Results of a prospective randomized study on chemotherapy versus chemotherapy plus

Results of a prospective randomized study on chemotherapy versus chemotherapy plus "biological response modifier" in metastatic colorectal carcinoma

F.R. Douwes, D.I. Wolfrum, F. Migeod

1.0 Introduction

After lung cancer in men and breast cancer in women, colorectal carcinomas are the second most frequent form of cancer. The annual number of deaths is about 22.000 in West Germany. The mortality rates from this tumor show a distinct tendency to rise in the last 20 years. The causes for this are to be seen in a disease-induc-ing lifestyle, in particular incorrect nutrition. The five year actuarial survival of all colon carcinomas is 30%, 50% in the local forms (dukes A and B). There has unfortunately been hardly any change in these percentages in the last 20 years.

Pharmacotherapy of advanced colon carcinoma is difficult, since reliably effective drugs are lacking. The regional perfusion with cytostatics which has recently been more intensively discussed has also not led to an improvement in the prognosis up to now. Even today, the mean life expectancy of a patient with the stage of metastases under chemotherapy is only one year, even though a measurable prolongation of life can be attained in responders.

An important factor on the comparability of clinical therapeutic studies is knowledge of the prognostic factors which can influence the result of therapy. The most important of these are

1. the general condition,
2. the localization of metastases,
3. the primary localization,
4. the patient’s sex,
5. the ESR,
6. albumin,
7. alkaline phosphatase.

Merely 5-fluorouracil (5-FU), the nitrosourea derivatives and mitomycin C have turned out to be cytostatics with proved efficacy in monothe-rapy. The 5-FU response rate is around 20%, and the mean duration of remission is six months. The survival time is not prolonged by this drug, and a slight increase is to be observed merely in responders. Combination treatment with several cytostatics has not produced the hoped-for results with regard to life expectancy apart from a somewhat higher response rate. However, combinations could be found time and again which suggest the possibility of improving therapy in this tumor type. Thus the combination of mitomycin C (MMC)/5-FU was superior to methyl-CCNU/ 5-FU with a 474/ response rate as compared to 25%, and a mean survival time (WST) of 12.3 months. These results could be improved once more by the 120-hour infusion and MMC with response rates of up to 70%.

Methotrexate (MTX) also intensifies the effectiveness of 5-FU. Sequential administration of MTX and leucovorin rescue leads to response rates between 50% and 80% in primarily untreated patients. The MST is also improved by this combination treatment, and increases to 13.6 months (Tab. 1 a and 1 b). However, the combination treatments have the disadvantage that the somewhat greater effect on the tumor is also accompanied by a broader toxicity spectrum, so that this therapy is unacceptable for many patients with this tumor type with such a low life expectancy. A logical consequence is hence the search for an effective, but less toxic means of therapy.

1.1 Therapeutic results of 5-FU and folic acid

Such a therapy appears to have been found in the combination of 5-FU and folic acid. As a pyrimidine analog, 5-FU develops its cytostatic action by incorporation in the RNA. The addition of high-dose folic acid leads to a triple enhancement of the efficacy of 5-FU in a second way by formation of a chelate of thymidilate synthetase, 5-FU and 2-deoxyuridine monophosphate (2’dUMP). The stabilization of this complex by high-dose intracellular and reduced folate results in a long-term suppression of thymidilate synthetase activity as the factor limiting cell growth.

Apart from a new combination of cytostatics which act in different phases of the cell cycle, with the combination of 5-FU with high-dose folic acid a way has been chosen to intensify the cytostatic, intracellular metabolism of 5-FU by long-term complex formation in simultaneously reduced toxicity. In a study of our own with 200 mg/m² folic acid and 370-400mg/m² 5-FU administered half as a bolus and half as an infusion (Fig. 1), we attained response rates (complete remission CR and partial remission PR) of 56% with a mean patient survival time of 12.6 months (Fig. 2 a and b) similar to Machover. We initially regarded these results as very encouraging with regard to the response rates, but not as concerns the durations of remission or the mean survival time. The question consequently arose as to whether we could improve this schedule of therapy which is actually relatively nontoxic, but evidently very effective in this tumor type by inclusion of biological response modifiers. We chose Viscum album (Helixor(R)), a phytothera-peutic, and xenogenic peptides from liver, spleen and thymus (Ney-Tumorin'), an organo-therapeutic.

1.2 Viscum album (Helixor), a biological response modulator of a special kind

The justification for including this biological response modifier in the study resulted from the following considerations:

Tumorigenesis is regarded at present almost exclusively as a cellular problem. According to Nigram, however, a uniform model has emerged for cellular tumorigenesis according to which genetic, viral and chemical components are interrelated. "Oncogenes" appear to play a particular role. They are of special significance in the control of cell growth, cellular differentiation and embryonic development. A raised activity of such oncogenes is also observed in "cell stress". A concept of carcinogenesis by overshoot activation of oncogenes is emerging in outline.

With exclusive orientation to the cancer cell or its disturbed mechanism of transcription and translation, no concept of therapy has been developed so far which includes the intracellular repair mechanism and above all the other important systems involved in tumor defence. In these intracellular and extracellular interactions, in particular the ground substance plays a major role. A quite different yardstick is thus to be applied to drugs which meet the overall conditions of cancer dynamics better, e.g. cytostatics. They must act both on the polysaccharide-protein structures and tiber proteins of the ground substance as well as acting directly on nucleocy-toplasmic metabolism, e.g. via polypetides. Their effect is thus mediated via autologous structures which must be activated or repaired. However, this means that the conventional concept of therapy of "one cause – one effect" which was conventional up to now must be abandoned. This has long happened, as is also apparent from the fact that hardly anyone still believes that cancer is a local problem, and therefore only to be controlled with local measures. On the basis of the most recent knowledge, the majority of researchers also no longer believes in a local disease, but in a general disease with complex disorders of the most diverse systems. Drugs which meet the criteria of this modern concept also no longer act directly on the tumor, but they stimulate the most diverse systems and also mostly act on the systems which Pischinger has subsumed under the term "systems of basic regulation", namely on the autonomic nervous system, the endocrine system and the immune system. Both Viscum album (Helixor"), a phytotherapeutic and the xenogenic peptides (Ney-Tumorin'),an organo-therapeutic are such drugs. Their complex effect is based on the concerted action of numerous constituents. In Viscum album, these are above all lectins, polysaccharides and polypeptides which act on the ground substance and can induce a nonspecific stimulation of resistance in the human and animal body (Tab. 3 and 4). Since nonspecific defence mechanisms are inter1inked in multifarious ways (e.g. complement, lysoso-mal enzymes, lymphokins, leucotrienes, prosta-glandins, interferons etc.), nonspecific immuno-stimulation has also been termed as "paraimmunity" and such substances have been designated as biological response modifiers.

It has already been known for a long time from clinical studies that despite a mild but direct tumoristatic action, Viscum album acts above all indirectly via the systems ot basic regulation. Several studies (also on colorectal carcinomas) were able to show that not only the mean survival time of the treated patients is markedly prolonged, but their quality of life is also improved under chronic application of this substance.

1.3 Xenogenic peptides (Ney-Tumorin(R)), mechanism of action

The xenogenic peptides (Ney-Tumorin) such as were used in this study constitute organ lysates of liver, spleen and thymus which were isolated and standardized in accordance with a special procedure. They are essentially peptides the effect of which is to alter the relationship between tbe tumor and the host by modulation of the biological reaction of the host against the tumor. In numerous cell culture trials and animal models, a stimulant action on healthy cells could also be demonstrated besides a direct tumorici-dal effect. In addition, it could be shown that these substances possess the capacity to modulate malignant cells in such a way that they display behavior like that of norma1 cells, indicating cytoplasmic "repair". Furthermore, it could be demonstrated that these substances lead to an immune restoration or to immunomodulation. We have seen a satisfactory effect with these substances ourselves in two clinical pilot studies in advanced plasmacytoma and metastatic hypernephroma. Not only was there a measurable regression of the tumor, but a satisfactory prolongation of life was also attained. In a comparative study in metastatic colon carcinoma with 5-FU as monosubstance, we were able to show that the direct tumor action was not greater, but was also not markedly poorer. The reasons mentioned were an occasion for us to include both Viscum album (Helixor) and the xenogenic peptide mixture (Ney-Tumorin) in the present study in order to clarify the following questions:

1. Can the cytoreductive action of 5-FU/folinic acid be enhanced by these biological response modifiers?

2. Do the biological response modifiers have an effect on the duration of remission or the survival time?

3. Do biological response modifiers improve the qvality of life?

2.0 Patients and Methods

The patients who were included in the study had histologically verified colorectal carcinomas and also had demonstrable organ manifestations at the time of admission to the study. The following criteria were prerequisites for inclusion in the study:

age less than 75 years,
prospective life expectancy over three months,
Karnofsky index 60% – 100%,
no severe additional internal disease,
last cytostatic therapy at least three months before.

Fig. 3 shows the scheme of randomization and stratification. It can be seen from Figure 3 that the patients were always randomized in such a way that they were either added to the arm A with pure chemotherapy or the arm B and C in which either Viscum album (Helixor) was added to arm B or xenogenic peptides (Ney-Tumo-rin) to arm C in accordance with a specific pattern. In each arm, 20 patients were included. The patient data are shown in Table 5. As can be seen, the distribution into all arms of the study is very even, both in terms of age and sex. The number of pretreated patients is roughly the same. A relatively good even distribution was also attained with regard to the primary location of the tumor. The metastases were localized in the liver, lungs, lymph nodes, peritoneum and loco-regionally. An adenocarcinoma of differing grading was present histologically in all cases. The Karnofsky index for appraisal of the restriction of physical performance due to the disease was between 60% and 100% (average 80%) in all patients.

Complete remission (CR) was assumed in disappearance of all tumor manifestations. A partial remission (PR) was present in decline in the volume of the largest tumor to less than 50% of the initial volume. With a smaller decline or altered size under therapy, a minimal response (MC) was assumed. A progression was present in increase of the tumor diameter (TD).

2.1 Scheme of treatment

Chemotherapy lasted five days and consisted of 200 mg/m²KOF-folic acid (Rescuvolin medac) i.v. as a bolus and 200 mg/m²KOF 5-FU i.v. as a bolus as well as 370 mg/m² KOF 5-FU in 1000 ml Sterofundin infused over six hours. The infusion was repeated from the 28th to the 32nd day. For the six-hour infusion, a battery-driven infusion pump was occasionally used on an ambulant basis, a reduced volume of 5-FU being infused. The treatment schedule is shown in Fig. 4.

In arm B, chemotherapy was given in accordance with the same scheduie. In addition, the patients finally received 200 mg Helixor s.c. after initial treatment which was gradually increased over different milligram ranges.

In arm C, the scheme of chemotherapy was as in arm A and B, but 2 x 30 mg Ney-Tumorin per week was applied i.v. or s.c. after a short pretreatment of the patients.

3.0 Results

Four hundred and eighty chemotherapy cycles were administered in all groups, 11 patients receiving two to four cycles, 21 patients between five and ten cycles and 18 patients between 11 and 16 cycles. Table 6 shows the numerical results of therapy. As can be seen, the results are the same in all three groups and are without significant differences. In Table 7, the results of therapy are specified with regard to duration of remission and mean survival time. Here, it becomes clearly evident that the survival time in the therapy arm B and C is very much better than in the pure chemotherapy group. As can be seen, the longer survival time does not only apply to the responders, but also to the nonre-sponders; the latter lived just as well as the responders of the chemotherapy, and signifi-cant1y longer than the nonresponders in arm A.

It may be concluded from this that the biological response modifiers employed here (Viscum album and xenogenic peptides) do indeed enable the tumor host to live longer with his tumor, i. e. the effect of these substances is not measurable so much by their action on the tumor, but their action on the host. They must also be appraised quite differently with regard to efficacy.

3.1 Toxicity

The side effects of therapy were generally slight and were markedly higher in the chemotherapy group. In the chemotherapy group, sto-matitis and diarrhea occurred more frequently than in the two other therapy groups. The most frequent side effects were a tolerable nausea, mostly in the last days of the therapeutic cycle. However, antiemetic treatment was rarely necessary. Thrombopenia was most frequent in the chemotherapy group, and the maximum was reached on the 8th to the 12th day. Stomatitis and diarrhea occurred to an equal extent in all groups, whereas two alopecias occurred in the pure chemotherapy group. Therapy did not have to be discontinued because of severe side effects in any case.

4.0 Discussion

The two-track modality ot 5-FU in the 5-FU/fol-ic acid schedule applied leads to a measurable tumor regression in 60% of the patients treated in this way. These results correspond to those which were attained in a prior pilot study and are somewhat better than the results communicated by Machover and Byron. We attribute this difference to the moditication of the 5-FU application in the bolus and subsequent six-hour infusion we administered. In this way, the effect of 5-FU is not only enhanced, but the infusion is also prolonged, so that the cytoreductive action of this form of therapy is so far the most effective for this tumor type with simultaneous substantially reduced or more tolerable toxicity. This form of therapy can doubtless be further improved, so that the primary cytoreductive effect may be even stronger; a synergistic effect on the tumor itself of the biological response modifiers used in this study is not demonstrated, since the response rate was the same in all therapy arms, but the duration of the remission could be significantly prolonged and the survival times thus also be increased, so that another synergism is emerging here. Both biological response modifiers have a demonstrated tumoricidal or tumoristatic effect, but this was evidently not manifested to a measurable extent in this study. Both biological response modifiers also have an effect on the intracellular level and in the immune system in the sense of a polytopic, but nonspecific immu-nostimulation. Via host factors which must be explored in more detail, this evidently leads to an improved overall situation which enables the host to live longer with his tumor. The development of resistance of tumor cells against cyto-static therapy also appears to begin later than usual. The host factor is the crucial factor, as it would otherwise not be possible to explain why nonresponders have also profited from the additional administration of these biological response modifiers. The results of this study are encouraging and clearly show that the concept of tumor therapy practised so far should be modified. As a result of another extended consideration which has been indicated to be correct by numerous recent indications, we should place the host as a whole (i.e. with its multimodal systems) rather than the tumor in the center of our therapeutic approacb. It is to be expected that we will attain greater advantages in this way in the near future than if we were to continue to concentrate only on the tumor and its destruction. The future in cancer chemotherapy will accordingly belong to drugs which are able to influence the malignant properties of the cancer cells and not only to destroy them (like cytostatics), which have an immunostimulant effect on the host and not an immunosuppressant effect (like most cytostatics), which enhance repair rather than promoting destruction.

It is known from the example of "spontaneous remissions" that a biological influence on tumor cells is possible, and that it can indeed occur spontaneously. There is probably no simple strangulation of tumor cells, such as is brought about by a chemical cytostatic, but more likely a modulation of the body’s own biological response to the tumor, which may also be aid to the disadvantage of the tumor.

The approach of combining cytoreductive therapy with one or more biological response modifiers suggested here should be tested in further controlled studies, especially since the patients' quality of life can be improved substantially by such a therapy.

Literature

Benz, C.; Schoenberg, M.; Choti, M.; Cadman, E.: Schedule-dependent cytotoxicity ot methotrexate and fluorouracil in human colon and breast tumor cell lines.J. clin. Invest. 66 (1980) 1162.

Bruckner, H.W. et. al.: Folinic acid and 5-Fluorouracil. AACR Abstracts 22 (1981) 752.

Bruckner, H.W.; Ohnuma, T.; Hart, R.; Jaffrey, l., Spiegelman, M. et al.: Leucovorin potentation of 5-Fluorouracil efficiency and potency. AACR Abstracts 23 (1982) 434.

Bruckner, H.W.; Roboz, J.; Spiegelman, M.; Ambinder, E.; Hart, R.; Holland, J.F.: An efficient Leucovorin and 5-Fluorouracil sequence: dosage escalation and pharmacological monitoring. AACR Abstracts 24 (1983) 547.

Byrne, P.; Smith, F.; Treat, J.; Bowers, M.W.; McVie, G. et al.: 5-Fluorouracil and higher folinic acid dose treatment of colorectal carcinoma patients Proc. Am. Ass. Cancer Res. Abstracts Vol. 2 (1983) C-474.

Douwes, F.R.; Migeod, F.: Klinische Erfahrungen mit Ney-Tumorin Sof - bei Hypernephrom und metastasierenden kolorektalen Karzinomen. Therapiewoche 35 26. Wo. (1985) 121-126.

Evans, R.M.; Laskin, J.D.; Hakala, M. T.: Effect of excess folates and desoxyinosine on the activity and site of action of 5-Rurouracil. Cancer Research 41 (1981) 3288-3295.

Fallrson, G.; Kalkson, H.C.: Fluorouracil, Methyl-CCNU and Vincristine in cancer of the colon. Cancer 38 (1976) 1468-1470.

Gastrointestinal Study Group: Adjuvant therapy of colon-cancer. Results of a prospectively randomized trial. New Engl. J. hfed. 310 (1984) 737-743.

Herberman, R.B.: Cell mediated immunity to tumor cells. Adv. Cancer Res; 19 (1974) 207-263.

Heim, M.E.; Roemer, W.; Edler, L; Queier, W.: Combination chemotherapy of chemotherapy of advanced colorectal cancer with 5-Fluorouracil, Carmustine and Mitomycin C. Tumor Diagnostik B, Therapie 4 (1983) 122-125.

Herrmann, R.; Manegold, C.; Holzmann, K; Fritze, D.: Sequen-tielle Verabreichung von Methotrexat und Fluorouracil bei metastasierenden kolorektalen Karzinomen. Ergeb-nisse einer Phase-II-Pilotstudie. Dtsch. med. Wschr. 107 (1982) 491-493.

Higgins, G.A.; Dwight, R.W.; Smith, J.V.; Keehn, R.J.; Ruoroura-cil as an adjuvant to surgery of carcinoma of the colon. Arch. Surg. 102 (1971) 339-341.

Hall, V.; Wolcott, M.: Modulation of Tumorcell growth by Thymus Extracts. Fed. Proc. 40 (1981) 3351.

Heine, H.: Mistelpräparate (Viscum album) Wirkungen auf menschliches Tumorgewebe. Phytotherapie 6 (1985) 67-72.

Karnofsky, D.A.; Burchenal, J.H.: Clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents in cancer. Hrsg. v. Madeod, C.M. New York1949,191-204.

Kienle, G.: Allg. Med. 57 (1981) 328.

Machover, D.; Schwarzenberg, L; Goldschmidt, E.; Tourani, J.M.; Michalski, B. et al.: Treatment of advanced colorec-tal and gastric adenocarcinomas with 5-FU combined with high dose folinic acid: a pilot study. Cancer Treatm. Rep. Vol. 68 (1982) 1803-1807.

Munder, P.G. et al.: Antitumorale Wirkung xenogener Subs-tanzen in vivo und in vitro. Onkologie 5 (198?) 2-7.

Nigram, V.iV.; Bibilovski, C.A. et al.: Glycosaminoglycas and Proteoglycans in Neoplastic Tissues and their Role in tumor growth and Metastasis. In: Varma, R.S. et al.: Gly-cocaminoglycans Processes of Bodey Systems. p. 354-37l, Karger, Basel (1982).

Stickl, H.; Ma+r, A.: Fortschr. Med. 97 (1979) 1781.

(For the authors: Prof. Dr. med. F.R. Douwes, Chefarzt, Klinik am Wendelstein, MuhlenstraBe 60, 8204 Brannenburg/FRG)