The compassionate, eulogy-like reactions to the news that Sen. John McCain is ending treatment for his brain cancer seem to equate this decision to ending life support. This response reveals an unfortunate misconception of cancer therapy among experts as well as lay people. The narrative suggests a belief that the chance of survival is a direct function of having treatment, and that stopping treatment means to abnegate the possibility that McCain is somehow benefitting from ongoing anti-cancer treatment, to however a small extent. But this is too simplistic. McCain’s glioblastoma, his war experience and his courage and wisdom jointly offer an opportunity to see the larger picture.

Cancer treatment is always a double edged-sword. While it takes out the mass of cancer cells by killing them, hence reducing tumor size, be it through beam, chemical or steel, tissue-stress and wounding imparted by these treatments eo ipso also stimulate cancer growth, making the cancer cells more like stem-cells, hence more resilient and more aggressive. In cancer treatment, almost never are all cells killed; and the surviving cancer cells, even at distant sites, are empowered by this stress-response. In addition, the dead cells in the tissue produced by therapy fuel inflammation and an aberrant regeneration which further enhance the tumor promoting stress-response.

This biological vicious cycle mechanism is a main driver of tumor recurrence but is commonly ignored. Since treatment never eliminates all cancer cells, cancer therapy is inherently a double-edge sword –like the war on terror: the more bad guys you kill, the more you empower the non-killed ones. The net outcome depends on the relative strength of these two opposite effects. Since, for ethical reasons, we never compare treating vs. not treating patients in clinical trials, it is difficult to assess the relative strength of these two opposite responses by the tumor tissue for each therapy strategy. Occasionally, an overwhelming majority of cells is killed by treatment, and the tumor collapses, taking down the few surviving cells: the patient is cured. But most of the time, the net outcome of the dual effect of partial killing and cancer promotion by therapy is a temporary relief from shrinking of most the tumor, and recurrence in more aggressive form is almost certain –a logical consequence of the aforementioned double-edge sword effect. Perhaps, instead of seeking maximal killing, using minimal dose for a gentler approach to avoid provoking the non-killed cells, as some bolder oncologists now try (often, motivated by alternative ideas), may yield a more favorable balance between the tumor-suppressing and the tumor-promoting effects of therapy. In fact, accumulating evidence suggest that there are settings in which standard (maximal dose) treatment accelerates tumor progression (e.g., in breast cancer, melanoma, etc), sometimes dramatically so, notably in the case of immunotherapy.

This phenomenon affords a rationale for the assumption that circumstances exist in which cessation of treatment actually might be beneficial. Hence, there is a rather small (given what we know about glioblastoma) but non-zero probability that John McCain may actually live longer without than with continuing chemotherapy. Scenarios in which treated but non-responsive (recurrent) tumors are more aggressive than non-treated ones can be readily observed in animal experiments but have never attracted much attention.

John McCain knows that maximizing the killing of thy enemy is a hopeless undertaken and not the solution — you only empower them. Restrain from using force is sometime wiser. But maximal killing of tumor cells à tout prix is still the prevailing doctrine in mainstream oncology.

Here is a solution, shown at least in preclinical studies: prevent the surviving and stressed tumor cells from causing more harm by using a new class of non-toxic drugs not aimed at more effective killing but at breaking the vicious cycle of tissue-damage-induced tumor progression.

Cancer experts could learn from John Mc Cain: Think outside the box. This takes courage and wisdom that the former sadly lack (with few exceptions): the wisdom to see the reality on the ground which differs from the ingrained doctrines of arm chair generals and the “thought-leaders” of cancer research. Specifically: think outside the box of killing cancer cells.

For more related ideas on MEDIUM, see posts here and here.

POST SCRIPTUM: The evening after I posted this, John McCain passed away. It seems that treatment was ceased for more encompassing medical reasons than the realization that the tumor is not responding to the (toxic) treatment anymore, that is, the term ‘treatment’ in the media referred to palliative intervention and or care to address other medical problems. Nevertheless the lessons presented above on the fundamental scientific principles in our fight against cancer remain valid. But more so, I am deeply grateful to the opportunity to communicate these ideas in the context of John McCain’s admirable spirit in fighting for a cause and thinking beyond the confines of established doctrines.

Scientifically, after ending (or declining) cancer treatment, otherwise healthy patients can live for weeks if not months. We just cannot predict the natural course of disease in individual case — and whether a patient would have lived longer after forgoing more therapy. In animal models, as mentioned above, there are cases where mice with a deadly tumor do better if untreated than the ones that were treated but did not respond to the therapy (but not better than the ones that were treated AND did respond). This is shown in the figure above (from this paper).

How the double-edged sword cuts depends on the individual patient.

Institute for Systems Biology

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