The Di Bella Method improved survival, objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck

Published on Friday, 25 January 2013

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 neckThe 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)



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.



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

  1. Cancer of the larynx (T1-N0-M0), squamous cell infiltrating tumour involving the anterior 2/3 of the left vocal cord, as for as approx. 1mm the anterior commisure. Complete regression and functional recovery after little more than a year's treatment with DBM. Discontinuation of the treatment for 14 months after hospitalisation for vascular problems and hyperglycemia seizures. Approx. 2 years after discontinuing DBM, recurrence with involvment of the anterior commisure, subcordal and contralateral extension, fixing of left vocal cord, absence of satellite adenopathies and metastates (T3-N0-M0). Resumption of DBM associated with radiation therapy, in complete remission for the last ten years.
  2. Carcinoma of the larynx (T2-N1-M0): vegetative growth of the laryngeal face of the epiglottis, extending to the vocal cords with limitation of mobility. Over 50% regressione after six months of treatment.
  3. Caricnoma of the larynx (T3-N1-M0) [Note]: infiltrating supraglottic tumour, extending to the vocal cords, bilateral anterior commisure with cordal fixity, refused laryngectomy, DBM associated with radiotherapy. Complete response, disease-free for approx. nine years, decease due to vascular problems.
  4. Medullary carcinoma of the thyroid (T3-N3-M1) [Note] with disseminated pulmonary lymph node repetitions, critical and severely declining conditions at the start of DBM, objective response of approx. 50% after 14 months, with evident recovery of performance status.
  5. Papillary carcinoma of the thyroid (T3-N3-M1) [Note] with multiple pulmonary and bone repetitions. More than 1 year after starting DBM, stability of the disease with evident improvement in quality of life.
  6. Papillary carcinoma of the thyroid (T3-N3-M1) [Note], after surgery and treatment with radio-iodine, radiotherapy and chemotherapy, mediastinal lymph node, disseminated bilateral pulmonary and pharolyngeal progression, with extension to the surrounding muscles, dysphagia due to esophageal compression. The patient underwent trachetomy, was discharged with pain therapy in August 2003, in September started DBM with regression almost 50%, good quality of life, resolution of dysphagia. Treatment continued unitl October 2008, deceased due to meningitis, followed by pneumonia.
  7. Squamous cell carcinoma of thr right tonsil (T1-N0-M0) [Note], no adenopathies or metastates, not operated on, treated only with DBM, objective response over 50%, stable for over a year. Good quality of life.
  8. Carcinoma of the righe tonsil poorly differentiated (T1-N0-M0), treated with neoadjuvant DBM, operated on, no surgical latero-cervical removal of lymph nodes, subsequent adjuvant application of DBM. No adenopathies or metastates, disease-free for 10 years.
  9. Sarcoma of the right maxillary sinus (T3-N1-M0), extending inferiorly to the alveolar and palatine bones. Neoadjuvant application of DBM. Non-radical surgery, treated with adjuvant DBM, in remission from 1996 to 2005, widespread recurrence at the end of 2006 (approx. 2 years after completely stopping DBM despite the indications for reduced dose maintenance). Surgery in 2007 and restart of DBM, no metastases, signs of slight local progression. Deceased approx. 1 year ago during revision surgery.
  10. Squamous cellcarcinoma of the esophagus (T2-N0-M0) [Note] localised in the middle 3rd. After 3 months of treatment with DBM improvement in quality of life, progression blocked with stability and recovery of ability of swallow.
  11. Squamous cellcarcinoma of the esophagus (T2-N0-M0) [Note] with poor cervical differentiation, no previous treatment. Evident endoscopic, radiological, subjective and clinical improvement after 10 months treatment, with recovery of ability to swallow and good performance status.
  12. Carcinoma of the esophagus (T3-N3-M1), poorly differentiated, superficially ulcerated with 360° involvement of the 5 distal cemtimetres of the esophagus close to the cardia ventriculi, unoperable. The patient underwent combined chemo-radiotherapi with objective response of approx. 50%. Treatment was stopped due to severe hemorrhagis complications and multiple transfusions were performed. The patient was discharged in June 1995 in very poor conditions with palliative and pain therapyat home. In August 1995 progressione of the disease, in September 1995 start of DBM. The patient is alive and continuing DBM with reduced maintenance doses; disease-free.
  13. Vegetating carcinoma of the rhinopharynx (T3-N2-M0), poorly differentiated with
  14. Adenocystic carcinoma (T4-N1-M1) [Note] of the left parotid gland, homolateral, laterocervical and pulmonary metastases, widespread...
  15. Carcinoma of the rhynopharynx (T3-N2-M0) with flat epithelium, highly undifferentiated and extending from the left tubal border...
  16. Carcinoma of the tongue and floor of the mouth (T3-N1-M0), infiltrating, ulcerative with lesions of the tongue and floor of the mouth...
  17. Ulcerated carcinoma of the right tonsil, with extracapsular extension to satellite adenopathy (T3-N1-M0) [Note]. Started neoadjuvant DBM and immediately after surgery, after less than 1 year reduced the doses continuing with 10mg of melatonin (MLT) and a spoonful of retinoids and Vit. D3 as maintenance therapy. In remission for 11 years.
  18. Carcinoma of the left parotid gland, NAS-G3 (T2-N1-M1), operated on at the age of 11 years for cylindroma of the left parotid and treated with radiotherapy. Recurrence at the age 34 years (2004), radical parotidectomy with homolateral laterocervical removal of the lymph nodes at the 3rd level, followed by chemo-radiotherapy. A few months later, progression extending throughout the pterygoid compartment and posteriorly to the ramus of mandible with functional block of the temporomandibular joint. Disseminated pulmonary mantle progression of the lower right lobe and a 1,7cm posetro-basal nodule in the upper right lobe were also detected. Sub-continuous and intense pain, accentuated by mastication which was extremely difficult. After a few months a chest CT scan showed widespread and massive bilateral pulmonary progression. Started DBM in October 2005 with progressive reduction of the functional damage and pain, and return to work. Instrumental tests showed a subtotal objective response at the site of the primaty lesion and over 50% al pulmonary level. A subsequent chest CAT scan showed the persistence of residual bilateral pulmonary nodules, but the various CT-PET scans did not show any absorption of the radio-compund due to the lack of proliferative activity of the lesions. The patient is continuing the DBM with good prefromance status and still working.
  19. Squamous cell carcinoma of the tonsil G2 (T3-N2-M0). In September 2008, a large, solid and expansive neoformation was detected in the right tonsillar pillar, 3.7 cm along its main axis and extending 7 cm craniocaudally, occupying 3/4 of the oropharynx, with some 2 cm lymph nodes in the cervical homolateral position and other larger ones along the controlateral nervo-vascular axis and in the rear neck triangle on both sides. Surgery was not performed as the patient suffers from post-ischemic dilatory heart disease. The patient started biological DBM in the following month and simultaneously underwent radiation treatment for approx. 30 days. Still following DBM, having achieved complete remission and good quality of life.
  20. Squamous cell maxillary carcinoma (T3-N2-M0) [Note]. 90-year-old patient in whom in May 2010 a lesion was detected which almost completely obliterated the maxillary sinus with complete bone destruction of the floor and of the posterior and lateral wall. Right latero-cervical lymph nodes increased in size (13mm). Due to the extent of the tumoral mass and the patient's age, no conventional surgical or pharmacological treatment was prescribed and the patient followed only biological DBM therapy. Improvement in quality of life and progression blocked. Stable.
  21. Basal cell carcinoma of the lips, extensively infiltrating the muscle planes, with perineural carcinoma (T1-N0-M0). In May 2008 the patient underwent exeresis and again in June due to widening of the resection margins which were focally involved. In August of the same year, the patient started DBM treatment. Currently in complete remission.
  22. Tympano-jugular paraganglioma treated surgically in 1987 with subsequent (2004) bilateral local recurrence (max 8 cm) associated at mediastinic level with 9 cm lesion. Right hemiparesis. Under treatment with DBM since 2006 and it is currently possible to confirm the stability with complete block of progression. Modest quality of life.
  23. Squamous cell infiltrating carcinoma (T4-N2-Mx) localised in the epiglottis and hypopharynx, with latero-cervical and supraclavicular lymph node involvement, diagnosed in 1997. The patient, a well-known actor, refused surgery so as not to compromise his career, and tarted first-line DBM treatment associated with radiotherapy. In complete remission until death due to other causes 6 years later.


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

  • All-Trans Retinoic Acid - Axerophthol palmitate - Betacarotene - Alpha tocopheryl acetate;

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;

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;

Bromocriptin 2.5 mg tablets, one tablet per day, ½ morning and evening.

  • Cabergoline;

Cabergoline 0.5 mg tablets. This can be used with or instead of Bromocriptin, administering ½ tablet twice a week.

  • Dihydrotachysterol;

Dihydrotachysterol, synthetic Vitamin D3, 10 drops before meals together with the retinoid solution 3 times a day.

  • Chondroitin sulfate;

Chondroitin sulfate, one 800 mg sachet morning and evening diluted in water.

  • Cyclophosphamide;

Cyclophosphamide 50 mg tablets, one/two a day.

  • Hydroxyurea;

Hydroxyurea 500 mg tablets, one/two a day instead of cyclophosphamide.

  • Somatostatin;

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;

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).

  • Vitamine C;

Vitamin C, 2–4 grams per day, orally.

  • Calcium;

Calcium, 2 grams per day, orally.



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.



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:

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.


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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