Clinical efficacy

Clinical efficacy
Avemar was used exclusively as a form of supportive therapy, i.e. as a supplement to active oncotherapy.

Colorectal cancer
Following radical surgery, supportive administration of Avemar delays the development of distant metastases, particularly in the liver. In clinical stage I-IV patients who had undergone radical surgery, Avemar significantly increased both the overall and progression-free survival rate.

Head and neck cancerrs
Patients suffering from tumours of the larynx, pharynx and salivary glands showed improvement in their quality of life parameters (relief in cachectic symptoms, increase in body weight). In five salivary gland tumour patients, long-term inhibition of progression was observed.

Cancer of the oral cavity
An open, prospective and controlled study was conducted on 43 patients treated 'lege artis': 22 were treated with Avemar + lege artis, while 21 were allocated to the lege artis group (i.e., chemotherapy and/or radiotherapy). In clinical stage II, III and localized stage IV patients who continued with Avemar during a 12 month follow-up period, the combination of Avemar with lege artis therapy resulted in a significant decrease of progression-related events (local recurrence, distant metastases, death).

Malignant melanoma of the skin
In stage III patients, the combination of Avemar with Dacarbazin therapy produced a significant decrease in progression-related events, including the development of new visceral and lymph node metastases. The time which lapsed before the formation of distant metastases and the progression-free survival time significantly increased.

Other effects:
1. Febrile neutropenia: Children with solid tumours undergoing intensive chemotherapy were treated with Avemar (11 control (i.e., standard therapy) patients and 11 Avemar + standard therapy patients, with allocation on a matched pair basis). The frequency of febrile neutropenia occurrences, as compared to the number of chemotherapy cycles, decreased significantly in the group receiving Avemar.
Quality of life A) In breast cancer patients, a 3 year long treatment with Avemar resulted in a significant improvement of the physical, emotional and global health status of the patient. Improvement was observed in the following symptoms: nausea/vomiting, insomnia, hair loss.
B) Advanced lung cancer. Avemar used for 8ą2 months as a supplement to standard oncotherapy resulted in an improvement in global health status and a significant decrease in fatigue.

PRECLINICAL RESULTS
Review - Conclusions drawn from experimental studies

Familiarity with different types of anti-cancer mechanisms can help to explain the tumour-inhibiting effect experienced in clinical trials. A better understanding and utilisation of these and other mechanisms would make a more effective and targeted field of application possible.

Avemar's anti-cancer effects were first demonstrated in animal experimental models which focused on tumour types widely used for the testing of anti-cancer agents, notably cytostatics. The results confirmed the evidence suggesting Avemar's anti-cancer activity.

Inhibition of metastases in mice
Experiments were carried out in inbred G57B1/6 mice of 8-10 weeks of age weighing 20-22g on the following cancer cell-lines: meta-stasizing Lewis lung carcinoma (3LL-HH) injected into the spleen, B-16 mouse melanoma injected into muscle tissue and HCR-25 human colon carcinoma xenograft injected into the spleen. The administration of Avemar began 24 hours after the tumor cells were implanted.


Results: metastasis formation in liver decreased by 71% (significant) following treatment with Avemar for the 3LL-HH tumor cells. For HCR-25 human colon carcinoma, 50 days of treatment with Avemar resulted in a significant (50%) decrease in both the number and size of liver metastases as well as the size of the primary tumor injected into spleen. The number of metastases in B-16 melanoma decreased by 85% (significant) after 21 days of treatment [1]. Control groups were used for all cancer types.

Conclusions: Avemar's tumour-inhibiting effect can be taken as a fact.

The combination of Avemar with cytostatics
A similar type of cancer-cell implantation was used in experiments investigating the respons of mouse-38 colon carcinoma to a combination of 5-fluoro-uracil (5-FU) i. p. and Avemar p. o. treatment. A signi-ficant reduction in number of liver metastases was observed when compared to the control group receiving 5-FU alone. A combination treatment of DTIC (dacarbazin) i. p. + Avemar p. o. resulted in a complete eradication of lung metastases in mice with B-16 melanoma.

This demonstrates a synergism between the first line drug for melanoma and Avemar when acting on a tumor resembling human malignant melanoma [5].

Another important finding revealed by the animal tests outlined above was that, while Avemar has no substantial influence on the effect of cytostatics on the primary tumor, it has a marked potentiating effect in inhibiting metastasis formation [2].

Conclusions: The synergistic effect expressed through Avemar's inhibition of metastases deserves attention, though its inhibition of primary tumour growth is also noteworthy.

Prevention
Avemar's ability to inhibit cancer-formation significantly inhibited the formation of azoxymethane-induced colon tumours in F344 rats, further proof of its chemo-preventive effect.

Azoxymethane, a carcinogenic agent, induces the formation of colon tumors in 4-week old inbred F344 rats. Four treatment groups comprised of 10 animals each were formed as follows: Group 1: untreated controls; Group 2: azoxymethane ad-ministered s.c.; Group 3: Avemar treatment started two weeks prior to the first injection of azoxymethane, with treatment continuing for 32 weeks; Group 4: Avemar administered without azoxymethane. At the end of the 32-week-long experimental period, the germin-ation of the tumor cells was examined comparing the per-centage of the animals that developed colon cancer in each group (=Value-1) and the number of tumor foci in each animal (as an average projected for the whole group = Value-2). The results were: Group 1: 0%; 0; Group 2: 83.0%; 2.3; Group 3: 44.8%; 1,3. Group 4: 0%; 0.
The difference in both the percentage and number of cancerous foci/per animal was significant between Groups 2 and 3 (p<0.001 and p<0.004, respectively).
When the diameters of the tumor in animals in the groups treated with azoxymethane alone and those treated with the combination of Avemar and azoxymethane were compared, the difference was noted to be markedly significant (p<0.0001), in favour of the group treated with both com-pounds. To summarise, Avemar caused a marked and signi-ficant decrease (70%) in the number of malignant colon tumors which developed in test animals induced with the carcinogen azoxymethane [15].

The above-mentioned results in experimental colon tumors pro-vided evidence supporting the chemo-preventive effect of Avemar. Even though these results do not have an immediate practical conclusion in clinical setting of patients with manifest tumors, it is noteworthy that most of our evidence concerning the cancer-combatting effect of Avemar comes from clinical data gathered during the treatment of human colorectal cancer.

Conclusions: This, combined with the evidence presented under point 2, helps to explain the results obtained when Avemar was used as a supplement in the treatment of human colorectal tumours.

Increase in haemopoiesis
The effect of Avemar on the regeneration of haemopoiesis was examined in animal experiments where a sublethal dosage of radiation or cyclophosphamide was used to provoke bone marrow impairment. On the seventh day following irradiation, the thrombocyte-count started to rise and returned to normal levels by the 21st day. No significant difference was observed in the leukocyte-count, as compared with the control group. After treatment with cyclophosphamide, thrombocyte-regener-ation improved due to the administration of Avemar; it also had a similar effect on the reticulocyte-count [14]. The results support the clinical evidence gathered over the past few years suggest-ing that Avemar has no haematologic side-effects, and that, it reduces the haematological side-effects of radiotherapy and chemotherapy.

Conclusions: This agrees with clinical evidence suggesting that Avemar has no haematology-related side effects.