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Di Bella Multitherapy

Common Name

Di Bella's tetralogy, DBM, Di Bella regimen

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Clinical Summary

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).

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Purported Uses
  • Alzheimer's disease
  • Cancer treatment
  • Lou Gehrigs Disease
  • Multiple sclerosis
  • Retinitis pigmentosa
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Constituents
  • Somatostatin
  • Solution of retinoic acid, vitamin A, beta carotene, vitamin E
  • Melatonin
  • Bromocriptine
  • Variable: Adrenocorticotropic hormone (ACTH) and low oral doses of cyclophosphamide and hydroxyurea
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Mechanism of Action

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 of this therapy have been studied thoroughly, but their combined activity and at the Di Bella doses is 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).

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Pharmacokinetics

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).

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Adverse Reactions

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).

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Herb-Drug Interactions

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.

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Literature Summary and Critique

Italian Study Group for the Di Bella Multitherapy Trials. Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): results of phase II trials in Italy. BMJ 1999;318:224-8.
A set of 11 independent, uncontrolled, open-label phase II studies of 395 patients with 8 types of cancers at 26 Italian hospitals. Main end point was objective tumor response. Cancers were refractory to or ineligible for standard treatment. Average treatment time was two months. No patient had a complete response; partial response was seen in one NHL, one breast cancer, and one pancreatic cancer patient. Adverse effects, including diarrhea, vomiting, nausea, and somnolence, were reported in 40% of patients. A phase III trial was not warranted, as only a 0.8% response rate and considerable toxicity were found. Di Bella and his followers criticized the study for its biased selection of terminally ill patients, and its variance from Di Bella's protocol. It has also been criticized for hasty, flawed design and lack of randomization

Buiatti E, et al. Results from a historical survey of the survival of cancer patients given Di Bella Multitherapy. Cancer 1999;86:2143-9.
A retrospective evaluation of survival in cancer patients treated with the Di Bella Multitherapy (MDB) between 1971-1997. Cases were searched in cancer registries and matched by site (but not stage), gender, age, and period of diagnosis to cases from Italian cancer registries to compare survival. Five-year survival was significantly lower than control cases in patients with childhood leukemia, breast carcinoma, and adult leukemia, and for all patients combined. 27 patients survived 10 or more years from diagnosis, and 20 from first MDB treatment; all were previously treated with conventional cancer therapies. This study had small site-specific groups, lack of matching by stage, variability of treatment between patients, and studied only a small percentage of Di Bella's patients (248 of 1523).

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.

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References
  1. Bousquet C, at al. Antiproliferative effects of somatostatin and analogs. Chemotherapy 2001;47(suppl 2):30-9.
  2. Xi SC, et al. Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Prostate 2001;46:52-61.
  3. Cos S, Garcia-Bolado A, Sanchez-Barcelo EJ. Direct antiproliferative effects of melatonin on two metastatic cell sublines of mouse melanoma (B18BL6 and PG19). Melanoma Res 2001;11:197-201.
  4. Blask E, Wilson ST, Zalatan F. Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. Cancer Res 1997;57:1909-14.
  5. Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med 2000;225:9-22.
  6. 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.
  7. Scarpignato C, Pelosini I. Somatostatin analogs for cancer treatment and diagnosis: an overview. Chemotherapy 2001;47(suppl 2):1-29.
  8. Sack RL, Lewy AJ, Hughes RJ. Use of melatonin for sleep and circadian rhythm disorders. Ann Med 1998;30:115-21.
  9. Hartter S, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther 2000;67:1-6.
  10. DeMuro RL, et al. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000;40:781-4.
  11. Ripamonti C, et al. Can somatostatin be administered in association with morphine in advanced cancer patients with pain? Ann Oncol 1998;9:921-4.
  12. Italian Study Group for the Di Bella Multitherapy Trials. Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): results of phase II trials in Italy. BMJ 1999;318:224-8.
  13. Sacco C, Patriarca F. Acute myeloid leukemia following chronic low-dose cyclophosphamide for metastatic breast cancer. Tumori 2001;87:101-3.
  14. Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Ann Med 1998:30:122-30.
  15. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
  16. Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol 2000;49:423.
  17. Von Bahr C, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects - an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol 2000;56:123-7.
  18. Mullner M. Di Bella's therapy: the last word? The evidence would be stronger if the researchers had randomised their studies. BMJ 1999;318:208-9.
  19. Remuzzi G, Schieppati A. Lessons from the Di Bella affair. Lancet 1999;353:1289-90.
  20. Traversa G, et al. The unconventional Di Bella cancer treatment. A reflection on the Italian experience. The Italian Study Group for the Di Bella Multitherapy Trials. Cancer 1999;86:1903-11.
  21. Simini B. Somatostatin fever mounts in Italy. Lancet 1998;351:428.
  22. Abbott A. Controversial cancer drug wins local approval in Italy. Nature 1998;391:217.
  23. Italian Study Group for the Di Bella Multitherapy Trials. Evaluation of an unconventional cancer treatment (the Di Bella multitherapy): results of phase II trials in Italy. BMJ 1999;318:224-8.
  24. Buiatti E, et al. Results from a historical survey of the survival of cancer patients given Di Bella Multitherapy. Cancer 1999;86:2143-9.
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How It Works

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.

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Purported Uses
  • 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.
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Research Evidence

Cancer treatment:
In response to public demand, the Italian government sponsored a set of 11 clinical trials in which 395 patients with various types of advanced cancer (non-Hodgkin's lymphoma, chronic lymphoid leukemia, stage IV breast cancer, metastatic non-small cell lung cancer, pancreatic cancer, advanced colorectal cancer, metastatic or recurrent squamous cell head, neck, or esophageal cancer, recurrent glioblastoma, or advanced solid tumors) volunteered to take the Di Bella therapy. Almost all of the patients had previously undergone ineffective chemotherapy or radiation therapy. There was no control group in this study, so the results from the Di Bella therapy could not be compared to how patients would fare with no treatment at all (placebo group) or with conventional cancer treatment. The patients were treated with the multitherapy for up to eight months (average, two months), after which time 219 patients had died and only three patients showed a partial response (tumor shrinkage) for less than one year. None of the patients had a complete response to the therapy, but many reported side effects. These results do not support the use of this therapy for treating cancer.

Non-Hodgkin's Lymphoma:
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, there are a number of problems to consider. First, 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. Secondly, there was no “placebo” group with which the researchers could compare their results.

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Do Not Take If
  • 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).
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Side Effects
  • Increased pain at tumor site in advanced cancer patients
  • Increased sleepiness
  • Diarrhea
  • Nausea
  • Vomiting
  • Loss of appetite
  • Low blood sugar
  • Edema (swelling) of the ankles and feet
  • Anemia
  • Thrombocytopenia (low platelet count)
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Dosage (Inside MSKCC Only)
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Last updated: July 18, 2011