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DOI: 10.1177/1473230009037006342009 37: 1961Journal of International Medical Research

N Hertz and RE Listerand other Antioxidants: A Pilot Study

10mproved Survival in Patients with End-Stage Cancer Treated with Coenzyme Q

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The Journal of International Medical Research

2009; 37: 1961 1971 [first published online as 37(6) 11]

1961

Improved Survival in Patients with End-

stage Cancer Treated with Coenzyme Q10and Other Antioxidants: a Pilot Study

N HERTZ1 ANDRE LISTER2

1Arnakkegrds alle 50, Vipperoed, Denmark; 2Institute of Brain Chemistry and HumanNutrition, London Metropolitan University, London, UK

This pilot study evaluated the survival ofpatients with end-stage cancer who

received supplements of coenzyme Q10and

a mixture of other antioxidants (e.g.

vitamin C, selenium, folic acid and b-

carotene). During a period of 9 years, 41

patients who had end-stage cancer were

included. Forty patients were followed until

death and one patient was lost to follow-up

and presumed dead. Primary cancers werelocated in the breast, brain, lungs, kidneys,

pancreas, oesophagus, stomach, colon,

prostate, ovaries and skin. The median

predicted survival time was calculatedfrom KaplanMeier curves for each patient

at inclusion. Median predicted survival was

12 months (range 3 29 months), whereas

median actual survival was 17 months (1

120 months), which is > 40% longer than

the median predicted survival. Mean

actual survival was 28.8 months versus 11.9

months for mean predicted survival. Ten

patients (24%) survived for less time thanpredicted, whereas 31 (76%) survived for

longer. Treatments were very well tolerated

with few adverse effects.

KEY WORDS: END-STAGE CANCER; ANTIOXIDANTS; COENZYMEQ10; SURVIVAL

IntroductionIn spite of unfavourable experiences with -

carotene, in particular an increasedincidence of lung cancer (but not other kinds

of cancer) among smokers in some large

trials,1 3 it is still possible that antioxidants

can assist in preventing cancer. This is

supported by extensive evidence from

molecular biological data,4 7 tissue and

animal experiments,8,9 as well as

epidemiological surveys.10 12 A few

intervention trials have even indicated aprotective effect of certain antioxidants,

including -carotene and selenium.13 17 It is

especially noteworthy that a combination of

antioxidants seems to be more effective than

individual antioxidants alone.18 20

Reactive oxygen species are able to activateall stages of carcinogenesis.21 Simplified, this

process can be regarded as a continuous

growth and accumulation of mutations in a

cellular clone. If combinations of

antioxidants have a preventive effect, it

would seem possible that they would also

retard the process at a later stage, i.e. when

the cancer is apparent. A controlled study of

patients with cancer of the urinary bladderseems to support this notion.22 The present

report describes a pilot study in which

consecutive patients with end-stage cancer

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N Hertz, RE Lister

Survival in end-stage cancer following antioxidant treatment

were included for 9 years and followed up

altogether for > 15 years. The patients were

offered treatment with coenzyme Q10 (Q10)

and other antioxidants and vitamins in

comparatively large but non-toxic amounts.

Patients and methodsPATIENTS

This was a long-term observational pilot

study in which consecutive patients with end-

stage cancer were included for 9 years and

followed up altogether for > 15 years in the

setting of a Danish private practice. The

patients included were those with solid

tumours (including primary cancers located

in the breast, brain, lungs, kidneys, pancreas,

oesophagus, stomach, colon, prostate,

ovaries and skin) who were diagnosed with

distant metastases, or who were inoperable

for the same kind of tumours, between

January 1990 and April 1999. Patients were

offered treatment with Q10 and other

antioxidants as supplements to their usualcancer therapy. Since this treatment would

not be expected to have immediate effect,

only those who survived and continued

treatment 2 months were included in the

evaluation. All patients received verbal

information on the treatments that they

received; however, it is important to note that

the treatment was not given as part of a

clinical trial, but was provided as a clinicalsupport for patients based on knowledge and

hypotheses at that time. For the same reasons

patients were not excluded from treatment,

only from reporting according to the above

mentioned criteria. Legal ethics review

committees did not exist in Denmark until

1992 and as a result the study protocol did

not undergo any ethical approval.

TREATMENTS

Patients were offered treatment with Q10and

other antioxidants as a supplement to their

usual cancer therapy. Daily doses included:

vitamin C 5.7 mg, -tocopherol 1.625 mg,

Q10300 mg, selenium (as selenomethionine)

487 g, folic acid 5 mg, vitamin A 25 000 IU,

and -carotene 76 mg (Table 1). For safety

reasons, patients with lung cancer did not

receive-carotene.1 3 The antioxidant tablets

were taken daily in two divided doses.

Patients also received small amounts of -

linoleic acid (375 mg) and fish oil (1.5 mg), as

well as niacin 45 mg, pantothenic acid 22.5

mg, vitamin B1213.5 g, vitamin B612.6 mg,

vitamin B28.4 mg and vitamin B15.4 mg.

PREDICTION OF SURVIVAL TIMES

At the time of inclusion, i.e. 2 months after

the start of treatment, the median predicted

length of survival for each patient was

estimated, mainly using KaplanMeier

curves derived from data from the National

Danish Cancer Registry.23

Breast cancer

The survival of patients with metastatic

Daily dosage(divided in two

Antioxidantsa daily doses)

Vitamin C 5.7 mg-Tocopherol 1.625 mgCoenzyme Q

10 300 mg

Selenium (as selenomethionine) 487 mgFolic acid 5 mg

Vitamin A 25 000 IU-Caroteneb 76 mg

aIn addition, patients received small amounts of-linoleic acid (375 mg) and fish oil (1.5 mg), as well

as niacin 45 mg, pantothenic acid 22.5 mg, vitaminB12

13.5 g, vitamin B6

12.6 mg, vitamin B2

8.4 mgand vitamin B

15.4 mg.

bFor safety reasons, patients with lung cancer didnot receive-carotene.1 3

TABLE 1:Antioxidant treatments given to the 41patients with end-stage cancer as asupplement to their usual cancer therapy



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N Hertz, RE Lister


breast cancer depends strongly on the site of

the metastases. Figures from the National

Danish Cancer Registry for breast cancer

were rather crude and did not reflect the

influence of different sites of metastases.24 For

this reason, estimates were based on

previously published prognostic data (Tables

2 4),25 29 although estimates based on

KaplanMeier curves from the National

Danish Cancer Registry24 gave roughly

similar results for the group as a whole (data

not shown). The prognostic calculations took

into account the localization of the

metastases, but not oestrogen receptor status,

since this was often unknown.2 4 2 9 Age-

specific KaplanMeier curves for individual

TABLE 2:Previously published prognostic data used to determine the median predicted survivaltime (MST) of patients with intrathoracic metastases from breast cancer

Source No. of patients MST (months)

Gawne-Cain et al.25 92 13.5Banerjee et al.26 40 11Clark et al.27 193 14Blanco et al.28 313 14

Total 638 Chosen median 14

TABLE 3:

Previously published prognostic data used to determine the median predicted survivaltime (MST) of patients with bone metastases from breast cancer

Source No. of patients MST (months)

Clark et al.27 404 19Blanco et al.28 75 19Koenders et al.29 70 34


TABLE 4:Previously published prognostic data used to determine the median predicted survivaltime (MST) of patients with cerebral metastases

MSTSource Primary cancer No. of patients (months)

Clark et al.27 Breast 62 6Sampson et al.30 Malignant melanoma 702 4Schoeggl et al.31 All types 97 6Sundstrm et al.32 All types 75 4Lagerwaard et al.33 All types 1292a 3.4b


aA total of 84% of the patients were treated with whole brain radiation.bMedian survival was 8.9 months for patients treated with whole brain irradiation and surgery.



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stages of the disease were used when possible.

Otherwise, it was assumed that mortality for

a given stage was constant, i.e. it was

assumed that expected residual survival for a

specific stage of the disease is the same at any

time. For stage IV breast cancer this has been

shown to be approximately correct for at

least the first 4 years after diagnosis.34

Lung cancer

Expected survival was predicted from

KaplanMeier curves derived from data from

the National Danish Cancer Registry that

did not distinguish between small-cell and

non-small-cell cancer, but were specific for

age, sex and stage of cancer.35

Cancer of the pancreas

Expected survival was derived from sex- and

age-specific KaplanMeier curves for regional

disease and metastatic disease, respectively.36

Cancer of the colon

Data from the National Danish Cancer

Registry indicated a median survival of 6

months for patients with metastatic colorectal

cancer.36 Other data, based on patients given

chemotherapy indicated a somewhat longer

survival (11 13 months).37,38 The median

predicted survival in the present study

reflected published data in terms of being

slightly shorter where chemotherapy was notgiven (10 months, patient 1, Table 5) and

longer where chemotherapy was given (12

months, patient 2, Table 5).39

Renal cell carcinoma

Reliable survival data are sparse for

untreated patients although, of 443

inoperable patients with renal cancer, 4%

survived 3 years and 1.7% survived 5 years,40Expected survival for one patient (patient 10,

Table 5), who had a tumour measuring 4 cm

in diameter, was arbitrarily predicted to be

12 months. For the remaining patients with

metastatic renal carcinoma, prognosis was

predicted with KaplanMeier curves

prepared from data from the National

Danish Cancer Registry specific for age, sex

and stage of disease.41

Brain tumour

One patient had advanced glioblastoma

multiforme (patient 7, Table 5). With

combined surgery, X-rays, and

dexamethasone treatment, average survival

for patients with this tumour is 11 13

months and the survival of this patient was

estimated from these data.42 44

Other end-stage cancers

Predicted survival times for the other cancers

were derived from KaplanMeier curves

based on data from the National Danish

Cancer Registry, specific for age and stage of

disease for cancer of the prostate,45 ovaries,46

oesophagus and stomach,36 and for malignant melanoma (one patient had with

brain metastases).47

STATISTICAL ANALYSIS

According to the null hypothesis, the

number of patients surviving longer than

expected would equal the number surviving

shorter than expected. The median gain or

loss in survival and the number of patientssurviving shorter or longer than predicted

were calculated, and differences in the

median predicted and median actual

survivals were compared by the Wilcoxon

signed rank test using Minitab statistical

software, version 15 (Minitab Inc.,

Pennsylvania, USA). A P-value < 0.05 was

considered to be statistically significant.

ResultsPATIENTS

A total of 103 patients with end-stage cancer



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TABLE 5:Expected and actual survival for the 41 patients with end-stage cancer who were treatedwith coenzyme Q10and other antioxidants

Expected Survival insurvival Achieved excess of

Patient at inclusion survival expectedNo. Sex Primary cancer Metastases (months) (months) (month)

1 Male Colon Liver 10 11 12 Male Colon Liver 12 19 73 Male Oesophagus Lymph nodes 5 3 24 Male Oesophagus Mediastinum 4 5 15 Male Oesophagus Lymph nodes 5 10 56 Male Oesophagus Stomach 3 13 107 Male Glioblastoma Incomplete 13 16 3

Grade 4 resection8 Female Kidney Both lungs 7 8 19 Male Kidney Liver 10 25 15

10 Female Kidney None, declined 12 113 101operation

11 Male Lung, non-small-cell Inoperable 7 3 412 Male Lung, non-small-cell Brain 6 3 313 Male Lung, non-small-cell Inoperable 9 22 1314 Male Lung, non-small-cell Inoperable 4 19 1515 Male Lung, small-cell Supraclavicular 14 18 4

lymph nodes16 Female Malignant melanoma Brain 8 10 2

17 Female Breast Lung 14 1 1318 Female Breast Pleura 12 10 219 Female Breast Brain 6 5 120 Female Breast Liver 14 15 121 Female Breast Bones 20 25 522 Female Breast Pleura and bones 14 21 723 Female Breast Lungs 14 21 724 Female Breast Both lungs 10 17 725 Female Breast Bones 21 33 1226 Female Breast Peritoneum, ovaries 14 34 2027 Female Breast Both lungs, bones 14 37 2328 Female Breast Lung and bones 14 43 29

29 Female Breast Bones 21 66 4530 Female Breast Bones 21 82 6131 Female Breast Scull, neurological signs 21 120 9932 Female Breast Pleura 14 111 9733 Female Ovary Liver 10 89 7934 Female Pancreas Regional 5 6 135 Male Pancreas Regional 4 2 236 Male Pancreas Regional 3 13 1037 Female Pancreas Liver 5 25 2038 Male Prostate Bones 28 8 2039 Male Prostate Bones 27 13 1440 Male Prostate Bones 29 79 50

41 Male Stomach Regional 6 4 2Mean 11.9 28.7 16.8

Median 12 17 7**

**P< 0.002, 95% CI 4.0, 18.5 months (two-tailed Wilcoxon signed rank test).



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visited the clinic and were evaluated for

eligibility to participate in the study. Twenty-

nine were subsequently treated for < 2

months and were, therefore, excluded from

the study as per protocol. Several of these

patients were extremely ill and died within

days or weeks. A further 21 patients were

excluded on the basis of not being

appropriate for this study: nine had types of

cancer other than solid tumours, and 12 had

only regional or local dissemination of the

cancer thereby making curative treatment

possible. Five patients were lost to follow up

and a precise diagnosis was not made in

another four patients. Three patients with

extremely prolonged survival were also

excluded mainly because of uncertainty

about their diagnosis. The remaining 41

patients were included in the study.

PRIMARY CANCERS

A total of 16 patients had breast cancer with

distant metastases. Eight of these hadmetastases to the lungs/pleurae, two to other

viscera and one to the brain, all implying

short survival. Five patients had metastases

to the bones only.

Five patients had inoperable lung cancer.

Four of these had non-small-cell cancer

while one had small-cell cancer. Only the

patient with small-cell cancer received

chemotherapy in addition to radiotherapy.Three patients were considered beyond

therapy and received neither radiation nor

chemotherapy whereas radiotherapy for the

other two patients was palliative only. Four

patients had inoperable regional cancer of

the pancreas. All except one received

palliative surgical intervention. None

received chemotherapy. Two patients with

colorectal cancer had liver metastases, butonly one of these (patient 2, Table 5) had a

clinically enlarged liver at inclusion. This

patient was not offered chemotherapy. Two

patients with metastatic renal cancer and

one who declined an operation (having only

one kidney after removal of the other

because of cancer) but were without

metastases were included in the study. Three

patients had cancer of the prostate and one

patient had metastases from malignant

melanoma in the frontal lobe of the brain,

for which she was initially operated on and

received radiation therapy, with severe

neurological sequelae. One patient had

cancer of the ovaries, four patients had

cancer of the oesophagus and one had

cancer of the stomach. One patient had

advanced glioblastoma multiforme, in

whom only an incomplete resection was

possible and stereotactic irradiation was not

available.

SURVIVAL TIMES

Of the 41 patients who entered the study, 40

were followed until death: one (patient 23,

Table 5) was lost to follow-up and, forpractical reasons, was presumed dead. Ten

(24%) patients survived for less time than

predicted, whereas 31 (76%) patients

survived for longer than predicted. Table 5

illustrates the gain and loss in survival

compared to the derived median.

Overall median predicted survival for the

41 patients studied was 12 months (range 3

29 months). Except for the patientmentioned above, all patients were followed

until death and the median actual survival

was 17 months (range 1 120 months), i.e.

> 40% longer than the median predicted

survival. The median difference was 7

months, which was statistically significant

(P < 0.002, 95% CI 4.0, 18.5 months [two-

tailed Wilcoxon signed rank test]). The mean

actual survival was more than double that ofthe mean predicted survival (28.7 versus

11.9 months).

Roughly half the patients (n = 20) began



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N Hertz, RE Lister


treatment with antioxidants within 1.5

months of being diagnosed with metastases

or otherwise being declared incurable.Among these, the actual median survival in

excess of the predicted survival time was 7

months. The others (n= 21) began treatment

> 1.5 months (median 5 months) after

diagnosis. Among these the actual median

survival in excess of the predicted survival

time was 1.5 months (Fig. 1). Compliance

with treatment was very good, although

most patients had trouble taking all or anyof the pills towards the end of their life.

SIDE EFFECTS

Side effects associated with antioxidant

therapy were very rare and minor, mainly

consisting of difficulties in swallowing the

many tablets and aversion to the odour of

the tablets, particularly once their general

physical condition had deteriorated. Noother physical side effects were noted. The

clear impression of the investigator was that

a large majority of the patients experienced

impressive improvement of their general

well-being after beginning the antioxidant

supplementation, although this was notmeasured.

CASE HISTORIES

Case 1 (patient 26)

This 57-year old woman had a second breast

cancer, the other breast having been

removed 6 years earlier. At recurrence, she

had considerable amounts of ascites,

carcinosis of the peritoneum, canceroustransformation of the ovaries and omentum

as well as growth of cancer around the

rectum, which caused pain on defecation.

Her case was considered terminal and she

was offered no conventional treatment. After

starting on antioxidants, her waist

circumference after 3 months shrunk by 9

cm, which was presumed to indicate the

disappearance of the ascites. She was feelingwell and pursued an active life for the next

few years, e.g. taking prolonged vacations

abroad. The unexpected course of the disease

FIGURE 1: Actual survival time relative to the predicted survival time, and the time toantioxidant treatment for the 41 patients with end-stage cancer

20

20

0

40

40

Gainorlossinsurvival(months)

Timetoantioxidanttreatment(months)

60

80

100

Survival relative to calculated median120

20

0

40

60

80

100

120

Time to antioxidant treatment

1 3 5 7 9 11 13 15 17 19 21

Patient No.

23 25 27 29 31 33 35 37 39 41



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in this case would, based on experience,

seem extremely improbable: she died from

brain metastases after 3 years.

Case 2 (patient 30)

This 37-year old woman with breast cancer

developed bony metastases in the cranium,

pelvis, lymph glands of the neck and in the

bone marrow after 4 years. Following

chemotherapy and irradiation of the ovaries

she had partial remission. She entered the

study after 29 months and continued an

active life (working as a full-time secretary)

until a few months before her death. Her

total survival was 7 years (82 months). Only

about 10% of patients with stage IV breast

cancer survive > 7 years.41

Case 3 (patient 9)

This 57-year old male developed metastases

in the liver, partly compressing the inferior

vena cava, 1 year after his left kidney was

removed because of cancer. When he enteredthe study 1 year later, his liver was grossly

enlarged, reaching the umbilicus, and was

hard and rugged. In spite of this, his

predicted survival time at inclusion was 10

months and he actually survived 25 months.

Only about 5% of patients with distant

metastases from kidney cancer survive > 3

years; median survival is just a few

months.41

Case 4 (patient 13)

This 47-year old male with inoperable

adenocarcinoma of the lung had an

additional complaint of a large pleural

effusion. In hospital he was offered no

therapy except tapping of the effusion. He

was included in the study after 1 month. For

the following 1.5 years his condition wasfairly good and he was able to continue

working as a caretaker. The effusion slowly

disappeared without further treatment. He

then developed metastases in the brain,

received irradiation and survived for a

further 6 months. Despite the lack of

effective conventional treatment, total

survival exceeded that expected (9 months)

by 13 months, i.e. a total survival of 22

months. Only about 10% of all patients with

lung cancer survive > 2 years according to

the National Danish Cancer Registry.35

Case 5 (patient 37)

This woman developed rapidly growing

metastases in the liver from an

adenocarcinoma of the pancreas at the age

of 60 years. At inclusion (after 1 month) her

liver was grossly enlarged, extending to the

spleen and filling out most of the

epigastrium. No conventional treatment was

offered. One year later, she was still fully

mobile and without apparent further

enlargement of the liver. She survived 25

months, i.e. 20 months more than expected.

DiscussionPerhaps the most interesting finding of the

present study was that the median (though

not the mean) survival time in excess of that

predicted was longer (7 versus 1.5 months) in

the 20 patients who began antioxidant

treatment within 1.5 months of being

diagnosed than in those who began

antioxidant treatment later. No evidenceexists, however, that alternative therapy

alone can improve survival in cancer. For

example, shark cartilage was shown to have

no effect on disease progression and no

positive effect on quality of life in a trial that

included 60 patients with advanced cancer.48

The strengths of the present study are that

all cancer patients were accounted for and

that the course of the disease was wellillustrated in all patients. Its limitations

include the retrospective design, lack of a

matched control group and lack of blinding.



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used to aid the management of advanced

cancer.

AcknowledgementPharma Nord, Vejle, Denmark, supplied all

medications free of charge without any kind

of involvement with this project.

Conflicts of interestThe authors had no conflicts of interest to

declare in relation to this article.

1969

N Hertz, RE Lister




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Authors address for correspondenceDr Niels Hertz

Arnakkegrds alle 50, DK 490 Vipperoed, Denmark.

E-mail: [email protected]

1971

N Hertz, RE Lister


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The Journal of International Medical Research

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Corrigendum

N Hertz, RE Lister: Improved survival in patients with end-stage cancer treated with

coenzyme Q10and other antioxidants: a pilot study. J Int Med Res 2009; 37: 1961 1971.

In Table 1 on page 1962, the units for selenium should be micrograms (g) not milligrams

(mg). Also, the amount of vitamin C should be 5700 mg, not 5.7 mg. The amount of-

tocopherol should be 1625 mg, not 1.625 mg. In the footnote, the amount of fish oil should

be 1500 mg not 1.5 mg. The correct version of Table 1 is, therefore, as follows:

Daily dosage(divided in two

Antioxidantsa daily doses)

Vitamin C 5700 mg-Tocopherol 1625 mgCoenzyme Q

10 300 mg

Selenium (as selenomethionine) 487 gFolic acid 5 mg

Vitamin A 25 000 IU-Caroteneb 76 mg

aIn addition, patients received small amounts of-linoleic acid (375 mg) and fish oil (1500 mg), aswell as niacin 45 mg, pantothenic acid 22.5 mg,vitamin B

1213.5 g, vitamin B

612.6 mg, vitamin B

28.4 mg and vitamin B

15.4 mg.

bFor safety reasons, patients with lung cancer didnot receive-carotene.1 3

TABLE 1:Antioxidant treatments given to the 41patients with end-stage cancer as asupplement to their usual cancer therapy


improved survival in patients with end-stage cancer treated with coenzyme q10

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