The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck (full PDF)
Abstract
In 23 cases of carcinoma of the head and neck, the combined use of Somatostatin and/or its analogue Octreotide, prolactin inhibitors, Melatonin, Retinoids, Vitamin E, Vitamin D3, Vitamin C, Calcium, Chondroitin-sulphate, and minimal oral doses of Cyclophosphamide (50-100 mg/day) led to a decided increase in survival with respect to the median values reported in the literature for the same tumours and stages, together with an evident improvement in the quality of life, partial or complete objective responses and, in some cases, complete and stable cure with functional recovery.
The rationale and the mechanisms of molecular biology of the treatment are discussed, showing that the treatment has a differentiating, apoptotic, antiproliferative, antiangiogenic and antimetastatic effect, and, unlike chemo- and/or radiotherapy, preserves and enhances the trophism and functionality of organs, tissues and immunitary and antitumoral homeostasis.
This result, achieved without toxicity, demonstrates the efficacy of this biological multitherapy (Prof. Luigi Di Bella's method or DBM) and is in agreement with the positive results already published on the use of the DBM in various neoplastic diseases. We believe it is of use to report these cases to invite greater interest in the possibilities opened up by this biological multitherapy.
Introduction
We present 23 cases of tuomurs of the head and neck which with DBM achieved a decidedly more favourable ratio between toxicity and therapeutic response compared to conventionatl treatments. The degree of toxicity was always low, and in any case transitory and easy to treat. In terms of survival, performance status, and objective responses an evident improvements was achieved with respect the usual therapeutic protocols forseen for theese forms of tumour. The components of the DBM biological treatment and the responses to the DBM treatment are reported.
The rationale of the DBM is briefly described, documenting, with reference to the literature, its scientific basis and pointing out the molecular biology mechanisms of action, the clincal response and the favourable toxicology profile. The diseases treated are all part of the ORL field, even though they differ in histological and immunohistochemical characteristics. Thanks to the constantly better responses compared to the usual treatments, this difference shows the ability of the DBM to effectively interact on the common denominators of cancer: the aimless and uncontrolled proliferation and the mutagenic ability of the neoplastic phenotype. The greates afficafy and response rapidity was observed in cases treated in the initial stage of the disease and not treated with chemo or radioterapy, in which the DBM was applied as first line therapy.
Tumours of the Head and Neck
In the ORL field, no great differences have been observed in the clinical response to mono or multi-chemoterapy (Casciato et al. 2004 and De Vita et al. 1993) that can even temporarily reduce the volume of tumours, the response lasting even less than 2 months.
The various cytotoxic and cytolytic protocols, penalised by their high level of toxicity, have not shown any ability to eradicate tumours nor to increase survivol (Hashimoto et al. 2003; Jacobs et al. 1990; Ensley at al. 1986; Rooney et al. 1985). Not even monoclonal antibodies, which act on tyrosine kinase protein and/or on epidermal growth factor receptors (EGFR) or vascular endothelial growth factor (VEGFR), have allowed any considerable increase in life expectancy, merely marginal imrpovements limited to between a few weeks and 4 months, and in any case penalised by potentially high toxicity. The best result in terms of life expectancy is probably the outcome achieved by the addition of Bevacizumab (trade name Avastin - Side effects) or other monoclonal antibodies to chemoterapy, extending mean general survival by 4 to 5 months. Lapitinib (trade name Tykerb - Side effetcs) inhibits the tyrosine kinase components of the ErbB1 and ErbB2 receptors, often over-expressed also in tumours of the head and neck, but like the other monoclonal antibodies it is unable to significantly increase survival, nor the disease-free interval. In a recent clinical study with a control group, Lapatinib associated with Capecitabine (trade name Xeloda - Side effects) increased the progressione time to 36.9 weeks, with respect to the 19.7 weeks in the group receiving only Capecitabine (p=0.00032), confirming the above-mentioned limits.
In tumours of the head and neck, post-operative adjuvant chemotherapy has no effect on disease-free or averall survival (Khafif et al. 1991; Jacobs et al. 1990). The correct sequence of radiotherapy - surgery - chemoterapy has not yet been defined due to the absence of statistically documented benefits of chemotherapy (Million et al. 1994; Perez et al. 1992). The advantages of combining chemotherapy with radiotherapy are still under assessment, and while on one hand it seems that the percentage of objective responses can be improved, on the other hand this result is penalised by the high degree of morbidity and the decline in quality of life without any increase in terms of mean values of survival (Hashimoto et al. 2003; Vokes et al. 1994; Khafif et al. 1993; Laramore et al. 1992; Perez et al. 1992).
Case series
Note: Cases which have applied to an Italian court to receive DBM free of charge, undergoing assessment by a panel of 3 medical consultants, and on the basis of a merit score, have obtained DBM treatmente free of charge. Thedecisions are based on data documenting the objective response, and clear improvement in the quality of life with DBM!
Drugs included in the DBM
These molecules are mixed in solution form, a formulation that allows maximum bioavailability, in these ratios:
- All-Trans Retinoic Acid 0.5 gr;
- Axerophthol palmitate 0.5 gr;
- Betacarotene 1 gr;
- Alpha tocopheryl acetate 1,000 gr;
The daily dose is based on body weight decimals: an adult weighing 70 kg can take 7 grams of solution 3 times a day.
Melatonin tablets, Prof. Di Bella’s formulation, chemically complexed as follows: Melatonin 12% - Adenosine 51% - Glycin 37%, administered in doses of from 20 to 60 mg per day.
Bromocriptin 2.5 mg tablets, one tablet per day, ½ morning and evening.
Cabergoline 0.5 mg tablets. This can be used with or instead of Bromocriptin, administering ½ tablet twice a week.
Dihydrotachysterol, synthetic Vitamin D3, 10 drops before meals together with the retinoid solution 3 times a day.
Chondroitin sulfate, one 800 mg sachet morning and evening diluted in water.
Cyclophosphamide 50 mg tablets, one/two a day.
Hydroxyurea 500 mg tablets, one/two a day instead of cyclophosphamide.
Somatostatin, peptide of 14 amino acids, 3 mg per day, injected after the evening meal, slowly and subcutaneously or intravenously with a 12-hour timed syringe (evening administration is indispensable since this coincides with the nocturnal peak in GH and GH-dependent growth factors).
Octreotide, peptide with 8 amino acids, in a 1 mg/die vials, with the same administration method as above (alternatively, the delayed-release formulation of Octreotide can be used intramuscularly at the same doses).
Vitamin C, 2–4 grams per day, orally.
Calcium, 2 grams per day, orally.
Conclusions
The biological neuro.immuno-endcrine treatment devised by Prof. Luigi Di Bella (DBM) applied in the cases described above acted by means of a receptorial, differentiating, apoptotic, antiproliferative and antiangiogenic mechanism of action which totally differs from the usual cytolytic therapies. Partial or complete objective responses were slowly and gradually achieved, demonstrating a high level of tolerability and a favourable toxicological profile, in addition to a distinctly better therapeutic response in terms of survival, quality of life and objective response with respect to chemotherapy protocols.
Discussion
Rationale of the treatment
An extensive and in-depth study of the medical-scientific data banks clearly shows a serious discrepancy between the scientific data and the oncological protocols. This is due to the lack of value attributed to differentiating and proaptotic, antiproliferative, antiangiogenic and antimetastatic antitumoral molecules with minimal toxicity and high antiblastic potential such as Somatostatin and its analogues, Melatonin, prolactin inhibitors, retinoids, and Vitamins D3, E and C. The use of 13 Cis-retinoic acid has been surpassed by the greater tolerability and therapeutic manageability of All-Trans Retinoic acid (ATRA), its bioavalaibility, efficay, tolerability and half-life being enhanced in the DBM by its inclusion in a solution with Vit E and other retinoids (in the above mentioned proportions of 0.5g of ATRA, together with 0.5g of Axeroftol Palmitate and 2g of Betacarotene in 1000g of Alpha Tocopheryl Acetate, protecting the retinoids from the high oxidative instability). The regular administration of minimum, apoptotic, non-cytolytic and thus non-mutagenic doses of cyclophosphamide, thanks to its myeloprotective, antidegenerative and trophic action on parenchyma and tissues, of Melatonin (MLT) and of high doses of Vitamine E, Retinoids, Vitamins C and D3, and acid folic eliminated in almost all cases the medullary toxicity of continuous administration for apoptotic purposes of 50-100 mg per day of Cyclophosphamide, allowing a gradual recovery and maintenance af good performance status (Pacini et al. 2011; Di Bella 2010; Di Bella et al. 1979; Di Bella et al. 2006). In the use of DBM, only in a small percentage of cases previously undergoing massive doses of chemo- or radiotherapy with significant medullary toxicity, might it be appropriate to reduce the dose of cyclophosphamide to 50 mg and to use erythorcyte and granulocyte growth factors. This does not compromise the effect of the cure but merely delays the apoptoticresponse to which all the other components of the DBM contribute synergically and factorially.
Loss of differentiation and proliferation are common denominators of all tumors, albeit to different extents. The ubiquitary receptorial expression of Prolactin (Ben-Jonathan et al. 2002; Hooghe et al. 1998) and of GH (Lincoln et al. 1998; De Souza et al. 1974) represent one of the aspects of the direct and generalized mitogenic role of these molecules.
Cellular proliferation is closely dependent on Prolactin, GH, the main growth factor, and on the GH-dependent mitogenic molecules which it positively regulates, such as EGF (Epidermal Growth Factor), FGF (Fibroblastic Growth Factor), HGF (Hepatocyte Growth Factor), IFG1-2 (Insulin-like Growth Factor 1-2), KGF , NGF (Nerve Growth Factor), PDGF (Platelet-Derived Growth Factor), VEGF (Vascular Endothelial Growth Factor) and TGF (Transforming Growth Factor), as well as on growth factors produced by the gastrointestinal system, such VIP (Vasoactive Intestinal Peptide), Cholecystokinin, Gastrin, and probably on P substance.
Both physiological and tumour cell proliferation are triggered by the same molecules used by the tumour cells to an exponential extent with respect to the healthy cells. Biological antidotes of GH, such as Somatostatin and its analogues, not only reduce the expression and transcription og highly mitogenic growth factors, such as IGF1-2 (Schally et al. 2003; Cascinu et al. 2001; Schally et al. 2001), but extend their negative regulation to the respective receptors with evident antiproliferative and antiangiogenic effects (Bocci et al. 2007; Florio et al. 2003; Albini et al. 1999; Szepesházi et al. 1999; Barrie et al. 1993).
It is known that the GH-IGF1 axis has a determining effect on the biological development of a tumour. The IGFRs respond mitogenically to IGF. The suppressing effect of SST and its analogues on the serum levels of IGF1 is both direct, through inhibition of the IGF gene, and indirect, through suppression of GH and thus of its hepatic induction of IGF1. Essential phases of angiogenesis (the main stage of tumour progression), such as GH-induced monocyte chemotaxis, interleukin 8, endothelial Nitric Oxide Synthase, Prostaglandin 2 and growth factors that are essential and synergic for the development of angiogenesis, such as VEGF, TGF, IGF1, FGF, HGF and PDGF, are all negatively regulated by Somatostatin and its analogues (Arena et al. 2007; Sall et al. 2004; Florio et al. 2003; Jia et al. 2003; Cascinu et al. 2001; Watson et al. 2001; Turner et al. 2000; Vidal et al. 2000; Albini et al. 1999; Barrie et al. 1993; Wiedermann et al. 1993). The inhibition of angiogenesis, induced by SST, is sinergically reinforced by the other components of DBM, such as Melatonin (Di Bella 2010; Di Bella et al. 1979; Di Bella et al. 2006; Lissoni et al. 2001), Retinoids (McMillan et al. 1999; Majewski et al 1994; Hassan et al. 1990), Vitamin D3 (Kisker et al. 2003; Mantell et al. 2000), Vitamin E (Neuzil et al. 2002; Tang et al. 2001; Shklar et al. 1996), Vitamin C (Ashino et al. 2003), prolactin inhibitors (Turner et al. 2000), and components of the extracellular matrix (Liu et al. 2005; Ozerdem et al. 2004). The components of DBM also extend their synergic action to the amplification of the cytostatic, antiproliferative and antimetastatic effects of Somatostatin:
A causal relationship has been demonstrated between the receptorial expression of GH and tumour induction and progression, by histochemically, detecting much higher concentrations of GHR in the tumour tissues compared to physiological tissues, and by showing the potent mitogenic role of GH with a dose-dependent proliferative index (Lincoln et al., 1998). This role os both direct, i.e. receptorial, and indirect, through GH-dependent (Friend 2000) induction of the hepatic expression of IGF1 and of the other GF. We believe it is worth insisting on the determining role of the GH-IGF1 axis in the biological behaviour of many tumours (Hagemeister et al. 2008; Murray et al. 2004). IGF1 receptors which respond mitogenically to the ligand have been identified in an extremely high and subtotal percentage of various neoplastic cells. Somatostatina exters its antiblastic activity both directly on the tumour cells (Lee et al. 2008), and indirectly, by suppressing the GH, on which the secretion of IGF1 depends as well as by inhibiting, the expression of the IGF1 gene (Hagemeister et al. 2008; Durand et al. 2008; Florio 2008; Murray et al. 2004; Sall et al. 2004; Barnett et al. 2003; Schally et al., 2001; Schally et al. 2003).
Several studies have also been published on the inhibitory activity of SST on another powerful mitogenic growth factor, EGF, through a number of mechanisms:
dose-dependent inhibition of the tyrosine phosphorylation induced by the activation of EGFR by EGF (Durand et al. 2008; Lee et al. 2008; Mishima et al. 1999; Pawlikowski et al. 1998);
reduction of EGFR in the tumour cells (Szepesházi et al. 1999);
reduction of expression of EGF (Held-Feindt et al. 1999);
suppression of the plasma concentrations of EGF (Cascinu et al. 2001);
Mitogens produced by the gastrointestinal system, such as VIP, CCK and G, are strongly inhibited by somatostatin and/or octreotide (Kath et al. 2000), the efficacy of which is reinforced through a synergic factorial mechanism with the other components of the DBM. The literature has therefore confirmed the antineoplastic, differentiating and antiproliferative, antiangiogenetic and antimetastatic mechanisms of action of all the components of the DBM.
The DBM biological treatment led to a net improvement in performance status, and, with respect to the chemotherapy, at all stages it increased the mean survival values reported in the literature in the same tumours and stages. This is confirmed by the results published in Cancer Biotherapy, regarding the application of the DBM in stage 3 and 4 non-small-cell-lung cancer (Norsa et al. 2006; Norsa et al. 2007), in low-grade non-Hodgkin's lymphoma (with the worst prognosis) (Todisco et al. 2001) and in breast cancer (Di Bella 2008; Di Bella 2010).
As the DBM is a biological treatment, it does not, unlike cytotoxic therapy, achieve rapid decreases in volume: instead it leads to slow and gradual objective responses by activating the above-mentioned receptorial targets, without any significant toxicity. Unlike chemotherapy, it does not induce but inhibits changes, oxidative reactions, and the increase of free radicals or immunitary depression, also enhancing the trophism and functionality of epithelia, endothelia, parenchya and tissues of the extracellular matrix, triggering antiblastic homeostasis and the bilogical conditions that allow physiological life to prevail over neoplastic biology. It is, therefore, reasonable to suggest that early application of this method as the first-line therapy in a patient who has not been debilitated by the toxic, mutagenic and immunodepressive effects of chemo-radiotherapy could achieve decidedly better results. We believe it is useful to report these cases in order to invite a greater interest and more in-depth atudies on the possibilities opened up in ocnology by the immuno-neuroendocrine, biological and receptorial treatment of the DBM.
The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck