failed conventional therapies. We have observed that a significant number of such patients benefit from the use of this drug either by subjective criteria such as pain reduction or objective criteria such as tumor shrinkage.4 We report on a 71-year-old male with poorly differentiated carcinoma of unknown primary metastatic to the right leg and liver who achieved excellent palliation of leg pain by using oral DCA after failing conventional therapy.

Case Presentation

A 71-year-old male presented to our clinic in April 2010 requesting palliative treatment for a cancer of unknown primary with metastases to the liver and right calf after standard treatment options had been exhausted. Extensive notes were reviewed from the regional cancer hospital where he had been treated initially. They revealed a history of right calf pain dating back to 2006, but a calf mass was only discovered by magnetic resonance imaging (MRI) in April 2009. The diagnosis of cancer was made via biopsy in October 2009, which was reviewed by three pathologists. The final diagnosis was poorly differentiated carcinoma embedded within the fibromuscular tissue of the calf, although epithelioid sarcoma could not be excluded. Workup by several physicians failed to reveal the primary site.

The patient’s case was reviewed by the tumor board at the regional cancer hospital, and the decision was made to treat him with palliative radiotherapy 66 Gy in 33 fractions. This began in November 2009 and was completed in January 2010. At the time, the patient had significant calf pain and swelling. His pain was treated by the palliative team at the regional cancer center with sustained release (SR) morphine 60 mg orally 2 times a day, gabapentin 900 mg orally 3 times a day, morphine 10 mg orally prn for breakthrough pain (patient was using 1–2 times daily), and oxycodone 5 mg orally prn.

By February 2010 (1 month post-radiotherapy), the gabapentin was discontinued and indomethacin 50 mg 3 times a day prn was added. The SR morphine was increased to 100 mg 2 times a day, and the morphine for breakthrough pain was adjusted to 25 mg hourly prn. (Immediate release morphine tablets are available in Canada in strengths of 5, 10, 20, 25, 30, 40, 50, and 60 mg.)

The patient was evaluated again in March 2010 (2 months post-radiotherapy) at which time he was re-staged with a leg MRI (Fig. 1). The right leg tumor can be clearly seen (single arrow). Edema of the subcutaneous tissue is also visible (double arrow), and the right calf diameter is visibly larger than the left. The patient was using about 2 doses of 25-mg breakthrough morphine per day at the time. The treating oncologist presented an option for palliative chemotherapy. Due to unproven survival benefits and serious potential side effects, the patient declined chemotherapy.

FIG. 1. 
FIG. 1. MRI showing right calf tumor (single arrow) and subcutaneous edema (double arrow).

The patient then elected to have a private, positron emission tomography (PET) scan to obtain additional information. The pertinent PET findings were a hypermetabolic lesion in the area of known tumor in the right calf with SUVmax of 4.0, and multiple new fluorodeoxyglucose (FDG)-avid liver metastases (largest lesion was 1.8 cm in maximal diameter with maximum standardized uptake value (SUVmax) of 3.5).

Treatment with Dichloroacetate (DCA)

The patient presented to our office in April 2010 (3 months post-radiotherapy) soon after receiving the PET scan report identifying disease progression to the liver. Review of symptoms at the time revealed low energy, constipation, restlessness, and right calf pain rated 4 to 5 out of 10 with no characteristic neuropathic component. He continued on the same pain regimen prescribed by the palliative team, except for taking indomethacin 50 mg once daily instead of 3 times daily. Breakthrough use was 1–2 morphine 25-mg tablets per day with good effect, resulting in a total morphine usage of 225–250 mg per day.

Examination revealed a generally healthy looking male with normal vital signs and a tense and edematous right calf. There was mild calf tenderness and no erythema. The rest of the examination was noncontributory.

Various off-label nonchemotherapy cancer treatment options were discussed. Initial blood tests were normal except for mild anemia (hemoglobin (HB) = 131 g/L). The patient decided to try oral DCA therapy. He was started on 500 mg 3 times a day (21 mg/kg/day for a body weight of 71 kg) on a 2 week on/1 week off cycle. Three natural medicines with documented neuroprotective effects were added to help prevent DCA-induced neuropathy. These were: R+ alpha lipoic acid5 150 mg orally 3 times a day, acetyl L-carnitine6 500 mg orally 3 times a day, and benfotiamine7 (vitamin B1) 80 mg orally 2 times a day. Comprehensive weekly blood tests were ordered including complete cell counts, renal function, electrolytes, liver enzymes, and liver function.

The patient returned for follow-up after completion of 2 cycles (6 weeks) of DCA therapy. Other than new daytime sedation, he felt well. He noted the right leg was smaller, pain severity was now 0 to 1 out of 10 and only present in the morning. No breakthrough morphine doses were needed, so he had reduced the SR morphine on his own from 100 mg 2 times a day to 60 mg 2 times a day. Despite the reduction, he reported occasional myoclonus. He also reported weight loss of about 8 lb, which he found to be concerning. He started gardening and reported being more physically active. The right calf edema had decreased significantly and the calf was no longer tender to palpation.

Due to the pain reduction and symptoms of mild relative opiate overdose (sedation and myoclonus), the SR morphine was reduced to 60 mg morning and 45 mg evening. The patient was also given megestrol acetate 160 mg orally 3 times a day for appetite enhancement. He was given advice about further morphine reduction based on pain self-assessment and breakthrough usage.

By June 2010, the patient had stopped using indomethacin and breakthrough morphine. Pain was rated 0 out of 10 most of the day, with only mild pain in the morning (present on waking and resolved after ambulating for a few minutes). He had reduced the SR morphine to 30 mg 2 times a day. His body weight had stabilized and appetite was good. The leg edema had completely resolved. Blood tests revealed a resolution of the mild anemia and no new abnormalities. A new, leg computed tomography (CT) scan showed a stable right calf tumor, reduced calf diameter, and resolution of subcutaneous edema (Fig. 2).

FIG. 2. 
FIG. 2. CT showing right calf tumor after 2 months of DCA therapy. Tumor is stable and calf edema has resolved.

By July 2010 (3 months on DCA therapy), the patient’s SR morphine dose was down to 30 mg total per day. Pain was rated 0 out of 10 for most of the day, and appetite was normal. Megestrol was stopped.

In August 2010, the SR morphine was brought down to 10 mg per day, and in September 2010 (5 months on DCA therapy) the patient completely stopped taking morphine. New CT scans showed mild growth of tumors in the liver (Fig. 3) and stable findings in the right leg (Fig. 4). Comprehensive blood tests remained normal.

FIG. 3. 
FIG. 3. CT showing multiple liver metastases.

FIG. 4. 
FIG. 4. CT after 5 months of DCA therapy showing stable right calf tumor and absence of calf edema.

As of November 2010, the patient had remained on DCA 500 mg orally 3 times a day, 2 weeks on/1week off for a total of 8 months, and had remained off opiates. He did not experience any side effects from the DCA treatment.

Summary and Conclusions

A 71-year-old male with poorly differentiated carcinoma metastatic to the right leg and liver (unknown primary) achieved an improvement in quality of life through pain reduction with DCA therapy.

Prior to DCA treatment, he was using 225–250mg/day of morphine plus indomethacin 50 mg/day. After starting DCA, the patient was able to gradually taper down his pain medications. By 5 months of DCA treatment, he was able to stop all pain medications. He experienced no adverse effects from DCA.

Because DCA treatment was initiated 3 months after completion of radiotherapy (and the patient’s leg pain was slowly increasing at that time), the reduction of pain can almost certainly be attributed to DCA. In retrospect, the 8-lb weight loss at the start of treatment was most likely related to reduction of edema fluid from the right leg, and megestrol had thus been prescribed unnecessarily.

In this case, it was demonstrated that dichloroacetate (DCA) led to a dramatic improvement in tumor pain over a period continuing beyond 8 months. The patient’s leg metastasis was stable during this period, whereas there was mild growth of the liver metastases. There were no drug side effects, and no alteration in hematologic parameters.

We believe DCA should be formally studied as a palliative treatment in advanced-stage malignancies due to its favorable side effect profile8 and potential for quality-of-life improvements as demonstrated by this case. Even though it has now been established that DCA has activity against cancer in humans,9 ongoing DCA phase I/II trials have not been designed to evaluate quality-of-life parameters.10 Rather, they are focused on measurement of survival and tumor response rates by Response Evaluation Criteria for Solid Tumors (RECIST) guidelines. We believe these and future cancer trials of DCA should be expanded to include assessment of pain and other quality-of-life indicators.

Based on the judgment of the treating physician, DCA may be given consideration as an experimental alternative to palliative chemotherapy in cases where the benefits of chemotherapy are unknown, or when the advantages of chemotherapy are outweighed by the risks.


The author wishes to thank the patient, his son-in-law, and Dr. Humaira Khan for their assistance in preparation of this case report.

Author Disclosure Statement

The author prescribes cancer treatment medications (including dichloroacetate) that are provided through Medicor Cancer Centres for a cost. This clinic is owned by a family member of the author.

Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate

Akbar Khan

Medical Director, Medicor Cancer Centres Inc., Toronto, Canada

Volume 2012 (2012), Article ID 441895, Advances in Cancer Research & Treatment, 7 pages, DOI: 10.5171/2012.441895

Received date : ; Accepted date : ; Published date : 19 July 2012


Renal squamous cell carcinoma is a rare form of renal cancer which is considered incurable once metastases develop. Prognosis is poor and average survival of advanced stage disease is typically in the range of several months, despite all available conventional therapies.We describe the case of a 72 year old female with metastatic renal squamous cell carcinoma who had a radical nephrectomy with positive surgical margins, renal vein invasion and metastases to multiple abdominal lymph nodes. She received a course of palliative radiotherapy to the abdomen with 4500cGy in 25 fractions over 5 weeks. Following radiotherapy, she was treated with a cyclic regimen of oral sodium dichloroacetate (“DCA”). Treatment was discontinued after 3 months due to development of peripheral neuropathy. Follow-up imaging upon completion of DCA treatment revealed no sign of metastatic disease. The neuropathy gradually improved and computed tomography imaging four years later demonstrated no cancer recurrence. The patient continues to feel well with no clinical evidence of recurrence five years after completion of therapy, and is living a normal and active life.

Keywords: Dichloroacetate, radiotherapy, renal squamous cell carcinoma, remission.


Renal squamous cell carcinoma (“RSCC”) is a rare form of renal cancer which originates from the renal pelvis. RSCC comprises about 0.5 – 0.8% of all malignant renal tumours (Bhaijee 2012). Although surgery is sometimes curative for localized disease, metastatic renal squamous cell carcinoma (“mRSCC”) is considered incurable (Holmang et al. 2007).Multiple publications from physicians with experience treating RSCC have established that this cancer type is radio-resistant, and that systemic chemotherapy provides little benefit. (Bhandari et al. 2010),  (Di Battista et al. 2012),  (Kimura et al. 2000),  (Li and Cheung 1987). Average survival of advanced stage disease is extremely poor (in the range of several months) and five year survival is reported to be less than 10% (Holmang et al. 2007). In a review of 15 cases, Lee et al. reported a median survival of 3.5 months (Lee et al. 1998).

A Medline search was conducted (Medline RSCC 2012) to determine if any cases of long-term complete remission of mRSCC had been recorded. This revealed over 200 citations of RSCC but only one published case of 5 year complete remission/cure (Carlson 1960). In this case, the patient had complete nephro-ureterectomy, including resection of peri-renal fat and a cuff of bladder. Pathology did not demonstrate any involvement of surgical margins and there were no metastases reported.

Sodium dichloroacetate (“DCA”) is a drug that has been extensively studied for the treatment of congenital lactic acidosis which is comprised of a group of inherited mitochondrial diseases (Stacpoole et al. 2006), (Stacpoole et al. 1992), (Stacpoole et al. 1988). The safety profile of DCA use in humans has been established though this body of work. It has been found to be a relatively safe drug, with no hematologic, cardiac, pulmonary or renal toxicity. The main toxicity is neurological (primarily peripheral neuropathy) and this is reversible (Kaufmann et al. 2006). DCA-induced delirium has been observed, and is also reversible upon discontinuation of the drug (Brandsma et al. 2010). Minor reversible liver enzyme elevation can occur in a small percentage of patients (Stacpoole et al. 2008).

In January 2007 a landmark paper was published which demonstrated that DCA was effective in treating human breast, lung and brain cancers in vitro and in vivo (rats) by novel metabolic pathways (Bonnet et al. 2007). It was shown that DCA inhibited mitochondrial pyruvate dehydrogenase kinase which resulted in an inhibition of aerobic glycolysis, the usual route for energy production in human cancer cells (known as the Warburg effect). Since cancer cells typically are not able to shift to glucose oxidation when glycolysis is inhibited, DCA-treated cells will be depleted of their ATP energy supply (Xu et al. 2005). It was also demonstrated that DCA triggered apoptosis selectively in cancer cells by a reduction in the membrane potential of hyperpolarized mitochondria and by activation of the voltage-gated potassium channels Kv1.5 (Bonnet et al. 2007).

Since 2007, DCA research has continued and DCA has been shown to have in vitro efficacy against multiple human cancer cell lines including ovarian (Saed et al. 2011), neuroblastoma (Vella et al. 2012), colon (Tong et al. 2011), lung carcinoid (Fiebiger et al. 2011), cervical (Xie et al. 2011) and endometrial (Wong et al. 2008). Synergism with radiotherapy has also been demonstrated in prostate cancer cell lines (Cao et al. 2008). A mechanism for the synergism proposed by Cao et al. is an increased expression of BCL-2-associated X protein (a pro-apoptotic intracellular protein) which results in an increased rate of apoptosis. DCA also has shown in vivo efficacy in humans against glioblastoma (Michelakis et al. 2010).

The author began to use “off-label” DCA therapy beginning in 2007 for treatment of cancer patients who had a poor prognosis or had failed to respond to conventional cancer therapies. Observation of DCA-treated patients revealed that a significant number appeared to benefit from the use of this drug either by subjective criteria such as pain reduction or objective criteria such as tumor shrinkage (Medicor DCA Data 2009). 
Case Presentation

A 72 year old female presented initially to her family physician with right hip pain, hematuria and weight loss. A mass in the right kidney was diagnosed by ultrasound. A computed tomography (“CT”) scan was performed which showed a tumor involving the right renal pelvis, upper and lower poles of the kidney, and extension into the proximal right ureter (Figure 1). There were multiple enlarged lymph nodes in the abdomen (Figure 2).  A bone scan was performed which was negative for bone metastases.

Figure 1 – Abdominal CT scan showing right renal tumor prior to any treatment.


Figure 2 – Abdominal CT scan showing a 2cm pathological retroperitoneal lymph node prior to any treatment.

The patient underwent a right radical nephrectomy in May 2007. It was noted in the operative report that a complete excision was not possible. The renal vein was involved and it could not be completely cleared of tumor. Multiple pathologic lymph nodes extending up the vena cava were visualized at the time of surgery but were not removed. An intra-operative biopsy of one of the lymph nodes was conducted. Final histopathology confirmed a diagnosis of renal squamous cell carcinoma with positive surgical margins and lymph node metastases. Post-operatively, the patient was referred for radiation oncology consultation. She received a course of external beam radiotherapy with palliative intent to the para-aortic region of the abdomen with 4500cGy in 25 fractions over 5 weeks from August to September 2007. Medical oncology was consulted, and she was not offered treatment with chemotherapy.

The patient learned of DCA cancer research from her local media, and decided to investigate the option of DCA as ongoing treatment, given her poor prognosis. She attended the author’s clinic for DCA therapy consultation.

At the first clinic visit, her complete history was reviewed. Examination revealed a healthy-looking female with normal vital signs and no significant physical findings. Initial blood tests were generally good. The only abnormalities were a mild elevation of urea at 7.4 (normal 3.0 – 7.1mmol/L), and a low lymphocyte count of 0.6 (normal 1.2 – 3.4 x 109/L). This was not concerning as a mild elevation of urea or creatinine would be expected in a post-nephrectomy patient. 
DCA Treatment

Risks and benefits of DCA were discussed, and the patient consented to DCA treatment which was initiated within 3 weeks following the last fraction of palliative radiotherapy. The patient was started on DCA 500mg orally twice a day (18mg/kg/day), on a cycle of 2 weeks on / 1 week off. Cyclic treatment was selected due to the author’s prior experience with an unacceptable level of side effects in adult patients using continuous DCA dosing. She was prescribed benfotiamine (a lipid soluble form of vitamin B1) 80mg orally twice a day and R-alpha lipoic acid 150mg orally 3 times a day to reduce the risk of DCA neuropathy, since both of these natural compounds have proven benefits in treating neuropathy of other etiologies (Ziegler et al. 1999), (Winkler et al. 1999). She was also started on pantoprazole 40mg orally once a day to prevent stomach upset from DCA. After the first 3 week cycle, the DCA was increased to 500mg orally three times a day (27mg/kg/day). The dose was raised in stepwise fashion to ensure tolerability because of the reduced metabolism of DCA with advanced patient age (Shroads et al. 2008).

The patient generally felt well during the first month of DCA treatment except for mild fatigue, which may also have been a radiotherapy side effect. Even with the increased DCA dose after 3 weeks, no problems were experienced through the second month of therapy. DCA was stopped towards the end of the third month due to new symptoms indicating peripheral neuropathy.

At the time the DCA was stopped, the patient had a triphasic CT scan which showed no evidence of residual cancer. After another 6 months, the patient had a CT scan which again showed no evidence of cancer (Figure 3).

Figure 3 – Abdominal CT scan showing no disease recurrence 6 months after completion of DCA treatment. Arrows show surgical clips in right renal bed post-nephrectomy.

The patient continued to be monitored regularly at the oncology clinic of her local hospital with routine CT scans about every 6 months. The latest CT scan of October 2011 showed no evidence of mRSCC recurrence. A follow-up visit with the radiation oncologist in December 2011 confirmed an absence of recurrence. Physical examination was normal and her performance status was ECOG level 0. September 2011 marked the 4 year point from radiotherapy and initiation of DCA treatment, and December 2011 marked the 4 year point from completion of 3 months of DCA therapy. As of September 2012, 5 years from the date of initiation of DCA therapy, the patient remains asymptomatic. She received no other cancer treatment during this time (including DCA) given that there was never any evidence of disease recurrence. 


We believe this to be the first published case of long-term complete remission (and probable cure) of mRSCC. There is only one similar reported case of 5 year complete remission of RSCC in the Medline-indexed literature dating back 50 years, however that patient did not have metastatic disease. Our case warrants close attention since mRSCC is very aggressive with a median survival in the range of several months with all available conventional therapy.

Radiotherapy alone provides little survival benefit for mRSCC (Holmang et al. 2007). The extended 5 week treatment time of palliative radiotherapy in this case further reduces the chance of cure (unlikely as it is to begin with based on the cancer type) by virtue of reduced cell kill through a process called “accelerated repopulation”. Repopulation is defined as the ability of cells within a tissue to replenish following a dose of radiation. Repopulation increases as the total treatment time to deliver a dose of radiation lengthens during a course of fractionated radiotherapy. This effect reduces harm to healthy tissue but also reduces cancer cell kill – consistent with the goal of palliation. Repopulation is most pronounced with a total radiation treatment time of 4-6 weeks and beyond, and this patient received her fractionated radiotherapy over 5 weeks (Abeloff May 21, 2008) .

As noted previously, DCA has synergism with radiotherapy in prostate cancer. The author’s experience in treating patients with DCA suggests that the synergism with radiotherapy can occur in various types of cancer other than prostate. Examples include: a 53 year old female with a 3 year complete remission of Bartholin’s gland carcinoma treated with radiation and adjuvant DCA, and a 32 year old female with a 3 year complete remission of anaplastic astrocytoma following chemoradiation with adjuvant DCA (cases being prepared for publication).

In this case of mRSCC, the adjuvant use of DCA following a course of radiotherapy produced a surprising complete remission, with no detrimental side effects aside from reversible peripheral neuropathy. In this patient, the prophylactic benfotiamine and R-alpha lipoic acid did not abort the development of peripheral neuropathy from DCA. The author now adds acetyl L-carnitine to the DCA neuropathy prevention regimen, since it also has proven benefits in treating neuropathy of other etiologies, such as diabetic, chemo-induced, and antiretroviral-induced neuropathy (Herzmann et al. 2005), (Quatraro et al. 1995), (De Grandis and Minardi 2002), (Bianchi et al. 2005).

Currently there are no active clinical trials investigating the role of DCA in combination with radiotherapy alone. One trial is currently investigating DCA in combination with chemotherapy and radiation for head and neck carcinoma (Clinicaltrials.gov 2012). Due to the non-proprietary status of DCA, it has been difficult for researchers to raise funds to conduct expensive human trials. It is our hope that publication of clear cases illustrating the benefits of DCA as an adjuvant to traditional cancer therapies will motivate researchers to find creative new fundraising mechanisms so DCA can be formally investigated in further human trials. We hope that DCA will thereby become more widely accepted in the oncology community, and used for the benefit of patients with incurable malignancy.

Since completion of human clinical trials can take many years, in the interim we believe it is ethical to cautiously prescribe “off-label” DCA combined with, or following palliative radiotherapy, for patients who fully understand and accept the risks and benefits. DCA may have a further role as a novel therapeutic approach in combination with radiotherapy for radio-resistant non-metastatic cancers, but this has yet to be clarified.

The author wishes to thank Dr. Humaira Khan and Dr. Isaac Eliaz for their assistance in preparation of this case report, and also the patient for consenting to publish her case.

Author Disclosure Statement

The author prescribes cancer treatment medications (including dichloroacetate) that are provided through Medicor Cancer Centres for a cost. This clinic is owned by a family member of the author.


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The Big Business of Breast Cancer Gold Mine for Pink Profiteers

September 14, 2011


The Big Business of Breast Cancer


Some $6 billion a year is committed to breast cancer research and awareness campaigns. Is it any wonder that the disease has become a gold mine for pink profiteers and old-fashioned hucksters?


By Lea Goldman

Read more: Breast Cancer Society Scam – Breast Cancer Industry Scams – Marie Claire

Aside from the slow-rolling hot dogs at concession stands and the sideline billboards for Hubba Bubba bubble gum, you’d be hard-pressed to find a hint of pink at any of the National Football League’s 31 stadiums, where, during most of the six-month season, the decor tends to match the distinctly masculine nature of the game. Not so in October, when pink becomes the de facto color of the sport. Players bound onto the field sporting pink cleats, wristbands, and chin straps, and punt pigskins emblazoned with pink decals under the watchful eyes of refs with pink whistles. It’s all part of the league’s massive sponsorship of National Breast Cancer Awareness Month, which by October’s end will have seen the distribution of 650,000 pink ribbons at stadiums across the country.


Though the NFL has, shall we say, a complicated history with women, its embrace of breast cancer awareness is perhaps only fitting. After all, in the nearly 20 years since the pink ribbon became the official symbol of the cause — Estée Lauder cosmetics counters handed out 1.5 million of them in 1992 as part of the first-ever nationwide awareness campaign to leverage the pink ribbon — breast cancer has become the NFL of diseases, glutted with corporate sponsorships, merchandise deals, and ad campaigns. This is true year-round, but especially in October, when breast cancer marketing reaches a frothy pink frenzy. This month, an awareness-minded consumer can buy almost any knickknack or household item in pink — from lint brushes and shoelaces to earbuds and Snuggies. If she happens to be in an American Airlines Admirals Club, she can snack on pink cookies while drinking pink champagne. If instead she finds herself at one of the nation’s 500 Jersey Mike’s Subs franchises, for about $7 she can order the “pink ribbon combo,” consisting of a sandwich, chips, and soda served in a limited-edition pink plastic cup (because nothing says “cancer awareness” like chips and soda).


Though breast cancer researchers and advocates perpetually plead for more money, the disease is, in fact, awash in it. Last year, the National Institutes of Health, the nation’s top agency for health-related research, allocated $763 million to the study of breast cancer, more than double what it committed to any other cancer. The Department of Defense also funds breast cancer research ($150 million this year), as do several states, most notably Texas and California. All that is in addition to the money raised by the roughly 1,400 IRS-recognized, tax-exempt charities in this country devoted to breast cancer. They operate in every state and in just about every major city. The largest of them, Dallas-based Susan G. Komen for the Cure, grossed $420 million last year alone. All told, an estimated $6 billion is raised every year in the name of breast cancer. And the money keeps pouring in.


Which seems like great news for the fight against breast cancer, and in part it is (though not as great as it sounds, and we’ll get back to that). But it’s also been a boon for charity scammers — the charlatans who prey on the public’s beneficence and its inveterate laziness when it comes to due diligence. The nonprofit world is full of them. (Greg Mortenson, the celebrated author of Three Cups of Tea, is only the latest philanthropist to battle allegations that his organization, the Central Asia Institute, misused funds.) Breast cancer makes a particularly alluring target — not just because there is so much money involved or because women across all income levels tend to give more than men, but because we give to breast cancer forcefully, eagerly, superstitiously. Breast cancer holds a peculiarly powerful sway with us — it’s a disease dreaded so profoundly that not supporting the cause feels like tempting fate.


When our minds wander to the unthinkable, breast cancer tops that black list of God-help-me scenarios, conjuring up images of surgery, mutilation, chemotherapy and its attendant nausea, and hair loss (as terrifying as losing a breast for some); of helpless partners convincing us (and themselves) that we’re still as desirable as before; of living with a constant, insidious fear that it’s never really over. It’s about our breasts, for chrissake, the embodiment of femininity, sex appeal, and motherhood. It is a disease of agonizing choices (Christina Applegate’s preventive double mastectomy) and unfathomable compromises (Elizabeth Edwards’ deathbed denouement with her wayward husband). This is what breast cancer means to many women, and it’s why, unlike even ovarian or uterine cancer, it makes us suckers for every pink-ribbon trinket and walkathon solicitation that crosses our paths.


In this environment, it’s difficult to ask questions. “You know, breast cancer has been untouchable for a while. If you question anything, well then, you must hate women,” says Gayle Sulik, author of Pink Ribbon Blues. “That mentality makes it really hard to say, ‘What’s working? What’s not working?’ The goal is eradication. Isn’t that what we say we want?” There is no denying that money raised for research has been instrumental in the fight against breast cancer. Sophisticated digital mammography has reduced the risk of false-positive diagnoses; the discovery of genetic markers has allowed women with increased risk for breast cancer to weigh their preventive options early; drugs like Herceptin, which targets the proteins responsible for a cancer cell’s growth, have demonstrated remarkable results in the 20 percent of patients afflicted with the particularly aggressive HER2-positive form of breast cancer. Doctors warn that there are never any absolutes when it comes to breast cancer, but for the 60 percent of women diagnosed at the earliest stage, survival is virtually guaranteed.


Yet what many in the breast cancer community are loathe to admit, despite all these lifesaving developments, is that, in fact, we are really no closer to a cure today than we were two decades ago. In 1991, 119 women in the U.S. died of breast cancer every day. Today, that figure is 110 — a victory no one is bragging about. Breast cancer remains the leading cancer killer among women ages 20 to 59; more than 1.4 million new cases are diagnosed annually worldwide. Roughly 5 percent, or 70,000, breast cancer patients are diagnosed at a late stage, after the cancer has metastasized — that rate hasn’t budged since 1975, despite all the medical advances and awareness campaigns. For these women, the prognosis remains grim: Only 1 in 5 will survive five years out. Fundamental questions still elude researchers: Why do a third of all women considered cured by their doctors suffer recurrences? Why are breast cancer rates rising in Asia, where they’ve been historically low? Is it even possible to prevent breast cancer, and if so, how?


A popular gripe among advocates is that too much is spent on awareness campaigns — walks, races, rallies — at the expense of research. (And really, when Snuggies go pink, haven’t we hit our awareness saturation point?) There’s a case to be made for that, of course, but there’s another explanation, one that exposes an ugly, even blasphemous truth of the movement: Breast cancer has made a lot of people very wealthy. The fact is, thousands of people earn a handsome living extending their proverbial pink tin cups, baiting their benefactors with the promise of a cure, as if one were realistically in sight. They divert press, volunteers, and public interest away from other, more legitimate organizations, to say nothing of the money they raise, which, despite the best intentions of donors, doesn’t always go where it’s supposed to.

In 2001, Hillary Rutter received a call at her Plainview, Long Island, home from an outfit called the Plainview Chapter of the Coalition Against Breast Cancer, asking for a contribution to help subsidize the medical expenses of local breast cancer survivors. Rutter, the director of the Adelphi New York Statewide Breast Cancer Hotline & Support Program, had never heard of the group and didn’t know any of its board members. When she asked pointed questions about where donations were going, the caller hung up on her. Three weeks later, she received an invoice from the CABC stating that she’d pledged $25.


Galled that a fly-by-night operation would exploit the issue of breast cancer in Long Island, where women have long suspected they are at an epicenter of the disease, Rutter secured a copy of the group’s financial records. (Tax returns of nonprofits are available to the public.) What she saw shocked her: Breast cancer patients saw virtually nothing from the $1 million the group had raised. Instead, those dollars went to telemarketers and salaries. Rutter began keeping a file on the group, which over the years grew thick with complaints about harassing calls and questionable fundraising tactics. “As far as I know, the CABC has done nothing but line their own pockets,” says Rutter. “They’re just horrible.”


Last June, New York Attorney General Eric Schneiderman filed suit against the Coalition Against Breast Cancer, calling it a “sham charity” that for 15 years “served as a personal piggy bank” for the group’s insiders. According to the complaint, founder Andrew Smith; his girlfriend, Debra Koppelman; and their associates pilfered almost all of the $9.1 million raised in the past five years alone. Other eye-opening claims: The telemarketing firm hired to solicit donations was owned by CABC cofounder Garrett Morgan, who billed the charity $3.5 million for his services. In total, Smith and Koppelman paid themselves more than $550,000 in salaries between 2005 and 2009, plus another $150,000 in retirement accounts, this though both held down full-time jobs as recruiters. The CABC issued Smith a $105,000 personal loan, which he squandered on bad investments; Koppelman authorized a $50,000 loan to herself toward the purchase of a home. (CABC is contesting these claims.)


“There is a lot of deception that goes on with breast cancer groups,” says Daniel Borochoff, president of the American Institute of Philanthropy, a Chicago-based nonprofit watchdog group. One problem, he says, is that breast cancer charities are often run by well-meaning but inexperienced survivors or relatives who duplicate the efforts of established organizations. They use donor dollars to print their own educational brochures, though they certainly exist elsewhere; they organize events to promote awareness — “Skydive to End Breast Cancer!” — then blow too much of their funds getting these events off the ground. There’s no requirement of a college degree or business experience to run a charity. You don’t even need a clean legal record. (The treasurer for the Coalition Against Breast Cancer was a Long Island housepainter with several warrants for unpaid child support.) Even the names of many charities are designed to fool donors into believing they are bigger and more impressive than they are. Case in point: Though its moniker suggests it presides over a vast network, The Breast Cancer Charities of America is a tiny, three-woman outfit operating just outside Houston that banked $2 million in 2009, mostly through telemarketers. (Founder Erica Harvey says she came up with the name “with a team of marketing consultants.”) “Any bozo can set up [a charity] and start soliciting,” adds Borochoff.


All charities must file detailed financial reports with the Internal Revenue Service, but they don’t have to be audited, or certified by a licensed accountant. In effect, anyone can write them up and turn them in. Some states require that a CPA review the books, but the rules vary widely. In California, only groups grossing $2 million or more per year need a CPA’s certification; there’s no auditing requirement at all in Texas. Even still, it’s alarmingly easy to boost a charity’s numbers to make it appear as if it’s spending more on its mission — education and support groups, for example — than it actually is, especially for the many nonprofit outfits that rely on telemarketing. Here’s how it’s done: If a telemarketer charges, say, 70 cents for every dollar it collects — telemarketers are as expensive as they are annoying — a charity can write off some of that expense as part of its educational mandate by stamping “Don’t forget to get a mammogram!” at the bottom of its invoices to donors. Another common accounting trick allows charities to accept gifts — say, a used car worth $500 — but then report these contributions at a much higher value. Neither tactic is illegal, by the way. What’s the point of all this financial monkey business? Size matters when it comes to charities. The bigger the organization, the more reputable it seems, and the more likely it is to receive your cash.


The Breast Cancer Society, based in Mesa, Arizona, has made an art form of this kind of creative accounting. Founded in 2007 by James T. Reynolds II, now 37, the organization provides critically ill breast cancer patients across the country with cash grants to pay for everything from groceries to medical bills, Reynolds says. In 2009 (the most recent year for which tax records are available), the BCS claims it raised $50 million in contributions, the bulk of which went to supplying medicines to hospitals in Third World countries like Guatemala and Ethiopia, ostensibly for the treatment of breast cancer. (Reynolds says he has visited only three of the eight hospitals that purportedly received these medicines.) Press him on his group’s finances and he admits that, in fact, BCS raised just $15 million in cash donations in 2009. The other $35 million represented his estimate of medications that the BCS accepted as gifts or bought at a major discount but then listed on its books as having much higher values. For example, BCS reported that it sent $8.8 million worth of goods to hospitals in East Asia. “I’d have to look it up, but it probably cost us maybe $40,000 to procure and distribute that,” Reynolds concedes in a phone interview. Where do these medicines come from? Reynolds says he gets them from other organizations, including the Ontario-based Universal Aide Society, which saw its Canadian charitable status revoked two years ago for malfeasance. (Its employees used funds to finance vacations and other personal expenses.) This so-called “gifts in kind” scheme makes BCS seem a whole lot bigger than it actually is and obscures the fact that the group spent 90 cents of every dollar that it raised on telemarketers, not patients.


Nonprofits don’t seem a likely place to make a fortune. But in 2009, Reynolds collected a $223,276 paycheck, nearly double what he made the year before. (Perhaps that’s only fair given that over the same period, he doubled his telemarketing efforts, which, in turn, nearly doubled what BCS brought in from solicitations.) He says his salary is comparable to that of executives running similar organizations and commensurate with his 18 years of nonprofit experience. He neglects to mention that his experience has been limited largely to his work with the Cancer Fund of America, a controversial group founded by his father, which has been blasted by both the Better Business Bureau and the nonprofit rating agency Charity Navigator for giving less than a penny of every dollar raised to cancer patients. Charity Navigator once listed the Cancer Fund of America Support Services, an affiliate Reynolds ran between 2003 and 2007, as one of “10 Non-Profits That Make Ebenezer Proud.” Reynolds was also one of the Cancer Fund of America’s highest-paid employees for several years, serving as its vice president between 2006 and 2008. In 2007, the Georgia Governor’s Office of Consumer Affairs accused that group of making false and misleading claims in its mail solicitations, allegations that the Cancer Fund of America ultimately settled for $50,000. Reynolds is nonplussed by critics who say he’s taken a page from his father’s “one for you, three for me” playbook and applied it to his Breast Cancer Society. “I’ve offered to have people come and visit our facilities and sit down with them and open our books up,” he says calmly. “I don’t ever want to run an organization that hides things.”

It’s good practice, say experts, for charities to make their financial records accessible to the public on their websites. But most, including the Breast Cancer Society, do not. “Nobody wants you poking around their financial drawers, asking why this much is spent on salaries versus this much on research. Who wants to deal with that?” explains charity consultant Gary Snyder, author of Silence: The Impending Threat to the Charitable Sector. Tax returns for all IRS-recognized nonprofits, dubbed “990s,” are free for perusal on guidestar.org, but these are usually two or three years old, and realistically, how many of us would even know how to read them? So donors rely on groups like Charity Navigator, which uses tax returns to rate organizations on transparency and how much they spend on actual services versus overhead and salaries. The problem is, these ratings are notoriously unreliable, since tax returns are prepared by the organizations themselves. It would be as if your Equifax credit score were based on credit card statements you devised for them. (Last year, Charity Navigator announced that it would revamp its evaluation process.)


For the past six years, Charity Navigator has conferred its highest four-star rating on the National Breast Cancer Foundation, based in Frisco, Texas, a suburb of Dallas. The NBCF is something of an institution in the area, each year doling out 50 or so grants of upwards of $40,000 apiece to clinics and hospitals across the country to subsidize mammograms for the uninsured. (All told, the NBCF claims to have paid for 130,000 mammograms.) The group was founded two decades ago by breast cancer survivor Janelle Hail, a charismatic Paula Deen look-alike. Despite its size — it garnered $10 million in donations last year — and blue-chip partnerships with the likes of Dannon and Fujifilm, the NBCF could be called a family business. Buried in the footnotes of its latest tax return: A significant wing of the Hail family is employed by the NBCF. In 2009, Janelle Hail took home a $172,000 salary, plus another $57,000 in “other compensation.” Her son Kevin Hail, NBCF’s chief operations officer, makes $130,000, plus another $55,000 in other compensation. (Both have enjoyed raises of upwards of $10,000 per year since 2005.) NBCF also employs Hail’s husband, Neal, as “senior consultant” and son Brent, who is the vice president of operations. But because the IRS requires that charities only disclose the salaries of its board members, key employees, and anyone else earning more than $100,000, Neal and Brent don’t qualify, and Hail won’t say how much she pays them, despite Marie Claire’s repeated requests.


Family-run charities are standard fare in breast cancer circles, and, not surprisingly, family ties raise some discomforting conflicts of interest. Phyllis Wolf and her son Joseph cofounded the Baltimore-based American Breast Cancer Foundation in 1998. Its mission: Provide financial assistance to uninsured breast cancer patients. For most of its history, the American Breast Cancer Foundation relied on telemarketers to solicit donations. But by 2002, Joseph had struck out on his own, opening a marketing firm called Non Profit Promotions, which, despite four other vendors providing similar services, quickly scored the ABCF’s biggest telemarketing contracts. “He always [tried] to give us the better deal, having had a relationship with the foundation,” says Sherri Walters, development associate at the ABCF. Non Profit Promotions generally pocketed about 40 cents for every dollar it collected, and over the course of nine years, Joseph billed his mother $18 million for his services. ABCF terminated its relationship with Non Profit Promotions in 2008, about a year before Phyllis Wolf took early retirement.


The net result of all this profiteering? Pink has lost its punch. “All these groups that have sprouted up around the country have diffused the attention to breast cancer,” contends Fran Visco, president of the National Breast Cancer Coalition and former chair of the Integration Panel of the Department of Defense Peer-Review Breast Cancer Research Program. “They take up dollars and put them into little pots all across the country. They take away from the efforts that can — and do — make a difference. They should all be focused on putting themselves out of business.” But who closes up shop when business is booming?


For anyone worried about where their donations are going, here’s a useful tip: Skip the pink-ribbon merchandise. Because no one really owns the rights to what has become the universal symbol of breast cancer (though Susan G. Komen for the Cure trademarked its own version), peddling the logo has become a massive racket, overrun by slick profiteers exploiting the public’s naive assumption that all pink purchases help the cause. Often they don’t. Tchotchke vendor Oriental Trading sells an extensive line of pink-ribbon party favors, including “Find the cure” car magnets and “I wear pink in honor of” buttons. Save for proceeds from its pink rubber duckies, part of a sponsorship deal with Komen, not a penny of Oriental Trading’s breast cancer novelties goes to breast cancer. Three years ago, veteran nurse Christina McCall, the daughter of a breast cancer survivor, launched Pink Ribbon Marketplace, an online store based in Germantown, Tennessee, with a vast array of pink-hued goodies. “As a woman and the mother of three daughters, it quickly became apparent that creating a business that gives back to breast cancer victims and their families was important to me,” she writes on her store’s website. “I personally chose our local American Cancer Society and Reach to Recovery Program to be the receipient [sic] of funds we donate.” But when asked about those donations, McCall fesses up that, in fact, no monies have ever gone to the American Cancer Society or its breast-cancer-targeted Reach to Recovery program. “I’m a little leery of [donating money],” McCall told Marie Claire. Instead, she says she gives away free products to charity events and donates to individuals — “depending on my profits.” (Shortly after MC contacted her, McCall removed any reference to the American Cancer Society from her website.)


Last year, the Better Business Bureau issued a warning to consumers about misleading or vague claims made on the packaging of pink-ribbon-festooned products. “Simply because a company puts a pink ribbon on its package doesn’t always mean a good breast cancer charity is benefiting from your purchase,” noted Michelle L. Corey, a BBB exec.

Google “pink ribbon,” and the first listing to pop up is pinkribbon.com, the glossy website of Pink Ribbon International, an Amsterdam-based outfit owned by Dutch businessman Walter Scheffrahn. The site serves up an eclectic mix of breast cancer information and merchandise, including a yard sign ($14.99) and barbecue apron ($16.99) embossed with the site’s logo. Over the past seven years, Scheffrahn has shelled out 200,000 euro ($288,000) to buy the rights to the enviable pinkribbon.com domain name in roughly 40 countries. “There’s not a real global awareness of the pink ribbon,” says Scheffrahn. “We want to take it to the next stage.” But despite its official-looking packaging, his site is riddled with misleading information, including a statement that Scheffrahn’s company donates “10 percent of its company capacity and funds” to charity. Exactly how much is that? Scheffrahn says it refers to manpower, not actual dollars. Scheffrahn also claims that 90 percent of donations made to breast cancer through his websites go to charity. (Ten percent is reserved for overhead, he says.) But this, as it turns out, is also a bit fuzzy. Scheffrahn says his entire Web network generated “something like $20,000” by the end of last year. (That’s hard to confirm given that, at press time, pinkribbon.com’s tax returns were not yet available to the public.) So where did the $20,000 go? Scheffrahn confesses that not only hasn’t he donated the money yet, he’s unsure which organization to give it to. “It will go to a fund we think is appropriate,” is all he can come up with, as though it were the first time he’d ever been asked the question.



These well-regarded breast cancer organizations spend most of their funds on research and treatment:

Breast Cancer Research Foundation

Memorial Sloan-Kettering Cancer Center

The University of Texas, M.D. Anderson Cancer Center

Dana-Farber Cancer Institute

The Johns Hopkins Avon Foundation Breast Center




Crucial questions to ask before donating to a breast cancer charity, courtesy of the American Institute of Philanthropy:


1. How forthcoming is this charity?

Never give to a charity you don’t know anything about. If you can’t find an annual report or tax return on the charity’s website, ask to see one before donating. Think twice about giving to a charity that drags its feet on such a basic request. You have a right to know how much the organization is raising and spending — and how it does that.


2. Where is the money going, exactly?

Find out how much of your donation goes to overhead — administrative and fundraising costs — versus actual programs and services. The American Institute of Philanthropy recommends that at least 60 percent of charitable donations go to actual services. (That means that the bulk of your dollars go to, say, research or underwriting mammographies versus, say, paying salaries and marketing costs for an event.) “Most highly efficient charities are able to spend 75 percent or more on programs,” according to the AIP. Note: Be especially wary of charities that list “public education” as a service — the oblique term is often used to disguise telemarketing expenses. If the charity rep says it sponsors educational programs, pin him on specifics.


3. How clear is the charity about its long and short term goals?

Be skeptical of breast cancer charities whose mission statement includes “awareness”. What exactly does that mean? How does it plan to make people more aware? At what point will it have satisfied its mission?


4. Am I being pressured to donate?

Do not give a dime to charities that use guilt, harassment or other aggressive tactics to solicit a donation. And you’re under no obligation to donate, even if the charity has sent you stamps, cards or other ‘gifts’ designed to sway you. It’s also OK to ask for more information about the charity in writing. If the charity balks, don’t give, period.


5. Don’t be fooled by impressive or familiar names of charities.

It’s astonishingly easy to set up a charity and name it whatever you’d like. Some dubious charities specifically use names that sound like larger, more reputable organizations to confuse donors. Check out whether the charity has ever received complaints with your local Better Business Bureau (www.bbb.org) and review the latest financial reports the charity has available at Guidestar.org.


6. Is the person soliciting a donation from you a volunteer or a professional fundraiser (ie. a telemarketer)?

You have a right to ask and a right to know. Keep in mind that telemarketers, while perfectly legal, are rather expensive. Which means less of your donation goes to the cause.



Not all pink ribbons benefit breast cancer. Before you buy a product anything to support “the fight against breast cancer”, ask these key questions:


How much money from the purchase actually goes toward breast cancer programs and services?

Can you tell? If the company selling the merchandise says “a portion of proceeds”, find out how much exactly. (The packaging or label ought to make this explicit.) Also, is there a cap on how much the company will donate to charity in total? Some companies will give a set donation, regardless of your purchase.


Where is the money going?

What organization will get the money? If you can’t tell or you don’t know what the organization does, reconsider your purchase.


What types of programs are being supported?

If research, what kind? If services, are they reading the people who need them most? Be wary of programs supporting “breast cancer awareness” — what exactly does that mean? How are they making consumers aware?


Is the product itself not contributing to the breast cancer epidemic?

In 2010, Susan G. Komen for the Cure controversially partnered with KFC on a “Buckets for the Cure” campaign, which promptly inspired howls from breast cancer advocates who argued that fatty foods like fried chicken actually raise your risk for breast cancer.

Dr. Michelakis May 2012 paper published in Oncogene

Dr. Michelakis May 2012 paper published in Oncogene


Oncogene , (21 May 2012) | doi:10.1038/onc.2012.198

Source link: http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2012198a.html

Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer


G Sutendra, P Dromparis, A Kinnaird, T H Stenson, A Haromy, J M R Parker, M S McMurtry and E D Michelakis



Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the ‘pseudohypoxic’ mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H2O2, as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.

Challenges in ductal carcinoma in situ risk communication and decision-making

Challenges in ductal carcinoma in situ risk communication and decision-making

Report from an American Cancer Society and National Cancer Institute Workshop

Ann H. Partridge MD, MPH1,*,

Joann G. Elmore MD, MPH2,

Debbie Saslow PhD3,

Worta McCaskill-Stevens MD, MS4,

Stuart J. Schnitt MD5

Article first published online: 4 APR 2012

DOI: 10.3322/caac.21140

Copyright © 2012 American Cancer Society, Inc.



CA: A Cancer Journal for Clinicians

Volume 62, Issue 3, pages 203–210, May/June 2012


Partridge, A. H., Elmore, J. G., Saslow, D., McCaskill-Stevens, W. and Schnitt, S. J. (2012), Challenges in ductal carcinoma in situ risk communication and decision-making. CA: A Cancer Journal for Clinicians, 62: 203–210. doi: 10.3322/caac.21140

Author Information


Associate Professor, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute,Boston,MA


Professor of Medicine, Adjunct Professor of Epidemiology, University of Washington School of Medicine, Section Head of General Medicine, Harborview Medical Center, Seattle, WA


Director of Breast and Gynecologic Cancer, American Cancer Society,Atlanta,GA


Program Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health,Bethesda,MD


Director, Anatomic Pathology, Beth Israel Deaconess Medical Center, Professor, Department of Pathology, Harvard Medical School, Boston, MA

Email: Ann H. Partridge MD, MPH (ann_partridge@dfci.harvard.edu)

*Dana-Farber Cancer Institute,450 Brookline Ave,Boston,MA02215

DISCLOSURES: Dr. Elmore serves as a medical editor for the nonprofit Foundation for Informed Medical Decision Making.

Publication History

Issue published online: 7 MAY 2012

Article first published online: 4 APR 2012




In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS. CA Cancer J Clin 2012. © 2012 American Cancer Society.




Knowledge and Communication About DCIS

Risk Perceptions, Anxiety, and Quality of Life in Women With DCIS

Decision-Making in DCIS

Nomenclature Issues: What’s in a Name?

Conclusions and Future Directions


At the National Institutes of Health (NIH) State-of-the-Science conference on ductal carcinoma in situ (DCIS) held in September 2009, it became evident that there were a number of issues related to the communication of risk to patients regarding the disease.1-4 Recommendations were made for more research to be done in the area of DCIS risk communication and for the development of decision aids and strategies to integrate them into clinical practice. The Consensus Panel Statement also concluded: “Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to remove the anxiety-producing term ‘carcinoma’ from the description of DCIS.”2

In consideration of these issues, the American Cancer Society (ACS) and National Cancer Institute (NCI) convened a workshop in September 2010 to review available evidence and issues regarding DCIS risk communication and decision-making and to identify directions for future research. Invited participants included a small group of clinical and basic scientists, advocates, and communication specialists (Table 1). Patient-provider communication and informed medical decision-making surrounding DCIS diagnosis and treatment, psychosocial outcomes of women with DCIS, and consideration of changing the nomenclature were addressed. The primary goal of the ACS/NCI workshop was to review what is known about these issues and to develop recommendations and strategies to improve them. A secondary goal was to discuss what we know about the association between DCIS nomenclature and distress or confusion, and the pros, cons, and feasibility of changing the nomenclature for DCIS and to identify areas where more information is needed.

Table 1. List of Workshop Participants (in Alphabetical Order)
Terri Ades, DNP, FNP-BC, AOCN
Director, Cancer Information, American Cancer Society,Atlanta,GA
D.Craig Allred,MD
Professor, Department of Pathology and Immunology,WashingtonUniversitySchoolof Medicine,St. Louis,MO
Kimberly Andrews
Research Associate, American Cancer Society,Atlanta,GA
Neeraj Arora, PhD
Health Systems Analyst, Outcomes Research Branch, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute,Bethesda,MD
Otis W. Brawley, MD
Chief Medical Officer, American Cancer Society,Atlanta,GA
KaraSmigel Croker,MS
Communications Manager, Division of Cancer Prevention, National Cancer Institute,Bethesda,MD
Stephen B. Edge, MD
Alfiero Foundation Endowed Chair in Breast Oncology, Professor of Surgery and Oncology, Roswell Park Cancer Institute,Buffalo,NY
Joann G. Elmore, MD, MPH
Professor of Medicine, Adjunct Professor of Epidemiology, University of Washington School of Medicine, Section Head of General Medicine, Harborview Medical Center, Seattle, WA
Ted Gansler, MD, MBA, MPH
Director of Medical Content, Editor, CA: A Cancer Journal for Clinicians, American Cancer Society,Atlanta,GA
Len Lichtenfeld,MD, MACP
Deputy Chief Medical Officer, American Cancer Society,Atlanta,GA
Worta McCaskill-Stevens, MD, MS
Program Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health,Bethesda,MD
Sandra Millon Underwood, RN, PhD
Ann H. Partridge, MD, MPH
Associate Professor, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute,Boston,MA
Barbara D. Powe, PhD, RN
Director, Communication Science, American Cancer Society,Atlanta,GA
AdaPatricia Romilly, MD
Medical Director of Breast Imaging,TaylorBreastHealthCenter,JacksonMemorialHospital,Miami,FL
Debbie Saslow, PhD
Director, Breast and Gynecologic Cancer, American Cancer Society,Atlanta,GA
Stuart J. Schnitt, MD
Director, Anatomic Pathology, Beth Israel Deaconess Medical Center, Professor, Department of Pathology, Harvard Medical School, Boston, MA
Karen Sepucha, PhD
Director, Health Decision Research Unit,Harvard Medical School,MassachusettsGeneralHospital,Boston,MA
Mary Lou Smith, JD, MBA
Cofounder, Research Advocacy Network,Plano,TX
Fattaneh A. Tavassoli, MD
Professor of Pathology and of Obstetrics, Gynecology, and Reproductive Sciences, Director, Pathology Women’s Health Program Department of Pathology, Yale University School of Medicine, New Haven, CT
Thea Tlsty, PhD
Professor, Department of Pathology,UniversityofCaliforniaatSan Francisco,San Francisco,CA
Umberto Veronesi,MD
Scientific Director, European Institute of Oncology,Milan,Italy
Diana Zuckerman, PhD
President,NationalResearchCenterfor Women and Families, Cancer Prevention and Treatment Fund,Washington,DC

Conference participants heard presentations by experts, followed by question-and-answer sessions and group discussions. The speakers included Worta McCaskill-Stevens, MD, MS; Ann H. Partridge, MD, MPH; Joann G. Elmore, MD, MPH; Karen Sepucha, PhD; Stuart J. Schnitt, MD; Fattaneh A. Tavassoli, MD; Umberto Veronesi, MD; Neeraj Arora, PhD; and Mary Lou Smith, JD, MBA. This article summarizes the key points from presentations and discussions in the context of the current literature from the ACS/NCI workshop as well as future directions to address the issues raised.

A brief overview of the NIH State-of-the-Science conference was presented to set the stage for the discussion.1, 2 For the purposes of discussion, the following definition of DCIS was used: DCIS is the replacement of normal ductal cells with a spectrum of abnormal cells confined to the breast ducts. The diagnosis has increased dramatically in the era of mammographic screening such that DCIS is now diagnosed in approximately 50,000 women in the United States alone annually.5-7 Research has revealed that DCIS is a term that encompasses a heterogeneous group of lesions with a variable natural history and risk of progression to invasive breast cancer.8-11 The natural history and risk of progression to invasive disease has been studied in women who were found to have DCIS on retrospective review of breast biopsies originally categorized as benign and who, therefore, underwent no more than a diagnostic biopsy. In these studies, which included primarily cases of low-grade DCIS, up to 40% of women were diagnosed with invasive cancer in the ipsilateral breast with follow-up of more than 30 years.12 Data such as these have historically been used to justify aggressive local therapy for the disease.13 Current standard treatment options for DCIS include excision followed by radiation, wide excision alone, mastectomy, and tamoxifen after excision, with or without radiation. Among women treated with breast-conserving methods, there remains a broad range of local recurrence rates, although this rate is generally lower than in the setting of invasive disease. Of note, approximately 50% of local recurrences following breast-conserving treatment will be invasive cancers and 50% will be DCIS (Fig. 1).


Figure 1. Risk of Recurrence After Ductal Carcinoma In Situ. Adapted from Burstein HJ, Polyak K, Wong JS, Lester SC, Kaelin CM. Ductal carcinoma in situ of the breast. N Engl J Med. 2004;350:1430-144113 by Thea Tlsty (2010); Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28:400-418.


Figure 2. Patient-Centered Communication Functions. Reprinted with permission from Epstein RM, Street RL. Patient-Centered Communication in Cancer Care: Promoting Healing and Reducing Suffering. Bethesda, MD: National Cancer Institute; 2007.50

Download figure to PowerPoint

Risk stratification among women with DCIS has been an area of active research for more than 2 decades but remains challenging. There are currently no clinical factors, histopathologic features, or molecular markers singly or in combination that permit the reliable stratification of risk of either invasive or noninvasive recurrence for individual patients. The role of molecular markers and gene expression signatures to identify patients at risk of future events of DCIS and invasive breast cancer is evolving, but the clinical usefulness of these tests is at the present time uncertain.14-16 Consequently, there is controversy about the optimal treatments for women with DCIS.13 Overall, however, women with DCIS have a very favorable prognosis and a diagnosis of DCIS is not likely to affect a woman’s survival. Furthermore, there has been concern about the overtreatment of DCIS, particularly small lesions that might not have ever become clinically evident.17 Thus, addressing the problem of suboptimal communication and the potential for poor-quality decision-making and psychosocial outcomes is of great clinical importance.


Evidence suggests that DCIS is not a disease with which most women are familiar. In a cross-sectional survey of 479 US women in 1997, only 6% reported that they had heard of DCIS and only 7% agreed that there are “some types of breast cancer that grow so slowly that even without treatment they would not affect a woman’s health.”18 Among women who are diagnosed with DCIS, there is a lack of understanding of the disease entity, particularly with regard to the noninvasive nature and whether or not it is “cancer” or could spread to other places in a woman’s body and become life-threatening.19-24 For example, in a letter to the BMJ, a patient with DCIS understandably bemoaned the fact that during one appointment with her physician, she was told both that she did have cancer and that she did not have cancer.20 Women’s confusion is potentially compounded by the use of the term “carcinoma,” as this implies for many women that they have invasive breast cancer. In addition, treatments recommended for DCIS such as mastectomy, partial mastectomy followed by radiation, and hormonal therapy are also often recommended for women with invasive disease, possibly leading women to think of DCIS as being the same as invasive cancer.21, 25, 26 However, there are no rigorous data available on the reaction of women to the use of the term carcinoma or to the alternative terms that have been proposed. Furthermore, while DCIS is classified as stage 0 breast cancer according to the American Joint Committee on Cancer, the common use of the terminology “breast cancer” to refer to both DCIS as well as invasive disease likely adds to the confusion given the different risks associated with invasive compared with noninvasive breast cancer.27, 28

There is very little available information regarding physicians’ perceptions and communication strategies in caring for women with DCIS despite the substantial evidence that the management of DCIS is strongly related to physician recommendations and varies substantially nationally and internationally.28-36 A cross-sectional survey of 151 US physicians who care for women with DCIS revealed heterogeneity among them regarding the terms used to describe DCIS when speaking with patients and management approaches for the disease.28 The majority of these physicians rated the emotional distress that women generally experience when diagnosed with DCIS as high and perceived the treatment decision-making process to be quite difficult for these women. Most (78%) also indicated that the DCIS decision-making process was as difficult (36%) or more difficult (42%) than that for women with invasive breast cancer. Finally, only 63% of respondents indicated that a diagnosis of DCIS posed little or no risk to a woman’s overall long-term health. A survey of 296 health professionals in the United Kingdom involved with the treatment of patients with DCIS confirmed diverse perceptions of the disease, difficulty explaining DCIS to patients, and heterogeneity in the terminology used.34 It is likely that the clinical heterogeneity and uncertainty about the natural history of DCIS (particularly for any given woman), as well as the controversies surrounding optimal treatment, contribute to the heterogeneous management approaches and likely some physician discomfort with the disease. Further evaluation of the effects of physician attitudes, communication strategies, and management approaches for women with DCIS on patient outcomes is clearly needed.


Given the confusion among patients about the entity of DCIS, and heterogeneous views among providers, it is not surprising that many women with DCIS are anxious about their disease and overestimate the risks they face.23, 37-47 In a recent cross-sectional survey of 144 women diagnosed with DCIS in Australia, many women expressed both misunderstanding and confusion about DCIS and the associated risks, and desired more information about their breast disease.23 In this study, 73% of women described their disease as early stage breast cancer, and only 19% of participants were aware that not all women with DCIS will develop invasive breast cancer. Approximately 60% of women thought DCIS can metastasize and 27% were unsure about this. Furthermore, approximately one-half of the women in the study expressed high decisional conflict when considering treatment options.

In a large prospective cohort study of US women with newly diagnosed DCIS (N = 487), a substantial proportion of participants harbored inaccurate perceptions about the breast cancer risks they faced, including both local and distant recurrence. For example, approximately 25% of women perceived at least a moderate risk of DCIS spreading to other parts of their bodies at the baseline, 18-month, and 5-year follow-ups.39, 47 Increased anxiety was significantly associated with inaccurate risk perceptions.

Several studies have also found that women with DCIS have similar risk perceptions and anxiety compared with women with invasive breast cancer.41-44 In a cross-sectional study of 228 women with either DCIS or invasive disease, women with DCIS perceived that they had essentially the same risks of local recurrence, distant recurrence, and death compared with women with invasive cancer.41 In a prospective study of 549 women with newly diagnosed early stage breast cancer, including a substantial proportion with only DCIS (34%), patients who were white (odds ratio [OR], 5.88; 95% confidence interval [95% CI], 3.39-10.19) and had greater state anxiety (OR, 1.04; 95% CI, 1.02-1.07) were more likely to report a higher risk of recurrence, while patients who received radiotherapy (OR, 0.72; 95% CI, 0.54-0.96) and had more social support (OR, 0.59; 95% CI, 0.46-0.75) were less likely to report a higher risk of recurrence. Cancer stage was not significantly associated with perceived risk of recurrence and perceived risk of recurrence did not change significantly over time.44

In the only published study with a premorbid assessment of health-related quality of life (HRQoL), Nekhlyudov et al compared changes among women who developed DCIS compared with those who did not in 2 Nurses’ Health Study cohorts using the Medical Outcomes Study 36-Item Short-Form Health Survey.38 Women who were diagnosed with DCIS had small, but statistically significantly greater, declines in the domains of role limitations due to physical problems, vitality, and social functioning than women without DCIS. Among those with DCIS, clinically significant declines were more often observed within 6 months of the diagnosis in the domains of social functioning and mental health than after 6 months from diagnosis.38 These data are consistent with other studies that suggest that despite increased anxiety and inaccurate risk perceptions among many women with DCIS, the effects of the diagnosis and treatment on overall HRQoL appear to be limited.28, 37, 42, 47

Inaccurate, heightened perceptions of breast cancer risks among women with DCIS have been associated repeatedly with increased anxiety. It is not clear from the current literature whether women with high baseline anxiety are more likely to perceive their risks inaccurately upon the diagnosis of DCIS or whether inaccurate risk perceptions are driving up anxiety levels. Regardless, it is likely that any intervention to improve risk perceptions will need to address not only understanding and informational gaps, but address and manage anxiety as well.


Inaccurate risk perceptions and anxiety about DCIS may hamper optimal, high-quality, shared decision-making. Patient-centered care entails shared decision-making between patients and providers and requires that the patient is engaged and accurately informed about options and outcomes so that treatment decisions can be consistent with the patient’s goals, preferences, and values (Fig. 2).48-52 Patient-centered care not only incorporates the patient’s (and, potentially, loved ones’) perspective into the care planning and delivery, but aims to provide ongoing support to meet patient needs (medical and psychosocial) as best as possible and implies responsiveness to those needs. This requires patient-centered communication, which includes fostering healing relationships with providers in which trust is key, accurate information exchange regarding the implications of disease and potential risks and benefits of treatments, provider response to emotions, and assistance with decision-making and managing uncertainty as well as enabling self-management.53 Providing this optimal care in our complex health care environment for every patient poses challenges and research has suggested that substantial gaps exist.50 In cancer survivors, there is evidence that physicians who adopt a participatory decision-making style are likely to facilitate patient empowerment and enhance the patient’s HRQoL.54

Optimizing patient-centered care may be particularly valuable when caring for patients with DCIS in whom there is such confusion regarding the diagnosis as well as uncertainty in available knowledge about the disease. Interventions directed toward improving communication styles among physicians who care for women with DCIS may lead to more accurate risk perceptions, more informed decision-making, and better psychosocial outcomes in this population, although this has not been studied prospectively. Among women with DCIS, large cross-sectional, population-based studies have revealed that many women do not perceive that they were offered a choice between surgical treatment options.29, 32 Not surprisingly, surgeon recommendations, which appear to take into account important clinical factors, heavily influence treatment decisions. Patient attitudes also appear to play an important role in treatment decisions. Knowledge about differences in clinical benefits and risks between surgery options has been found to be low among patients and satisfaction with the decision-making process significantly lower in women who did not perceive a choice between surgery options.29

There is also some evidence that attention to distress, as well as informational needs, in women with DCIS may improve psychosocial outcomes. A small cross-sectional interview study of a multiethnic group of women with DCIS revealed ethnic differences in cognitive and emotional responses to DCIS.55 White women generally reported a better understanding of their diagnosis and treatment, and Latinas generally reported more distress. Regardless of ethnicity, the women preferred that physicians discuss DCIS treatment options and attend to their informational and emotional needs. Furthermore, satisfaction was associated with adequate information, expediency of care, and the physician’s sensitivity to the patient’s emotional needs.

Patient decision aids may help to improve risk communication, decision-making, and distress for women with DCIS. They have been shown to be feasible and acceptable; increase patient involvement; and are more likely to lead to informed, values-based health-related decisions.56 They also help patients to make health decisions and reduce decisional conflict. Furthermore, decisions made with the use of decision aids are more likely to be based on better knowledge, more realistic expectations, clearer values, and better communication. They have been studied among women with invasive breast cancer and found to improve communication and knowledge, reduce decisional conflict, and enable women to make a choice regarding surgical treatments.57, 58 No published studies of a decision aid have focused on women with DCIS, although there are available decision aids in use currently focused on treatment decisions for women with DCIS (available at: http://decisionaid.ohri.ca/Azsumm.php?ID=1187 [accessed January 5, 2012]).

There is clearly a need to identify the mediators and moderators of the link between communication and patient outcomes in women with DCIS. Future research is warranted to understand and intervene in the complex relationship between risk perceptions, anxiety/distress, and decision-making. Decision aids are important tools to facilitate ongoing patient-clinician communication (not replace it) and further research on how decision aids affect communications, decision-making, knowledge, and risk perceptions as well as psychosocial outcomes among women with DCIS should be conducted.


There has been discussion over the past few decades about modifying the nomenclature of DCIS to remove the term “carcinoma.” In particular, proponents of this approach have recommended replacing DCIS with “ductal intraepithelial neoplasia” or “DIN” terminology.59-61 A new clinical and biological TNM classification for breast cancer currently being used in Italy has renamed DCIS as “DIN, ductal intraepithelial neoplasia.”61-63 Proponents of this approach note that the term “intraepithelial neoplasia” would be consistent with the terminology currently used for precursor lesions in other organs such as the cervix, vulva, prostate, and pancreas. It has also been argued that a name change to “DIN” would improve interobserver agreement in the diagnosis of preinvasive breast lesions and would eliminate the need to make the subjective distinction between atypical ductal hyperplasia and low-grade DCIS. At this time, however, there are no data to indicate that changing the nomenclature would improve observer reproducibility.60

It has also been suggested that removing “carcinoma” from the terminology for a disease that should not be able to spread to other parts of the body and threaten a woman’s life could lead to decreased anxiety among patients, improve risk perceptions, and help in decision-making.8 However, there are no data at this point to suggest that a name change will have an effect on risk perceptions, anxiety/distress, or decision-making.

Concern has been raised that the heterogeneity of DCIS, the use of treatment options that are similar to those used for patients with invasive breast cancer, and the limited ability to stratify risk using available clinical and pathologic parameters would limit the potential for a name change to improve risk perceptions and reduce anxiety. In addition, a change in terminology would not result in a change in the treatment options for patients with this disease and might lead to more confusion rather than less for patients and providers, particularly those providers at the periphery of the care of patients with breast cancer. The traditional terminology is well established and deeply embedded with an associated extensive scientific literature. There are few citations from a limited number of authors considering the proposed DIN terminology. Some patient advocates have also expressed concern that changing the name could be construed by women as duplicitous and patronizing, and patients may ultimately experience similar distress to the term “neoplasia” in the DIN terminology compared with the term “carcinoma” in DCIS. It has been noted that the term “lobular carcinoma in situ” does not appear to generate the same anxiety or concerns as DCIS, possibly because the treatment recommendations for women with DCIS are much more aggressive, a fact that would not change with a name change. Some advocates have suggested that research on biology, such as predictive and prognostic markers for DCIS that might help guide treatment decisions, and research to improve communication is a better use of resources than implementing a new nomenclature.

However, proponents suggest that a name change could be feasible if it were done in a phased approach: 1) first, discussions regarding terminology introduced in interdisciplinary settings; 2) next, pathology reports transitioning to include the traditional terminology along with the DIN equivalent in parentheses; 3) subsequently, the DIN designation being placed first on the pathology report followed by the traditional DCIS terminology in parentheses; and 4) finally, only the DIN terminology being used on pathology reports.60

In 2011, the World Health Organization Working Group for classification of tumors of the breast noted that the DIN terminology has not gained widespread acceptance, in part because no new diagnostic criteria are used, and suggested that a change in terminology would therefore not help with improving interobserver reproducibility.15 In light of ongoing and future work in this area, the Working Group recommended that the “classification of intraductal proliferative lesions should be viewed as an evolving concept that may be modified as additional molecular and genetic data become available.”15

In summary, while a change in terminology may be worthy of consideration in the future, there are no data to support the contention that a name change at the present time will reduce observer variability in diagnosis, alleviate patient anxiety, or assist patients and clinicians in choosing among the various treatment options for DCIS, which will be the same regardless of the terminology used. Furthermore, a name change should not be viewed as a substitute for communicating what DCIS means in terms of prognosis and treatment options. Many believe that clinical usefulness and patient benefit should drive the efforts for changing DCIS nomenclature and that at this time, efforts should be focused on ensuring that pathologists provide as accurate and consistent reporting of DCIS cases as possible.


The accuracy of perceived risk, anxiety, and decision-making among women with DCIS would likely be improved by better patient-clinician communication about the disease, the enhanced provision of psychosocial support, and better recognition and treatment of coexisting anxiety.43, 44 However, until we have a better understanding of the disease and predictors of risk and biologic behavior and are able to develop more tailored therapy for individuals, the high level of uncertainty about the disease will continue to pose substantial challenges to informed decision-making and psychosocial outcomes.51 Nevertheless, to improve the situation, decisions aids are important tools to facilitate ongoing patient-clinician communication (not replace it), and further research among women with DCIS is clearly warranted. Careful attention to shared decision-making and eliciting and considering a woman’s preferences when helping her to make treatment decisions, as well as screening for and addressing anxiety in such patients, can improve the care of individual patients.

Continued increases in DCIS diagnoses due to imaging advances and an aging population mandate improved communication about DCIS among professionals involved in the diagnosis and treatment of patients with the disease. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, and to improve communication between patients and providers. There was no consensus among attendees at the workshop to support changing the nomenclature of DCIS. In the future, we seek to 1) evaluate the process by which nomenclature changes were made in other diseases and determine the extent to which communication influenced implementation and the QoL of the patients, and 2) obtain information from other countries (including Italy) where recent nomenclature changes have been adopted regarding the resulting effects of the changes on risk perceptions, psychosocial outcomes, and decision-making.



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New Findings Support Warburg Theory Of Cancer

New Findings Support Warburg Theory Of Cancer


Main Category: Cancer / Oncology

Also Included In: Biology / Biochemistry


New Findings Support Warburg Theory Of Cancer

Article Date: 13 Jan 2009 – 7:00 PDT

German scientist Otto H. Warburg’s theory on the origin of cancer earned him the Nobel Prize in 1931, but the biochemical basis for his theory remained elusive.


His theory that cancer starts from irreversible injury to cellular respiration eventually fell out of favor amid research pointing to genomic mutations as the cause of uncontrolled cell growth.

Seventy-eight years after Warburg received science’s highest honor, researchers from Boston College and Washington University School of Medicine report new evidence in support of the original Warburg Theory of Cancer.

A descendant of German aristocrats, World War I cavalry officer and pioneering biochemist, Warburg first proposed in 1924 that the prime cause of cancer was injury to a cell caused by impairment to a cell’s power plant – or energy metabolism – found in its mitochondria.

In contrast to healthy cells, which generate energy by the oxidative breakdown of a simple acid within the mitochondria, tumors and cancer cells generate energy through the non-oxidative breakdown of glucose, a process called glycolysis. Indeed, glycolysis is the biochemical hallmark of most, if not all, types of cancers. Because of this difference between healthy cells and cancer cells, Warburg argued, cancer should be interpreted as a type of mitochondrial disease.

In the years that followed, Warburg’s theory inspired controversy and debate as researchers instead found that genetic mutations within cells caused malignant transformation and uncontrolled cell growth. Many researchers argued Warburg’s findings really identified the effects, and not the causes, of cancer since no mitochondrial defects could be found that were consistently associated with malignant transformation in cancers.

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg’s theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.


The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell’s inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities “can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer,” according to the co-authors.


These findings can provide insight into new cancer therapies that could exploit the bioenergetic defects of tumor cells without harming normal body cells.


Seyfried, Chuang and Kiebish were joined by co-authors Xianlin Han and Hua Cheng from the Washington University School of Medicine, Department of Internal Medicine, in St. Louis.


The paper, “Cardiolipin and Electron Transport Chain Abnormalities in Mouse Brain Tumor Mitochondria: Lipidomic Evidence Supporting the Warburg Theory of Cancer,” can be viewed at: http://www.jlr.org/cgi/content/full/49/12/2545


Source: Ed Hayward

Boston College