Efficacy of IP₆ + inositol in the treatment of breast cancer patients receiving chemotherapy: prospective, randomized, pilot clinical study

Breast cancer is the most common cancer in women worldwide. Around 1.15 million cases were recorded in 2002, representing 23% of all female and 11% overall cancers [1]. Breast cancer incidence rates for 2002 vary internationally by more than 25-fold, ranging from 3.9 cases per 100 000 in Mozambique to 101.1 in the US, in part reflecting low screening rates and incomplete reporting in developing countries [2]. Breast cancer is fatal in almost half of all cases. It is the leading cause of cancer death from cancer among woman worldwide, accounting for 16% of cancer deaths in adult women [1, 2].

Depending on the stage of breast cancer, the treatment is carried out by surgery, chemotherapy, ionizing radiation, hormone therapy and supportive measures that aim to reduce the side effects of treatment. Most patients are treated with chemotherapy in order to prevent the systemic dissemination of basic diseases. Patients are subjected to polychemotherapy - combination of three different drugs which are extremely aggressive and hard to bear. There are several protocols used in the treatment of breast cancer - FEC, FAC and CMF; FEC is the most frequently used protocol. Side effects of polychemotherapy (nausea, vomiting, loss of body weight, hair fall out, insomnia, depression, disorders in blood counts) appear in majority of patients and are the most common reasons for stopping the treatment. About 10% of patients interrupt the treatment which increases the risk of the appearance of distant metastasis, and reduces their chances for healing.

Inositol hexaphosphate (IP₆) is a naturally occuring polyphosphorylated carbohydrate, present in almost all plant and mammalian cells, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation and differentiation [3, 4]. For a long time, IP₆ has been recognized as a strong antioxidant. Recently, a striking anticancer effect of IP₆ was demonstrated in different experimental models [3–14]. Inositol is also a natural constituent possesing moderate anticancer activity [3, 4]. However, it was shown that inositol potentiates both the antiproliferative and antineoplastic effects of IP₆in vivo, and that the combination of IP₆ and inositol was significantly better in different cancers (colon, breast and metastatic lung cancer model) than was either one alone [3, 4]. Due to its strong antioxidant activity, and health beneficial effects, such as immune stimulation, prevention of kidney stone formation and hypocholesterolemic effect, IP₆ + Inositol is available as dietary supplement.

Current cancer treatment recognizes the importance of combination therapy in order to increase efficacy and decrease side effects of conventional chemotherapy. It has been shown in vitro that IP₆ acts synergistically with doxorubicin and tamoxifen, being particularly effective against estrogen receptor-negative and doxorubicin-resistant breast cancer cell lines [15]. Furthermore, several case studies have shown that when IP₆ and inositol were given in combination with chemotherapy, side effects of chemotherapy were diminished and patients were able to perform their daily activities [16–18]. Based on these properties, this study has been designed to evaluate in a small controlled clinical trial if the combination of IP₆ + Inositol and traditional chemotherapy will increase efficacy and decrease side effects of chemotherapy, and in particular if the IP₆ + Inositol will be able to improve the quality of life in patients undergoing the treatment for breast cancer.

All 14 patients involved in the study were regularly taking IP₆ + Inositol or placebo during 6 months. Not a single patient interrupted chemotherapy. The average age of life of patients who have taken IP₆ + Inositol was 56.2 years (26-76), while in the group of patients who had taken placebo average age of life was 59 years (42-77).

The average number of platelets before treatment was 229.57 (204-296) × 10⁹/L in a group of patients who were taking IP₆ + Inositol, while after the treatment it was 231.86 (182-322)× 10⁹/L, representing an increase of 2.29 × 10⁹/L platelets. In the control group, the average number of platelets before the treatment was 272.71 (176-525) × 10⁹/L, while after the treatment it was 205.00 (85-357) × 10⁹/L, representing a a drop of 67.71 × 10⁹/L (p = 0.05). Drop in the number of platelets in the control group of patients was statistically significant, while the number of platelets in the experimental group remained the same (Table 4).

In the IP₆ + Inositol group, the red bloood cell counts were 4.23 (3.56-5.22) × 10¹²/L and the hemoglobin level was 127.00 (110-151) g/L before treatment, while after the treatment the erythrocytes were 4.48 (4.08-4.78) × 10¹²/L and the hemoglobin level was 135.86 g L, representing an increase of 0.25 in the number of erythrocytes and 8.86 g/L in the hemoglobin level, although not significant. In the control group of patients the average number of erythrocytes before the treatment amounted to 4.45 × 10¹²/L, and 4.03 × 10¹²/L after the treatment, while the hemoglobin level prior to treatment was 122.00 (103-142) g/L and 119.43 (106-135) g/L after treatment, which represented a decrease of 0.4 in the average number of erythrocytes and decrease of 2.57 in the hemoglobin level. Changes in red blood cell counts and in the hemoglobin levels are not statistically significant for either group. These relations are evident from the Table 4.

Other laboratory parameters that were monitored during the treatment (LDH, AST, ALT, AP, bilirubin, urea, creatinine, and electrolytes) were stable in both groups of patients and there were no deviations from the reference value.

IP₆ has been known for a long time for its beneficial effects, including boosting immune system, preventing kidney stone formation and lowering serum cholesterol [3, 4]. Additionally, IP₆ has shown a significant anticancer effect against different experimental cancers [3–15]. For some time, IP₆ is available as a dietary supplement. Although few case studies in which IP₆ plus inositol was given in combination with chemotherapy clearly showed encouraging data, organized, controlled, randomized clinical studies were never organized [16–18]. Therefore, this study conducted at the Department of Surgery, General Hospital, Zadar on the group of voluntary patients who were treated for breast cancer, is the first study of its kind in the world. From this small clinical testing we concluded that IP₆ + Inositol was able to improve the quality of life of breast cancer patients undergoing chemotherapy compared to control, placebo group with the same histological type of cancer and the therapeutic protocol.

It is difficult to be objective and to numerically express the quality of life of individual patients or groups of patients in order to compare the quality of life of another patient, because it depends on a number of parameters. The European Association for research and treatment of cancer (EORTC) has developed questionnaires for assessing the quality of life of patients which have fallen ill from cancer, and thus tried to compare objectively the quality of life that we utilized. Our results show that patients who were taking IP₆ + Inositol in combination with chemotherapy, had overall statistically significantly better quality of life than patients who were on placebo. Analyzing the answers to questions about the side effects of treatment and symptoms of disease, we have seen that the frequency and intensity of side effects associated with patients who were taking IP₆ + Inositol were statistically significantly lower in comparison to patients who were taking placebo.

Drugs that are implemented in chemotherapy are agressive and have impact to the tumor cells as well as to the cells in the blood. Most patients who are undergoing chemotherapy have some anomalies in their complete blood count, primarily in the number of leukocytes and plateletes. Our results show that patients who have taken IP₆ + Inositol did not show drop in the number of leukocytes and plateletes, on the contrary, these were even slightly increased. A slight increase in red blood cell counts and hemoglobin levels were also noticed in the IP₆ + Inositol group. Tumor markers, liver enzymes, bilirubin, urea, creatinine and electrolytes were not disturbed in either group during the 6-month period of treatment.

Although our clinical study was conducted on a small number of patients, our results confirmed previous observations and clearly demonstrated that IP₆ + Inositol when included in chemotherapy for breast cancer significantly improved patients' quality of life and protected patients from the loss in the number of leukocytes and plateletes [16–18].

The question remains to what extent we can include IP₆ + Inositol in the therapeutic program for breast cancer. The dosage of 6 g daily represents a low dose level of IP₆ + Inositol. Extrapolated from animal data, in the absence of a dose-determination study in humans, the recommended prophylactic dosage of IP₆ + Inositol is 1-2 g/day and a cancer therapeutic dosage is 8-12 g/day [4]. Even though our dosage was low, its efficacy to diminish the side effects of chemotherapy was significant.

Recent phase I study of inositol for lung cancer chemoprevention showed that in a daily dose of 18 g p.o. for 3 months, inositol was safe and well tolerated [21]. Recently it was reported that the combination of beta-(1,3)/(1,6) D-glucan and IP6 was well tolerated and had beneficial effect on hematopoesis in the treatment of patients with advanced malignancies receiving chemotherapy [22]. Although the results of our pilot studies are encouraging, it is necessary to conduct further multicentric clinical testing on a larger number of patients for further evaluation of the impact that IP₆ + Inositol on the quality of life of patients treated from breast cancer.