The results of these trials indicate that Di Bella multitherapy does not have sufficient efficacy in advanced cancer to warrant further clinical testing. The three cases of partial response among the 386 patients represent a 0.8% response rate, which is well below any reasonable threshold for declaring that a new regimen shows promise.
These low response rates seem to rule out the possibility that the entire regimen has any effect over and above the moderate activity already seen for some of its components. Objective responses in patients treated with somatostatin or its analogues have been described in phase II trials in pancreatic, colorectal, and breast cancer.8
Retinoids are being extensively studied in several haematological and solid malignancies, with results that range from little or no effect to the spectacular success obtained in acute promyelocytic leukaemia, where all-trans retinoic acid induces complete remission in a high proportion of patients.8
Cyclophosphamide is one of the most widely used anticancer drugs, as a single agent or in combination chemotherapy regimens, and it is active in many haematological and solid malignancies, including breast cancer and non-Hodgkin’s lymphoma.8
mg of cyclophosphamide daily that was used in the multitherapy regimen is not much lower than the dose commonly used in chemotherapy.
Overall, the results of these trials fail to justify the use of Di Bella multitherapy and they even suggest that it may be associated with considerable toxicity. Furthermore, the observation that Di Bella multitherapy was discontinued after several months in 85% of the patients because of progression, toxicity, or death means that this treatment is unlikely to be effective in the long term.
As in most phase II trials, the eligibility criteria restricted the enrolment to patients who could not receive standard treatments, since it would have been unethical to withdraw from patients treatments of known efficacy. However, only two trials (more severe breast cancer, and solid neoplasms among terminally ill patients) focused on critically ill patients; in all other trials, most patients had a fair to good performance status. Terminally ill patients were included because of the increasing number of court orders for terminal cancer patients to be given Di Bella multitherapy, but the results of these two trials show that the treatment neither cures nor stops the progression of tumours in patients with terminal cancer.
Eighty patients who had not had previous chemotherapy were enrolled in two of the trials. Only one pancreatic cancer patients showed any response, and no response was seen in lung cancer patients who had not previously had chemotherapy.
The trials, with their rigid treatment protocols, did not reproduce one element of the method that Di Bella claims is crucial: tailoring the treatment to individual patients. Unfortunately, no trial can be conducted without a treatment protocol, and details on the criteria followed by Di Bella and his disciples when adjusting the treatment have not been released. Therefore, it cannot be ruled out that better results could have been obtained by modulating treatment. However, in all trials the protocols followed written indications provided by Di Bella. Furthermore, the potential for widespread use of a new treatment is greatly reduced if its effectiveness depends on the doctor’s ability to modulate it and no explicit criteria are available.
The Di Bella multitherapy has been widely prescribed in Italy despite lack of scientific evidence. Given the high mortality from cancer, it is not surprising that thousands of people continue to seek unconventional treatments. Although claims of “wonder drugs” are occasionally reported by the media, public expectation in this case reached unprecedented levels in Italy.
Phase III randomised controlled trials (which were intended as a further step if results were positive) would not have been feasible for both ethical and practical reasons. On the one hand, preliminary evidence about the antitumor activity of Di Bella multitherapy was lacking and, on the other, patients who were seeking this treatment would have hardly agreed to be randomly allocated to different treatments. These uncontrolled phase II trials, which were planned, conducted, and concluded in less than 10 months, have given the Italian scientific community a solid base for the ongoing debate. We believe that this approach was the best way to cope with an unconventional treatment that was gaining widespread public acceptance in the absence of scientific evidence.