- Di Bella's tetralogy
- Di Bella regimen
For Patients & Caregivers
Bottom Line: Di Bella Multitherapy, based on an unconfirmed theory, has been proven ineffective as a cancer treatment.
The Di Bella Multitherapy was developed by the Italian physician Luigi Di Bella in the 1990s. This treatment was very popular in Italy, despite the fact that clinical trials have not shown that it works. It is based on the unconfirmed theory that cancers, especially lymphomas and leukemias, are stimulated to grow by the hormones prolactin and growth hormone. By giving low-dose chemotherapy along with treatments that would lower prolactin and growth hormone levels, Di Bella reasoned that his therapy could help stimulate the body’s self-healing without the toxicity of conventional chemotherapy. He has not provided sufficient evidence, however, to back up these claims. The Di Bella Multitherapy includes:
- Somatostatin, an inhibitor of growth hormone
- Melatonin, a hormone that mediates the sleep-wake cycle and is also an antioxidant. Laboratory and animal studies of melatonin suggest a possible anti-cancer activity, but no studies in humans have shown such an effect. See melatonin monograph for additional information.
- Bromocriptine, which inhibits the secretion of prolactin from the pituitary gland.
- A solution of retinoic acid, vitamin A, beta carotene, and vitamin E. These retinoids are antioxidants, and independently have shown benefit in clinical trials of promyelotic leukemia and cutaneous T-cell lymphoma.
Di Bella’s theory about cancer has not been confirmed, and the clinical trials that have been performed with this therapy do not provide any support for it.
- To treat Alzheimer’s disease
No scientific evidence supports this use.
- To treat cancer
Clinical trials do not support this use.
- To treat Lou Gehrig’s disease (amyotrophic lateral sclerosis)
There is no evidence to support this claim.
- To treat multiple sclerosis
No scientific evidence supports this use.
- To treat retinitis pigmentosa
This use is not backed by research.
A group of Italian researchers used a therapy similar to Di Bella’s to treat 20 patients with low-grade stage III or IV non-Hodgkin’s lymphoma (NHL). Some of the patients had already used conventional cancer treatments, while others had not. After two years, seven patients had a complete response. However, patients who had undergone conventional therapy more recently responded better to this “Di Bella-like” multitherapy, so it is hard to tell which therapy exerted the positive effects. Although these results appear promising, only 20 patients were treated, so it is difficult to know if these results are merely by chance or if the same effects would be seen in the general population.
- You are taking opioid mediation (such as percocet, codeine, oxycodone, morphine, or methadone) (Somatostatin can lessen or eliminate their effects).
- You are taking immunosuppressants (such as cyclosporine or tacrolimus) (Bromocriptine might inhibit the metabolism of these medications in the liver, leading to higher-than-normal blood levels that can cause toxicity).
- You are taking macrolide antibiotics (These can worsen the side effects of bromocriptine).
- You are taking efavirenz (This medication can increase the effect of bromocriptine).
- You are taking protease inhibitors (Bromocriptine can heighten their effect).
- You are taking anti-hypertension drugs (Bromocriptine can lower blood pressure even further).
- You are taking nifedipine (Melatonin, when taken at the same time, can cause high blood pressure and increased heart rate).
- You are taking fluvoxamine (This medication can increase blood levels of melatonin, resulting in sedation).
- You are taking digoxin (Cyclophosphamide decreases the effects of digoxin).
- You are taking St. Johns wort (This herb can decrease the effect of cyclophosphamide).
For Healthcare Professionals
Questionable alternative therapy comprised of somatostatin, melatonin, bromocriptine, a solution of retinoids, and low doses of cyclophosphamide or hydroxyurea. Physiologist Luigi Di Bella developed the regimen and promotes it as an effective treatment for cancer, retinitis pigmentosa, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. Treatment is tailored to the individual patient, and purportedly stimulates the body’s self-healing without the toxicity of conventional chemotherapy.
Di Bella multitherapy (DBM) is based on the theory that growth hormone (GH) and prolactin are involved in neoplastic growth. Somatostatin and its analog octreotide inhibit GH and IGF-1 secretion in humans (1), while bromocriptine is a prolactin inhibitor (6). This treatment was very popular in Italy in the late 1990s as Di Bella claimed he cured thousands on an outpatient basis and physicians in other countries, such as Canada, also prescribed it. DBM was highly publicized and politicized in Italy, raising the issue of “freedom of treatment” for patients who could not afford the expensive regimen. In response, local judges ordered that somatostatin be added to the list of effective reimbursable medications (21)(22), and the Italian National Institute of Health supported 11 separate open-label uncontrolled phase II studies of 8 different cancers, organized by Di Bella and the National Cancer Advisory Committee (20). These trials found no complete responses (23)(24), 0.8% partial response rate, and considerable toxicity (12)(18). However, an uncontrolled study of 20 patients with late stage non-Hodgkin’s lymphoma had a 70% response rate with a similar regimen (6).
Adverse effects include increased pain at tumor site, nausea, vomiting, anorexia, diarrhea, and somnolence (6). Somatostatin may reduce or eliminate the efficacy of painkillers (e.g., methadone, morphine) (11).
The Di Bella Multitherapy is based on the theory that growth hormone (GH) and prolactin are involved in neoplastic growth, particularly in lymphomas and leukemias. The following components have been studied, but their combined activities and at the Di Bella doses are unknown.
Somatostatin inhibits growth hormone (GH) secretion. Its synthetic analog, octreotide, shows antineoplastic activity in vitro and in vivo, and is used clinically for the treatment of acromegaly and neuroendocrine tumors. Their biological effects are mediated via high affinity plasma membrane receptors that are found throughout the body and on many human tumors. Clinical studies show a reduction in serum IGF-1 and IGF-1 gene expression after treatment with octreotide (1). Somatostatin and analogs also enhance secretion and expression of IGF-binding protein-1, which negatively regulates plasma IGF-1, while inhibiting mitogens and secretion of gastrointestinal hormones implicated in tumor growth. Somatostatin analogs also show immune-modulating activity in vitro and inhibit angiogenesis and directly induce cell growth arrest and apoptosis in vivo and in vitro (7).
Melatonin is a free-radical scavenger and displays anti-proliferative effects on various cancer cell lines in vitro, but no human studies show evidence of anti-tumor activity. Melatonin shows antimyelodysplastic activity and reduces bone marrow toxicity of chemotherapeutic agents in animal models. See melatonin for additional information (2)(3)(4)(5).
Bromocriptine is a dopamine agonist and prolactin inhibitor. Prolactin stimulates growth of lymphomas in vivo and in vitro, and prolactin receptors are present on normal and neoplastic lymphoid cells.
Retinoids act as antioxidants and immunostimulants, cause cell growth arrest in B-cell lymphomas in vitro, and have shown benefit in trials of promyelotic leukemia and cutaneous T-cell lymphoma.
ACTH receptors can be found on T and B lymphocytes and ACTH has been seen to depress lymphocyte blastogenesis and modulate NK cell activity in vitro (6).
No formal pharmacokinetic studies have been performed on the Di Bella multitherapy.
Somatostatin peptides have a short half-life of approximately 1 minute, while its synthetic analog octreotide exhibits a half-life of 80 to 100 minutes. Octreotide plasma levels are proportional to the dose administered intravenously or subcutaneously. Peak plasma levels occur after 30 minutes, and octreotide displays linear pharmacokinetics. Octreotide is found mainly in the plasma, bound to lipoprotein and albumin. Continuous infusion of somatostatin is necessary to maintain desired plasma concentrations (7).
Melatonin is absorbed following oral administration, but undergoes extensive first pass metabolism. Melatonin is metabolized rapidly in the liver to hydroxy metabolites, possibly by cytochrome P450 isoenzymes 1A2 and 2C19. Oral bioavailability is estimated to be 15% for the parent compound. Elimination half-life is approximately 45 minutes with a total body clearance of 10 hours for a 3 mg dose (9)(10).
Approximately 28% of oral bromocriptine is absorbed through the GI tract, and only 6% reaches systemic circulation after extensive first-pass metabolism. Peak plasma levels are attained in 1-1.5 h, where 90-96% of bromocriptine is bound to serum albumin. Bromocriptine does not distribute appreciably into erythrocytes. Metabolism takes place in the liver by cytochrome P450IIIA isoenzymes and excretion occurs principally in the feces via biliary elimination, with a small amount in the urine. Elimination time is 4-4.5 h for initial phase and 45-50 h for terminal phase (6).
Reported (DBM): Increased pain at tumor site in advanced cancer patients; somnolence, diarrhea, nausea, vomiting, anorexia, grade I hyperglycemia, ankle-feet edema; anemia and thrombocytopenia were noted in trials using cyclophosphamide (12).
Case Report (DBM): A breast cancer patient with lung and liver metastases developed acute myeloid leukemia, which her physicians associate with chronic cyclophosphamide use, after treatment with Di Bella therapy. Her leukemia led rapidly to death due to cerebral hemorrhage (13).
Common (Somatostatin): Gastrointestinal complaints (diarrhea, vomiting, and nausea), cholelithiasis, and effects on glucose metabolism (6).
Toxicity (Somatostatin): Pain at injection site, allergic reactions, hair loss, a few cases of reversible hepatic dysfunction (11).
Reported (Bromocriptine): Hypotension, peripheral vasoconstriction, dyskinesias, fatigue, nausea, vomiting, postpartum MI, headache, dizziness, psychosis (6).
Reported (Melatonin): Drowsiness, alterations in sleep patterns, altered mental status, disorientation, tachycardia, flushing, pruritus, abdominal cramps, headache, hypothermia (6)(8)(14)(15).
Opiates: Somatostatin has opioid antagonist properties and has been observed to decrease or eliminate the analgesic effects of methadone and morphine in advanced cancer patients requiring pain relief (11).
Immunosuppressants (e.g., Cyclosporine, Tacrolimus): Bromocriptine is thought to inhibit the cytochrome P450IIIA isoenzyme family and reduce the metabolism of drugs such as cyclosporine and tacrolimus, increasing the risk of toxicity from these medications.
Macrolides: Potentiate adverse effects of bromocriptine.
Efavirenz: Increases the effect of bromocriptine.
Protease inhibitors: Bromocriptine may potentiate their effect.
Anti-hypertension drugs: Bromocriptine may have an added hypotensive effect.
Bromocriptine is inhibited by drugs that increase prolactin concentration (e.g., amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine) (17).
Nifedipine: Concomitant administration of melatonin and nifedipine has resulted in elevations in blood pressure and heart rate (16).
Fluvoxamine: Fluvoxamine may increase circulating plasma levels of melatonin resulting in sedation (9).
Succinylcholine: Cyclophosphamide potentiates the effect of succinylcholine.
Digoxin: Cyclophosphamide decreases the effect of digoxin.
St. Johns Wort: May decrease the effect of cyclophosphamide.
Todisco M, Casaccia P, Rossi N. Cyclophosphamide plus somatostatin, bromocriptine, retinoids, melatonin and ACTH in the treatment of low-grade non-Hodgkin’s lymphomas at advanced stage: results of a phase II trial. Cancer Biother Radiopharm 2001;16:171-7.
A prospective phase II evaluation of a multi-drug therapy similar to the Di Bella regimen in 20 patients with low-grade stage III or IV non-Hodgkin’s lymphoma (NHL). Patients received 75 mg/day oral cyclophosphamide in split doses; 1.5 mg/day subcutaneous somatostatin over 8 hours or 0.5 mg/day octreotide in a single injection; 2.5 mg/day bromocriptine in split doses; 5 mg all-trans retinoic acid, 5000 IU vitamin A palmitate, and 20 mg/day beta-carotene; 20 mg/day melatonin in split doses; 1 mg/week ACTH intramuscularly. After an average of 21 months follow-up, 14 patients had stable disease, 7 had a complete response. Response to therapy was found to be dependent upon the type of pervious therapy and time from last treatment (patients >/= 1.5 months refractory to single agent or combination chemotherapy did not show response). Side effects included diarrhea, nausea, vomiting, anorexia, drowsiness, hyperglycemia and edema.