INTRODUCTION

Although the molecular signaling pathways leading to the progression of normal melanocytes to melanoma have been explored to a great extent, clinical management of skin melanoma has remained a challenge, and the third and fourth stages of this neoplasia are still incurable.1 Despite the fact that we have learned a lot about the independent prognostic factors influencing the clinical outcomes of this malignancy, and several treatment modalities (e.g., interleukin-2, interferon alpha, and vaccines, all also combined with cytotoxic drugs) have been tried in clinical studies, none of these resulted in satisfactory improvements in terms of survival parameters.2,3 Among the cytotoxic drugs, dacarbazine (DTIC) on its own or in combination with other agents remains the standard of choice of adjuvant therapy.Nutritional interventions or regular or excessive intake of dietary supplements, herbal remedies, and/or different natural extracts or concentrates have also demonstrated no beneficial effect on the progression of this disease. 

 Time-related events were measured from the date of entry into the trial, of which the calculation has now been generally accepted.15 The main aim (i.e., primary endpoint) of this study was to compare PFS in the two groups. For this, a twotailed, unstratified log-rank test (Kaplan-Meier method), where p 0.05 indicated a statistical significance, was used. For other comparisons, the Fisher’s exact test was applied. It was also aimed to collect data about the safety of FWGE in cancer patients. Although the administration of FWGE lasted for 12 months to test if this dietary food had any effect on PFS, poststudy patients were followed up for about an additional 7-year period. Once progressed, patients received combination chemotherapy of cisplatin, vinblastine, and aranoza16 and/or interferon (IFN)-alpha therapy, and were treated until the terminal state or death. Additionally, OS was also compared in the two groups.

RESULTS

At the N. N. Blokhin Cancer Research Center in Moscow, between 2000 and 2001, 58 intent-totreat patients were recruited into this study. In the FWGE group (29 patients), 2 patients refused therapy due to nausea, and 1 patient had progressive disease just prior to study entry. These 3 patients were not included into the analysis. In the control group (29 patients), 2 patients refused treatments (1 due to nausea and 1 due to hematologic toxicity), and 1 patient, probably due to disease progression, was lost. These patients were not included in the data analysis.

The baseline clinical characteristics of the 52 treated patients are shown in Table 1. There were no statistical differences in the prognostic parameters (e.g., gender, age, primary site, Breslow’s staging, Clark’s invasiveness, ulceration, number of metastatic nodes, and time from diagnosis to study entry) between the two groups. There were also no significant differences in the number of patients receiving combination chemotherapy (FWGE: 8; 30.8% versus control: 9; 37.5%) and IFN-alpha (FWGE: 4; 15.4% versus control: 8; 33.3%) treatments after DTIC therapies between the two groups. The FWGE treatment lasted for 10.2  3.4 months. The administration of the medical nutriment was found to be safe. The adverse events in the FWGE group were transient and mild (Table 2). Notably, there were fewer toxic sideeffects in patients receiving the combined therapy than in those of the control group.

PFS

Log-rank analysis (Kaplan-Meier estimate) showed a significant difference, in favor of the FWGE patients, in the duration of PFS. Mean values were: 55.8 (FWGE) versus 29.9 months (control) (p 0.0137) (Table 3, Fig. 1).

OS

Log-rank analysis (Kaplan-Meier estimate) also showed a significant difference in the OS values in favor of the FWGE group. Mean values were: 66.2 (FWGE) versus 44.7 months (control) (p 0.0298) (Table 3, Fig. 2).

Endpoint Analysis

Percentage of patients with progressive disease was as follows: FWGE: 42.3 versus control: 73.1 (significant, p 0.05); percentage of deaths: FWGE: 34.6 versus control: 61.5 (significant, p 0.05).

DISCUSSION

A randomized, clinical study was carried out to test the supportive effect of FWGE administered orally in stage III skin melanoma patients receiving adjuvant chemotherapy. The wheatgerm-derived nutraceutical was given for about 1 year, while patients also received cycles of DTIC infusions. The latter regimen supplemented with FWGE was superior to chemotherapy on its own, in terms of PFS and the most important OS, determined after a long-term (7-year) follow-up period. We could also demonstrate a lesser amount of adverse events in the FWGE group than in the control group. There are several anticancer mechanisms that have already been demonstrated in connection with the effects of FWGE.17–21 The encouraging results of the above clinical study, showing even some long-lasting benefit of the adjuvant DTIC plus FWGE combination, might be explained by a preferable interaction between DTIC and FWGE, since these two agents were applied synchronously. As already mentioned, such interaction in the form of a synergism between the two agents had been found in a preclinical experiment, where DTIC plus FWGE completely inhibited the development of metastases in melanoma-bearing mice.

 The explanation of this synergism may come from a study where it was found that FWGE selectively and significantly inhibited the DNA repair enzyme, poly(ADP-ribose) polymerase, which is overactivated in cancer cells.22 DTIC’s mechanism of action has been well established, as this drug induced DNA lesions in cells synthesizing new DNA.23 Thus, when poly(ADP-ribosylation) was inhibited by FWGE, repair of the dacarbazine-induced DNA lesions could be reduced. This inhibition could be paralleled by increased cytotoxicity of the drug, resulting in better efficacy of the adjuvant chemotherapy in the patients.

CONCLUSIONS

We, therefore, highly recommend the inclusion of this fermented wheat-germ-extract-based medical nutriment into the adjuvant protocols of highrisk skin melanoma patients. We also encourage colleagues worldwide to further test this nontoxic active preparation in melanoma and in other types of human cancers.

ACKNOWLEDGMENT

The authors thank Dr. Andras Paksy of the Biometric Unit, School of Medicine, Semmelweis University (Budapest, Hungary) for his advice in the statistical analyses.