The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer

Background: Breast cancer is still the leading cause of death in women worldwide. Study question: Our purpose is to improve survival, objective response and quality of life with a non-toxic biological therapy. Study design: The DBM (Di Bella Method) with MLT (Melatonin), Retinoids, solubilized in vitamin E, D3, and C, Folates, proteoglycans and calcium, has a differentiating, cytostatic, anti-angiogenic, immune-modulating, factorially synergic effect, simultaneously reinforcing the functions which physiology considers to be essential for life. With Somatostatin/Octreotide, prolactin and estrogen inhibitors, DBM has an antiproliferative, antiangiogenic and antimetastatic effect. These molecules govern negatively pituitary secretions like GH-PRL, whose mitogenic properties are enhanced by the combination of ovarian hormones such as estrogen. The negative regulation of GH extends to IGF-1, EGF (Epidermal Growth Factor), VEGF (Vascular Endothelial Growth Factor), and GHdependent growth factors. The DBM (Di Bella Method) uses minimal metronomic apoptotic, non-cytotoxic and non-mutagenic doses of cyclophosphamide. The tolerability of which is enhanced by MLT and by the vitamins included in the DBM. We report a retrospective observational study with 5-year follow-up, carried out on 297 patients affected by breast cancer and treated with the Di Bella Method biological therapy. Results and conclusion: complete and stable objective responses without cytolytic chemotherapy, in some cases even without surgery or radiotherapy, with a generalized improvement in quality of life and no significant and/or prolonged toxicity. The most important 5-year survival rate was 69.4% at stage IV cancer versus 26.3% reported by the National Cancer Institute.


Introduction
Breast cancer is usually treated with surgery, which may be associated singly or in various forms with chemotherapy, estrogen block, radiotherapy and selective monoclonal antibodies for epidermal growth factor receptors (EGFR). Breast cancer is the most frequent form of cancer in women and the leading cause of death in women.

Enrolment criteria of 297 cases of breast cancer
Only patients with a histological diagnosis of breast cancer and disease characteristics that could be measured according to the Response Evaluation Criteria in Solid Tumors (RECIST) were enrolled [17].
The study included 297 patients suffering from breast cancer and each one of these were subject to blood chemistry, hystological and immunoistocheminal tests expected for this pathology.
The patients were divided into three groups according to the stage of their breast cancer at the start of the treatment.
• The first group, Regional Breast Cancer, consisted of patients whose tumor was limited to a single anatomical district.
• The second group, Local Breast Cancer, consisted of patients whose tumor had spread to the lymph nodes.
• The third group, Advanced Breast Cancer, consisted of patients with metastases.
The DBM was administered in one of the following forms: 1) First-line treatment, for patients who had previously undergone only surgery 2) Second-line treatment, for patients who had previously followed traditional adjuvant oncological protocols for a maximum of 6 months.
3) Last-resort treatment, for patients with stage IV cancer who had undergone repeated multi-chemo/radiotherapy treatments for more than a year.
The objective clinical responses were statistically classified in three groups: REGRESSION, STABILITY, PROGRESSION. Among the effects of the DBM, toxicity and quality of life were also evaluated. RELATIVE survival was also assessed, i.e. the percentage of patients still alive 5 years after the diagnosis of breast cancer, compared to the average survival of a group of women of the same age, from the same geographical area, and in good health. This last index was then compared with the results published by the National Cancer Institute (Figure 1 statistical analysis of cases by stage), the leading American agency for the collection and management of data relative to cancer patients ( Figure 1).

Enrolment criteria 40 cases of breast cancer-Sub-analysis
A sub-analysis is setup with only 40 cases, treated with DBM in Exclusive Therapy. In the present study only patients with an Eastern Cooperative Oncology Group (ECOG) status 2 were diagnosed with histologic diagnosis of breast cancer and measurable disease characteristics in accordance with the Solid Tumors Response Evaluation Criteria (RECIST) [17]. Another requirement for enrollment was the absence of standard therapeutic regimens (surgical interventions, polycotherotherapy, radionuclide therapy, monoclonal antibodies), and to accept, with prior informed consent, the administration of biological therapy as a first-line treatment. The 40 cases are classified according to the type of response received during the observation period (according to the RECIST criteria): • OVERALL RESPONSE=CR(Complete) -PR(Partial) -SD (Stable Disease)-PD (Progressive Disease) • DFS=Disease-Free Survival • PFS=Progression-Free Survival

Therapeutic treatment
All the patients received a daily combination of Somatostatin/ octreotide, Melatonin, Retinoids solubilized in Alpha Tocopherol Acetate, dopaminergic agonists, estrogen inhibitors and minimal doses of cyclophosphamide.
• Somatostatin at gradually increasing doses (1 mg for the first 7 days, increasing 1 mg for week, to 3 mg at day 21).
• Tetracosactide acetate (0.25 mg) added every other day to the syringe with somatostatin, compatibly with pressure and glycemia.
• Cabergoline orally with the main meal, 1 mg (equal to 1\2 tablet) twice a week.
• Cyclophosphamide (50-100 mg) orally, variable dosage: start with 1 tablet with the main meal for 1 week, then 1 tablet in the morning and the evening one day and the next day just in the evening.
• Hydroxyurea 500-1000 mg/day; replace with Endoxan if not tolerated or if cerebral metastases are present due to the ability of hydroxyurea to pass through the blood-brain barrier.
• Ascorbic Acid (Vit C) orally: 1/2 teaspoon (4 gr) in a glass of water during the midday and evening meals together with: • Calcium lactate gluconate +calcium carbonate equal to 1000 mg of calcium, half a sachet in the same glass.
• Chondroitin sulfate (500 mg) one tablet in the morning, at midday and in the evening, with meals.
• Calcium levofolinate one 22 mg tablet a day.
• Ursodeoxycholic acid (UDCA) 300 mg to contrast the choleretic and cholagog inhibition of the SST (Somatostatin) and/or octreotide.
• Taurine 1500-2000 mg/day when necessary, to improve cardiac and hepatic function.
Therapeutic treatment has been administered continuously, even after complete remission, and its effects are appropriately and consistently monitored over time, through chemotherapy and with the aid of instrumental diagnostics.
As long as the tumor is in progress, the therapy should be given without any variation, or with the possible changes that may be made on the course, and only after obtaining complete remission over time can be appropriately reduced in a very gradual manner until reaching a "maintenance" therapeutic threshold, also calibrated on the basis of individual individual staging and histological features. Somatostatin was administered subcutaneously by means of a timed 10-hour syringe, taking into account the short half-life (3 minutes) and concurrent GH nighttime peak.

Evaluation of safety and toxicity
For the toxicity evaluation, only the side effects that could have been due to this specific treatment were considered (degrees of correlation: possible, probable or certain, expressed as absolute frequency (n), relative frequency (%), and 95% confidence interval (CI), as described by the National Cancer Institute (NCICTC) criteria (http://www.eortc.be/services/doc/ctc/). 1 All patients therefore gave their informed consent to participate in the study.
These phenomena were the only ones observed, and generally there was a subsequent, progressive and gradual adaptation and improvement within a few weeks. A reduction, delay or temporary suspension of treatment due to toxicity has been necessary in patients with leucopenia (cyclophosphamide suspension until recovery of leukocyte counts) and in cases of severe gastrointestinal effects (Somatostatin).
Such circumstances, though limited, have occurred much more frequently and more clearly, especially in patients with critical stage, advanced especially if chemotherapy/radiotherapy/ monoclonal antibodies are pre-treated.
There have been no deaths associated with the treatment. Table 1 shows the clinical result in terms of REGRESSION, STABILITY and PROGRESSION of the disease. The best clinical outcomes were achieved, as expected, in the first group of patients, those with Regional Breast Cancer, with a clinical response of regression always greater than 80%. In the second group of patients with locally advanced cancer, the most promising results were seen with the DBM administered in the second-line form, where 87.5% of patients achieved regression. As regards the patients with advanced stage breast cancer, both the first and second-line forms of treatment achieved regression in 20% of cases, while the success rate was only 10% in patients who had repeatedly undergone multiple sessions of chemo-and radiotherapy, were no longer responsive and were generally in critical conditions before starting the DBM (Table 1).

Results and Discussion
In order to compare our results with NCI data, a preliminary 1 Note: This is a study on the combined use of drugs that have already passed all the reliability and anticancer tests. Thus, since all the drugs have been extensively tested and their use has been approved by the international health organizations, and here they are merely used in a new combination, it was decided not to submit the study protocol to an ethics committee. The study was carried out in accordance with The Good Clinical Practices directives and the Declaration of Helsinki.

Translational Biomedicine ISSN 2172-0479
Relative Survival is obtained for every stage and reported in Table  2. In Figure 2 is shown an evaluation of the percentage of women still alive 5 years after diagnosis, treated with the DBM, versus data on official oncological treatment reported by the National Cancer Institute. DMB method appears more efficient for the treatment of distant tumor in particular (Table 2) (Figure 2).
By identifying Progressive Survival Survival (PFS) -Free Disease Survival (DFS) and Global Response (OR) as the primary endpoint, the following summary was elaborated (Table 3). Comparative graphics of breast cancer survival 5 years after diagnosis between DBM oncological treatment and official oncological treatment reported by Nation Cancer Institute. The statistic evaluation depends from the type of tumor (localized, regional and distant).

Figure 2
Identity

Conclusion
The DBM therapy proposes to counter the progression of the neoplastic phenotype by: a) Inhibiting the neoplastic proliferation by cell processes of apoptosis/necrosis and depletion of hormones and cell growth factors; b) Countering the marked mutagenic tendency by direct activation of the DNA repair systems, and by epigenetic cell programming.
c) Blocking neoplastic progression by reducing the formation of new blood vessels (Neoangiogenesis-Lymphoangiogenesis) and of cell motility phenomena (migration), essential for neoplastic dissemination d) Reinforcing natural defense mechanisms against neoplastic aggression (natural and acquired immunity and improvement of vital functions).
In cases of breast cancer monitored at 5 years, the DBM biological multitherapy significantly improved quality of life, objective response and survival with respect to the same stages of breast cancer treated with conventional oncological protocols. The negative regulation of the main interactive mitogen systems -GH-GF-Prolactin-Estrogen -by means of somatostatin and analogues, D2R agonists, aromatase inhibitors, analogues of LH-FSH, together with the differentiating, cytostatic, homeostatic action of Retinoids, Vitamins E, D3, and C, Folates, Ca, MLT (Melatonin), Proteoglycans with factorial interaction, without significant toxicity, made this result possible [18][19][20][21][22]. We report these therapeutic results to improve the prognosis of tumors in general and of breast cancer in particular. Breast cancer remains the leading cause of death worldwide in women, demonstrating the deficiencies of the current measures of cancer prevention and treatment and the need to overcome these serious limits of oncological therapy by taking advantage of still underestimated scientific evidence.