What is the main message the study of spontaneous regressions can provide ?
The curative power of the human body with respect to cancer has been underestimated. This should have consequences for the therapy, but even more in prophylaxis.
How frequent are spontaneous regressions and remissions ?
Until recently, it was believed that these are rare events. It has been estimated that they occur with a frequency of 1/10000 - 1/1 Mio cancer cases with bias for particular forms of cancer like melanoma, sarcoma, neuroblastoma. A majority of these regressions is temporarily. How large the fraction of curative events is, is difficult to estimate, since patients often are “lost on follow-up”, i.e. do not show up in the clinic again. In 2001 we could show that many, if not a majority of spontaneous regressions were preceded by a feverish infection. Our 2001-hypothesis that an unspecific activation of the innate immune system is at the core of spontaneous regressions has gained evidence since.
A new study indicates that the rate of spontaneous regression has been underestimated ?
In a 2008 publication (Arch.Intern.Med 168,21; Nov.24 2008; www.archinternmed.com) it has been shown that spontaneous regressions can be very frequent for small lesions: they happen in up to 20% of breast cancer cases. How many of those regression happened after an infection was not investigated in this study. If this result becomes confirmed, the self-healing capacity of the human body has been drastically underestimated. This would have profound consequences in therapy: the gap between tumor rejection and non-rejection might be smaller than we thought, as might be the effort needed to assist the immune system.
Why has the phenomenon of spontaneous regression from cancer not been investigated thoroughly ?
Spontaneous regressions and remissions from cancer have been observed since cancer has been defined as a distinct remedy. Nevertheless, the phenomenon of spontaneous healing in cancer has never been regarded as instructive in main stream research. Several causes for this neglect can be outlined. The phenomenon is thought to be rare; its circumstances must be fathomed retrospectively; casual events without clear causative evidence are difficult to publish; a certain closed-eyes attitude among many clinicians, if not blunt ignorance: even in November 2005, an article in “Deutsches Ärzteblatt” states “There is still no indication how a spontaneous regression could be stimulated.”
Some literature seems to indicate a cancer inducing effect of infections ?
This correlation is certain for some viral infections, e.g. papillomavirus, and chronical viral liver infections. It is imperative to distinguish acute and chronic infections here. As a rule of thumb, chronic infections tone down the immune system, while acute infections activate it. The majority of evidence indicates beneficial effects of short term, curated and healed proliferative infections on the risk to develop cancer.
If there is a real beneficial effect of fever, why has it not been considered so far in cancer immunotherapy ?
The body of literature showing beneficial effects of feverish infection on cancer is immense, it consists of several hundred publications. One can find many voices in the medical literature over the last 150 years back which address these findings. But these voices have infrequently been spoken out, did not provide any or no convincing explanation, have not been heard by many and were not considered important by many. The supportive evidence these voices present has been disregarded or was interpreted as too weak. On top, for many, radiotherapy and chemotherapy deemed to be answer enough.
More than 100 years ago Busch, Coley and contemporaries infected cancer patients deliberately using bacterial extracts. How were the results ?
Coley and others achieved miraculous cures in some patients and failed in others by injecting bacterial extracts (Strep.pyogenes and Serr.marcescens mixed) multiple times. Their publications were not written according to present day standards, so crucial parameters are difficult to pinpoint. Benefit seemed to depend on i) the particular form of cancer, ii) extract preparation, iii) length of treatment, iv) site of injection, v) level of fever achieved and perhaps vi) patients individual genetic background. In an attempt to compare Coley's results, Richardson et al. (Alt.Ther.Health.Med .5 (1999) 42) tried to match 128 Coley cases with 1675 controls from the SEER cancer registry, with groups matched on age, ethnicity, stage and radiation treatment status. The median survival was 8.9 years for Coley's patients and 7.0 years for the modern group. Ralph Moss (pers.comm.) points out that Coley's results varied depending on the extract preparation. While there was no five-year survival with "Lister formula VIII and Sloan-Kettering formula XIV", 5-year survival was 58% with "Buxton formulas IV, V, VI" and 67% with "Tracy formulas X,XI". Injections close to tumor seemed to fare better than systemic injections. His daughter Helen Coley-Nauts published a paper in 1990 (Adv.Exp.Med.biol 267, 483-500) indicating that when treatment was continued for long (>= 6 month) and the best preparations are considered, 5-year survival reached an astonishing 80% in cases of inoperable soft tissue sarcoma.
How could fever therapy be implemented ?
Coley treated his patients by injecting a heat sterilized extract of Streptococcus and Serratia once or twice a week. Other bacterial or viral extracts leading to stimulation of the innate immune system and to generation of a Th1-response might be applicable as well. Dosage was increased until high fever above 39C was induced. This treatment was continued for weeks and month, a treatment of great strain (modern therapies can mean great strain as well). We believe, the molecular mediators for the induction of fever and the stimulation of the innate immune system are PRRL, i.e. substances produced by pathogens, such that PRRL mixes could be used for a fever therapy rather than bacterial extracts.
Which substances belong to PRRL ?
PRRL is a diverse class of molecules like LPS (lipopolysaccharide from bacterial cell walls), flagellin (a protein found in bacterial propellers), dsRNA (double stranded RNA found in viruses), CpG-DNA (DNA characteristic for bacteria), zymosan (a substance found in infectious fungi) and many others. Common to PRRL is that they are not produced by human tissues and that receptors on dendritic cells in humans are specialised in detecting PRRL rapidly. PAMP are PRRL binding to a special class of receptors, so-called Toll-like receptors.
What would be the advantage of PRRL compared to bacterial extracts ?
FDA approval for a bacterial extract is difficult today. One pre-requisite for drug approval are so called "structure-function-relationships", i.e. a clear understanding which substance in the drug interacts with which receptor in the human body. To achieve such an understanding is not possible with bacterial extracts.
Are spontaneous regressions triggered by PRRL ?
That is our hypothesis, which has been outlined in 2008. If that is correct, spontaneous regressions might not be really "spontaneous", after all.
Can PRRL be tested in cancer immunotherapy ?
Several PRRL are in clinical trials as adjuvants - i.e. as helpers, not main actors - at the moment, however, those therapy regimen did no respect lessons from the old experiments and from recent insights into the innate immune system appropriately. In these trials i) fever is regarded and treated as toxic adverse event rather than treatment enhancer; ii) single PRRL are applied rather than multiple; iii) number of treatments usually is much smaller than in Coley's time; iv) most patients are immune-compromised from prior treatment. The full potential of PRRL-therapy most likely will be missed, if PRRL are applied the wrong way.
Epidemiological studies indicate an anti-correlation between feverish infection and the risk to develop cancer later. Are there implications for prophylaxis ?
A hypothetical explanation for these effects would be that feverish infections destroy pre-cancerous cells. If that turns out to be correct, we should reflect whether it is wise to vaccinate against each childhood disease, to take antibiotics with each infection, to take aspirin und antipyretics against each fever. In one study, Kölmel et al. (Melanoma Res. 9, 1999, 511) showed a reduced risk of 40 percent to develop melanoma, when people with and without a personal history of infections were compared. Consider the reduction in personal sorrow and social expense if the incidence of cancer could be reduced by 40 percent.
What do you tell a cancer patient asking for your assistance ?
We believe that it should not be impossible to achieve remissions similar to the "old" fever therapy with bacterial extracts, now with a modified form of mistletoe therapy we call augmented mistletoe therapy (AMT). We have outlined our hypothesis and respective details in more depth in my book "Healing Heat" (amazon 2016) and in a recent publication (Orange, Reuter, Hobohm 2016). AMT is in test in some private clinics in Germany and Switzerland.
In brief, how does AMT work and is it dangerous ?
We need a window of 4-5 weeks for AMT. AMT can be applied in an ambulant setting. There should not have been any chemotherapy or radiation during the last 6, better 24, month. Using a selection of pharmaceutically approved drugs, we start with very low dosage applied subcutaneously on day one. We continue i.v. and increase dosage from day to day, to determine a fever inducing dose where fever comes down to normal within one day; this dose may be different for different patients. Then, AMT is applied 3 times a week over the next 3-4 weeks.
Exclusion criteria for AMT can be found in "Healing Heat". Fever can be unpleasant. If patients are weak, we recommend to have one fever inducing application per week plus two subfebrile doses. Compared to chemotherapy, radiation, checkpoint inhibitors, AMT is not dangerous. Very rarely, circulatory problems can occur, hence AMT should be done under medical observation.