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Improved Survival in Patients with End-Stage Cancer Treated with Coenzyme Q10 and other Antioxidants: A Pilot Study
N Hertz and RE Lister Journal of International Medical Research 2009 37: 1961 DOI: 10.1177/147323000903700634 The online version of this article can be found at: http://imr.sagepub.com/content/37/6/1961

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The Journal of International Medical Research 2009; 37: 1961 1971 [first published online as 37(6) 11]

Improved Survival in Patients with Endstage Cancer Treated with Coenzyme Q10 and Other Antioxidants: a Pilot Study
N HERTZ1
1

AND

RE LISTER2

Arnakkegrds alle 50, Vipperoed, Denmark; 2Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, UK predicted survival time was calculated from 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 than predicted, whereas 31 (76%) survived for longer. Treatments were very well tolerated with few adverse effects.

This pilot study evaluated the survival of patients with end-stage cancer who received supplements of coenzyme Q10 and a mixture of other antioxidants (e.g. vitamin C, selenium, folic acid and bcarotene). 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 were located in the breast, brain, lungs, kidneys, pancreas, oesophagus, stomach, colon, prostate, ovaries and skin. The median KEY WORDS: END-STAGE
CANCER;

ANTIOXIDANTS; COENZYME Q10; SURVIVAL antioxidants seems to be more effective than individual antioxidants alone.18 20 Reactive oxygen species are able to activate all 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 bladder seems to support this notion.22 The present report describes a pilot study in which consecutive patients with end-stage cancer

Introduction
In spite of unfavourable experiences with carotene, in particular an increased incidence 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 a protective effect of certain antioxidants, including -carotene and selenium.13 17 It is especially noteworthy that a combination of

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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. usual cancer therapy. Daily doses included: vitamin C 5.7 mg, -tocopherol 1.625 mg, Q10 300 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 B12 13.5 g, vitamin B6 12.6 mg, vitamin B2 8.4 mg and vitamin B1 5.4 mg.

Patients and methods

PATIENTS
This was a long-term observational pilot study in which consecutive patients with endstage 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 usual cancer 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 clinical support 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.

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

TABLE 1: Antioxidant treatments given to the 41 patients with end-stage cancer as a supplement to their usual cancer therapy Daily dosage (divided in two daily doses)

Antioxidantsa

Vitamin C 5.7 mg -Tocopherol 1.625 mg Coenzyme Q10 300 mg Selenium (as selenomethionine) 487 mg Folic acid 5 mg Vitamin A 25 000 IU -Caroteneb 76 mg
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, vitamin B12 13.5 g, vitamin B6 12.6 mg, vitamin B2 8.4 mg and vitamin B1 5.4 mg. bFor safety reasons, patients with lung cancer did not receive -carotene.1 3
aIn

TREATMENTS
Patients were offered treatment with Q10 and other antioxidants as a supplement to their

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

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.24 29 Agespecific KaplanMeier curves for individual

TABLE 2: Previously published prognostic data used to determine the median predicted survival time (MST) of patients with intrathoracic metastases from breast cancer Source Gawne-Cain et al. Banerjee et al.26 Clark et al.27 Blanco et al.28
25

No. of patients 92 40 193 313 638

MST (months) 13.5 11 14 14 14

Total Chosen median

TABLE 3: Previously published prognostic data used to determine the median predicted survival time (MST) of patients with bone metastases from breast cancer Source Clark et al. Blanco et al.28 Koenders et al.29 Total Chosen median
27

No. of patients 404 75 70 549

MST (months) 19 19 34 21

TABLE 4: Previously published prognostic data used to determine the median predicted survival time (MST) of patients with cerebral metastases Source Clark et al.27 Sampson et al.30 Schoeggl et al.31 Sundstrm et al.32 Lagerwaard et al.33 Primary cancer Breast Malignant melanoma All types All types All types Total Chosen median
aA bMedian

No. of patients 62 702 97 75 1292a 2228

MST (months) 6 4 6 4 3.4b 6

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

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

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 not given (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,40 Expected 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 patients surviving 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.

Results
PATIENTS
A total of 103 patients with end-stage cancer

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

TABLE 5: Expected and actual survival for the 41 patients with end-stage cancer who were treated with coenzyme Q10 and other antioxidants Expected survival Achieved at inclusion survival (months) (months) 11 19 3 5 10 13 16 8 25 113 3 3 22 19 18 10 1 10 5 15 25 21 21 17 33 34 37 43 66 82 120 111 89 6 2 13 25 8 13 79 4 28.7 17 Survival in excess of expected (month) 1 7 2 1 5 10 3 1 15 101 4 3 13 15 4 2 13 2 1 1 5 7 7 7 12 20 23 29 45 61 99 97 79 1 2 10 20 20 14 50 2 16.8 7**

Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Sex Male Male Male Male Male Male Male Female Male Female Male Male Male Male Male Female Female Female Female Female Female Female Female Female Female Female Female Female Female Female Female Female Female Female Male Male Female Male Male Male Male

Primary cancer Colon Colon Oesophagus Oesophagus Oesophagus Oesophagus Glioblastoma Grade 4 Kidney Kidney Kidney

Metastases

Liver 10 Liver 12 Lymph nodes 5 Mediastinum 4 Lymph nodes 5 Stomach 3 Incomplete 13 resection Both lungs 7 Liver 10 None, declined 12 operation Lung, non-small-cell Inoperable 7 Lung, non-small-cell Brain 6 Lung, non-small-cell Inoperable 9 Lung, non-small-cell Inoperable 4 Lung, small-cell Supraclavicular 14 lymph nodes Malignant melanoma Brain 8 Breast Lung 14 Breast Pleura 12 Breast Brain 6 Breast Liver 14 Breast Bones 20 Breast Pleura and bones 14 Breast Lungs 14 Breast Both lungs 10 Breast Bones 21 Breast Peritoneum, ovaries 14 Breast Both lungs, bones 14 Breast Lung and bones 14 Breast Bones 21 Breast Bones 21 Breast Scull, neurological signs 21 Breast Pleura 14 Ovary Liver 10 Pancreas Regional 5 Pancreas Regional 4 Pancreas Regional 3 Pancreas Liver 5 Prostate Bones 28 Prostate Bones 27 Prostate Bones 29 Stomach Regional 6 Mean 11.9 Median 12

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

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

visited the clinic and were evaluated for eligibility to participate in the study. Twentynine 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. 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 PRIMARY CANCERS

A total of 16 patients had breast cancer with distant metastases. Eight of these had metastases 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, but only one of these (patient 2, Table 5) had a clinically enlarged liver at inclusion. This patient was not offered chemotherapy. Two Of the 41 patients who entered the study, 40 were followed until death: one (patient 23, Table 5) was lost to follow-up and, for practical 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 patient mentioned 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 [twotailed Wilcoxon signed rank test]). The mean actual survival was more than double that of the mean predicted survival (28.7 versus 11.9 months). Roughly half the patients (n = 20) began

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

120

Survival relative to calculated median Time to antioxidant treatment

120

Time to antioxidant treatment (months)

100

100

80 Gain or loss in survival (months)

80

60

60

40

40

20

20

0 1 20 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 Patient No.

40

FIGURE 1: Actual survival time relative to the predicted survival time, and the time to antioxidant treatment for the 41 patients with end-stage cancer 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 any of the pills towards the end of their life. impressive improvement of their general well-being after beginning the antioxidant supplementation, although this was not measured.

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, cancerous transformation 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 feeling well and pursued an active life for the next few years, e.g. taking prolonged vacations abroad. The unexpected course of the disease

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. No other physical side effects were noted. The clear impression of the investigator was that a large majority of the patients experienced

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

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 entered the 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 was fairly 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.

Discussion
Perhaps 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 evidence exists, 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 well illustrated in all patients. Its limitations include the retrospective design, lack of a matched control group and lack of blinding.

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N Hertz, RE Lister Survival in end-stage cancer following antioxidant treatment

These were countered, as far as possible, by using prognostic models based on large and representative contemporary surveys, particularly KaplanMeier survival curves from the National Danish Cancer Registry, which includes all cancer deaths that occurred in Denmark between 1978 and 1987.23 A further limitation was that the positive selection of the patients included in the study cannot be ruled out. There are several putative mechanisms for the potential anticancer effect of antioxidants. Most important among these are possible effects on cytokines and inflammation, modulation of the expression of the tumour suppressor gene p53, inhibition of mutations, and inhibition of tumour angiogenesis.5,49,50 A study in rats demonstrated that the administration of Q10 along with tamoxifen in dimethylbenzanthracene-induced mammary carcinoma increased the antioxidant activity by restoring the activities of glutathione-metabolizing enzymes close to control levels.51 This effect may have contributed to the benefits observed in breast cancer patients treated with tamoxifen who were also receiving Q10. Sachdanandam52 found that, in women treated for breast cancer with tamoxifen, coadministration of Q10 reduced the level of angiogenesis. This could have inhibited the metastatic spread of tumours in these patients. It was also found that the levels of cytokines interleukin (IL)-1, IL-6 and matrix metalloproteins (MMPs) were decreased. Furthermore, MMPs have been implicated in regulation of the growth of mammary cancers.53,54 All these factors could have played a part in the beneficial effects on cancer growth in the breast cancer patients in the present study. The present study seems to show an impressive effect of a combination of antioxidants, including Q10, on the course of advanced cancer and underscores the need for larger clinical trials. If these results can be duplicated they would support the notion that a combination of antioxidants can be used to aid the management of advanced cancer.

Acknowledgement
Pharma Nord, Vejle, Denmark, supplied all medications free of charge without any kind of involvement with this project.

Conflicts of interest
The authors had no conflicts of interest to declare in relation to this article.

Received for publication 1 June 2009 Accepted subject to revision 4 June 2009 Revised accepted 13 October 2009 Copyright 2009 Field House Publishing LLP
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Authors address for correspondence Dr Niels Hertz Arnakkegrds alle 50, DK 490 Vipperoed, Denmark. E-mail: nhj@dadlnet.dk

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Corrigendum
N Hertz, RE Lister: Improved survival in patients with end-stage cancer treated with coenzyme Q10 and 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:

TABLE 1: Antioxidant treatments given to the 41 patients with end-stage cancer as a supplement to their usual cancer therapy Daily dosage (divided in two daily doses)

Antioxidantsa

Vitamin C 5700 mg -Tocopherol 1625 mg Coenzyme Q10 300 mg Selenium (as selenomethionine) 487 g Folic 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), as well as niacin 45 mg, pantothenic acid 22.5 mg, vitamin B12 13.5 g, vitamin B6 12.6 mg, vitamin B2 8.4 mg and vitamin B1 5.4 mg. bFor safety reasons, patients with lung cancer did not receive -carotene.1 3

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