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  Chronological Phenomena in Cancerous Diseases
  

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By: Hans Broder von Laue and Wolfram Henn

Paper presented June 9, 1990 at the 39th Congress for continuing medical education in Berlin. Pres. Prof. Dr. Dr. G. Schettler. Transl. by Harold Jurgens.

Living organisms develop in time, and each of them has a specific time order or time structure. Each time structure or order contains certain rhythms. These rhythms can always be looked at from two points of view. We will give a general description of these two viewpoints and apply them to the human tumor carrier and to the tumor itself. Then we will go into the changes in rhythm which are produced by viscum album therapy (Abnobaviscum®). [Ed. Note: Viscum album remedies include Abnobaviscum®, Iscador®, Iscucin, Helixor®, Vysorel®]

1. One can find a change in every rhythmic phenomenon in the course of an organism's life. For example, the circadian temperature rhythm in man is not yet present at birth, but it gradually develops during his early life and then characteristically flattens into a plateau in later life. The circadian interior temperature rhythm is inserted into the organism's overall temporal order in a sequential way between birth and death. A corresponding "sequential order" can be found for every rhythm.

2. Independent of this first time structure or order, we can also find a simultaneous, side by side spatial order in various human rhythms. A time order consisting of rapid frequencies in man's nerve-sense region, slower ones in the circulatory and respiratory systems, and slow ultradian frequencies in the metabolism was described by Hildebrandt in his classic studies. The specific way in which rhythms change under stress also belongs to this "simultaneous order."

a.) The primary reaction of the rapid frequencies in the nervous system is frequency change.

b.) The middle circulatory and respiratory rhythms are the ones which are most dependent on amplitude. They can be modulated according to both phase and frequencies.

c.) Slow, ultradian rhythms change through frequency jumps (in whole numbered, harmonic ratios), and through phase modulations, where the acrophase or the time of the maximum, is displaced, while the frequency stays roughly the same.

The slow, circadian temperature-change rhythm in this "simultaneous order" has all the characteristics of a metabolic process. In addition to simultaneous and sequential orders, Voigt (1827) also spoke about an "in­-one-another" order in the development of plants in space and time. How­ever, rhythm research has not yet found any examples of this.

Every single rhythmic phenomenon can be described on the back­ground of these different time orders, and can be distinguished as a part of a differentiated time order. Hitherto it has not been customary to think of a cancerous disease as a rhythm problem. We would like to make a first at­tempt here, and we will show how observable de-synchronized processes can be synchronized again by a therapy with viscum album preparations. [Ed.: Information and data presented here is based upon the viscum preparation Abnobaviscum]


Fig. 1   Age distribution of cancer deaths 1955 (Bauer).

The first aspect of rhythms, their sequentiality, describes the specific emergence of tumors at various times in a person's life. Figures 1 and 2 from K.H. Bauer's classic textbook Das Krebsproblem (1963) show the distribution of deaths due to cancer in various organs at various ages (fig. 1), and those due to leukemia (fig. 2). The graphs in fig.1 demonstrate the tendency to die from cancer in various organs is the greatest. The question about the development of tumors also belongs in the same sequential time order; e.g., it takes about five years for breast cancer to become manifest. The histologi­cal picture shows the degree of differentiation and allows one to make certain inferences about the rate of cellular division. Tumor growth and its me­tabolic processes seem to occur rhythmically. Garcia-Sainz (1966) found ultradian and some circadian mitotic rhythms in various human carcinomas. However, we don't know of any rhythmical investigations on the sequential order of tumor development, or on temporal metastasization models.


Fig.2   Age distribution of leukemia deaths 1955 (Bauer).

The second aspect of rhythms, simultaneity, considers rhythmic changes in the organism which arise at the same time that the tumor does. A number of papers have discussed this theme in the last few years. Some of the results will be briefly discussed here.

Most of the rhythmic changes which are found in cancer patients are connected with the temperature rhythms of the skin or the body core (oral or rectal temperature). Corresponding de-synchronizations can also be seen in other parameters. Some patients with manifest tumors have a changed circadian rhythm in their core temperatures. A flattening of the normal amplitude was described by Halberg(1974), Wilson(1983), and Bail­leul(1986). Their investigations involved patients with breast or ovarian car­cinoma. A displacement of the acrophase was sometimes also observed, more frequently to the left than to the right, (i.e., the temperature maximum tended to appear earlier than is normal). Figure 3 shows graphs of the chan­ges; a differentiation of the so-called morning and evening types (Home, 1976) has yet to be carried out.


Fig.3   Normal and deteriorating circadian rhythms of core temperature

Aside from these changes in the interior temperature of carcinoma patients the temperature rhythm of the tumor and its environment also changes. The skin temperature above the tumor reflects the temperature phases of the tumor itself fairly accurately. Smolenkski described some rhythmic changes in breast cancer in 1973. He found, over the tumor, an elevation of the median temperature (Mesor) of about 1°C and an acceleration of the acrophase by about 2 hrs. as compared with the opposite breast. An acceleration seems to be the most common finding here. Gautherie (1977) also compared skin temperatures over breast carcinomas with those on the contralateral side, and he studied the rapidity of tumor growth (tumor doubling time), the histological differentiation, and the warmth production of the tumor. His investigations showed the following:

1.) Slow growing, histologically differentiated, and cooler tumors have, as compared to the normal side:

a.) a decrease by about 50% in the amplitude of the circalunar, circa­septan, and circadian (24 hr.) temperature rhythms by about 50%.

b.) an acceleration of the acrophase in the skin temperature curve by 6 hours, from 10 PM to about 4 PM

2.) Fast growing, histologically undifferentiated and hot tumors, as compared to the contralateral (normal) side:

a.) are lacking the circaseptan and circalunar rhythms which are present on the normal side.

b.) have shortenings of the circadian rhythm to periods of 20 to 23 hours, while the other side is still synchronized to 24 hours.

c.) exhibit infradian rhythms which appear as multiples or sub-multiples of the circadian and circaseptan rhythms.

Simpson (1989) investigated "high-risk" premenopausal patients status post breast cancer operations, and healthy women with a "normal-risk" of developing breast cancer. He compared the circalunar temperature rhythms above the breasts of normal risk women with the temperature rhythms over partially resected breasts and the contralateral side. Oral temperature and the progesterone content of the saliva were also determined daily. His in­vestigations showed the following:

1.) The breast carcinoma patients had only a slightly developed cir­calunar temperature rhythm over both breasts, and after subtracting the oral temperature rhythm, no circalunar rhythm could be shown at all. These changes could be demonstrated despite normal ovulation cycles.

2.) In the high-risk group, instead of the normal circalunar rhythm fre­quency, multiplications in approximately whole-numbered ratios appeared over both breasts. Thus, as a deterioration of the 28 day rhythm, seven day rhythms (28 divided by 22), and 3.2 day rhythms (about 28 divided by 2 squared) were found. No such sub-rhythms were present in the healthy women. Fig. 4 shows the typical changes in the circalunar courses.

3.) In the high-risk patient, the amplitude of the circalunar temperature rhythms of the inside of the body (oral temperature) was about 50% less.

Simpson's group proposes the use of circalunar skin temperature change examinations for screening purposes, for they would enable one to distinguish between normal-risk and high-risk breast cancer patients. To complement this we will cite the following rhythmological changes in car­cinoma patients.


Fig. 4   Course of breast-skin temperature of women with normal-risk (left) and, high-risk (right) to develop breast-ca., measured 10 days before and after the endogenous progesterone peak (Simpson).

Singh (1985) found an acceleration in the 17-hydroxycortisone rhythm, Brown (1983) and Bailleul (1986) described the loss or flattening in amplitude of the circadian rhythm of peripheral blood cells (erythrocytes, leukocytes, lymphocytes, and neutrophils). Benvenuti (1983) described a loss in amplitude in the circalunar rhythms of ferritin and iron in serum.

To sum up, the following rhythmological changes occur directly over a tumor:

1.) A tendency for elevation of the median temperature (Mesor).

2.) A tendency for phase acceleration in slowly growing tumors.

3.) The appearance of circaseptan periods as a degeneration of the circalunar rhythm.

4.) A tendency for an increase in frequency with the de-synchronization of the circadian rhythm (i.e. shortening of the circadian rhythm) in the skin temperature over fast growing tumors.

The following rhythm changes occur in the time structure of the overall or­ganism:

1.) The circadian and circalunar interior temperature rhythms degenerate through a decrease in or a loss of amplitude and a phase dis­placement (acceleration).

2.) The circadian and circalunar rhythms of various other laboratory data also show displacements and amplitude flattenings up to the complete loss of a rhythm.


Fig. 5: Typical rhythm changes in cancer

These changes are shown diagrammatically in fig. 5. Of course this overview will remain somewhat hypothetical until several more chrono­pathological investigations of carcinoma patients have been done. Neverthe­less, this gives an outline of the chrono-pathology of the "simultaneous order" for carcinoma patients. Similar rhythm changes in the geriatric population have also been described (Touitou 1983, Haus 1988). Seen rhyth­mologically, the cancer patient is considerably older than his actual age. Laue already pointed to this rhythm acceleration in cancerous diseases in 1977.

In the third part following, temperature curves and curves for in­dividual patients' daily variation-in-temperature are given as examples of rhythmological changes before and during therapy.

Our own investigations arose through the following views:

1.) Rhythmological changes in the overall organism often occur in con­nection with tumor disease.

2.) The kind of rhythm changes are typical for the tumorous disease.

3.) Findings of rhythmological changes can be used in individual cases in addition to quantitative tumor criteria in the assessment of tumor therapy.

In the following investigations the internal temperature was determined by:

—Regular oral or rectal measurements:

a.) In the morning before rising (if possible, before 7 AM)

b.) In the afternoon following bed rest for at least half an hour (between 2 PM and 6 PM)

—Measurements always at the same time

Fig. 6   Conditions of temperature measurement for dosage control of viscum therapy. [kw note: there was no figure 6 included in the text]

The daily difference obtained in this way (afternoon temperature minus morning temperature) gives an adequate measure of the circadian tempera­ture rhythm. This has already been mentioned before (Laue 1989). The statistical variance-analysis was done by Scheffe's method.


Fig. 7   Temperature curve patient M.G. (rectal carcinoma and liver metastases).

Figure 7 shows the temperature curve of a 68 year old patient with a rectal carcinoma and liver metastases in various phases of therapy (Surgery '87; pT3, N1, Mx, G1, Duke C, liver metastases III/88). We show the raw data temperature curve because this is the form in which the oncologist gets the data from the patient. With a little experience, all the conclusions in figures 8 and 9 can be read directly from this curve.


Fig. 8   Median values of morning and evening measurements, 4-(3-) week median with std. deviation (Patient M.G.).

Phase A shows the course of the temperature during the four weeks without treatment, and five months after an surgery. The amplitude of 0.16°C in this phase is quite small. The change which is brought about by therapy can be seen in phases B - E. The course has a distinct and regular rhythm.

Fig. 8 shows the median values of the morning and afternoon tempera­ture measurements in groups of 3 or 4 weeks, and the corresponding stand­ard deviations. Between B and C there is a two month trip to another country with continued therapy but no temperature measurements, other­wise the temperature curve is continuous.

Fig. 9 shows the results of a statistical comparison of the median values for the daily difference before viscum therapy, and during the various therapy phases. There is a significant increase in the daily difference in temperature for all therapy phases B to E versus the difference in phase A (before viscum therapy), with a P 0.01. There are no further statistically sig­nificant differences between the therapy phases. In all the viscum therapy phases there is an increase in the amplitudes through a decline in the morn­ing temperature and an increase in the afternoon temperature. (The term amplitude is used here more in a figurative sense than in a mathematical one).


Fig. 9   Therapy-phase median values of the daily difference (14hr value minus 7hr value) in the therapy phases A through E by means of the analysis of variance according to Scheffe. Phase A prior to viscum therapy (Patient M.G.).

The clinical condition of the patient improved distinctly after the begin­ning of the mistletoe therapy, but it is difficult to say whether the progres­sion of the neoplastic process was affected. An attempt was made to attain an optimum amplitude by altering the doses. The insignificant decrease in amplitude from phase C to D may have resulted from an increase in the weekly dose from about 10 mg to about 33 mg. This dose increase probably occurred too suddenly. A reduction in the weekly dose in phase E gave no deterioration from a chronobiological viewpoint. A febrile infection oc­curred in therapy phase E. The scattering is thereby greatly increased; the amplitude might possibly have been better without this effect. To sum up, the curve shows a significant improvement in the daily amplitude as an ex­pression of the circadian temperature rhythm. An overly-rapid increase in dose is probably related to a decreasing of the amplitude.

In the next example the patient's temperature curve extends over a period of two and a half years. The only therapy which the 59 year old woman patient received for polycythemia vera before treatment with vis­cum fraxini was phlebotomy about 1 - 2 times every two weeks. The com­plete temperature curve is too long, so only the median values for each set of two weeks are shown, and also the median values, (horizontal lines), for periods when the therapy stayed the same (fig. 10). Again, we can immedi­ately see a rapid increase in the amplitude as the morning temperature falls and the afternoon temperature rises. This new structure in the circadian rhythm was accompanied by a distinct improvement in the patient's condi­tion, which first led to an ability to work part-time, and then full-time, during the treatment period. In therapy phase F there again was a significant larger amplitude. This resulted from a further drop in the morning temperature and an elevation in the evening temperature and it occurred after a stay in a spa and a vacation of about ten weeks. Hematocrit values (figs. 11 and 12) were used to assess this patient's response to therapy in ad­dition to the circadian rhythmics. The phlebotomy times are shown at the top of each graph. After frequent withdrawals of 250 or 300 ml. of blood in the beginning it was only necessary to withdraw it 3 or 4 times a year there­after, (although the hematocrit level rose somewhat). The viscum fraxini D10 therapy twice per week now agrees quite well with the patient.

The problem of therapy assessment with the aid of rhythmological criteria will be illustrated with a third patient (fig. 13). The now 74 year old patient has a bladder carcinoma (Surgery 1/88; pT1, G3, multifocal). This patient gets continuous therapy but only takes measurements for 2-6 weeks at a time. Phase A shows the rhythmological findings before therapy, and after the beginning of therapy with abnobaviscum quercus the findings at first remain about the same. After an increase in the dose there is a temporary inversion of the rhythm. For two weeks the morning temperatures were higher than the evening temperatures (phase C). Thus through the in­crease in dose the phase of the rhythm was modulated, and this was fol­lowed by a normalization of the course. This phase modulation is sig­nificant. The patient continued to take the same therapy on his own, and when he came back after five months the amplitude was narrower (phases F and G) than before the beginning of therapy. After an increase in the dose by about 65% there is a possible phase reversal and then there is a widening of the amplitude. The narrowing of the amplitude in phase N is connected with a cessation of all viscum therapy. This was reason enough for us to continue the therapy.

Fig. 10   Median curves of morning and evening measurements; 14 day medians with standard deviation and determination of significance of the therapy-phase median values of the daily difference by means of the analysis of variance according to Scheffe. (Patient F.F., polycythemia vera).

Fig. 11   Course of therapy and hematocrit 1987/1988 (Patient F.K.)

Fig. 12   Course of therapy and hematocrit 1989/1990 (Patient F.K.)


Fig. 13   Median curve of morning and evening measurements; 14 day medians with standard deviation (Patient K.R., urinary bladder ca.)

Fig 14   Temperature curve (Patient B.J., fibroadenoma of the breast)

 

 
In conclusion let us look again at Simpson's indication of the existence of circalunar rhythm changes in "high-risk" and "normal-risk" patients. We now present the temperature curve of a young woman born in 1967 who had surgery because of the suspicion of breast carcinoma. It turned out to be only a fibroadenoma (fig. 14). The temperature curve was determined before, after, and during therapy with Abnobaviscum mali. The patient took no temperatures for a period of three months between cycles 5 and 6. In each case the statistical evaluation covered the time span from fourteen days before the beginning of the menstrual period on. The cycle lengths were be­tween eighteen to thirty days. The evaluation (fig. 15) shows a significant widening in the daily amplitude after the beginning of therapy. The widen­ing of the amplitude occurs here through a drop in the morning tempera­ture, with little change in the afternoon temperature. Since it turned out to be a benign fibroadenoma and not a carcinoma, the therapy was interrupted after three months to see what would happen. The temperature curve con­tinued to maintain a stable rhythm. As long as no clinical or rhythmological worsening occurs, we see no reason to continue the therapy.


Fig. 15: Statistical evaluation of the daily temperature differences (14-hr value minus 7-hr value) according to analusis of variance after Scheffe.

With the above, we have presented examples of temperature curves of several carcinoma patients and one fibroadenoma patient, which indicate a de-synchronization of the circadian internal temperature rhythm. These findings are not tumor-specific but they are connected with the overall con­dition of the tumor patient. One can successfully rebuild the circadian rhythm through therapy with Abnobaviscum®. This measurable resychronization is clearly connected with the condition of the patient, but at this time nothing can be said about an influence on tumor progression in this connection. We maintain, however, that a normalization of the cir­cadian rhythm can already be looked upon as an indication of a successful therapy. The goal of our further work is to develop organism-specific criteria for the proof of the effectiveness of viscum preparations.

 

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