I have no idea about the case and no interest in it.

As far as your question about proton therapy goes, if your standard required to use proton therapy is high level evidence then there is no place it is indicated because there is no high level evidence. If you are happy with limited clinical data and indirect comparisons together with the argument that it should work better because of the theory of dose distribution then you may consider it for pediatric brain tumors, chordomas and ocular melanoma.. See Allen M et al Radiotherapy Oncology 2012; 103:8 for an overview. 

I think it is an ongoing scandal that the burden of proof for procedural treatments is often very much lower than for medications, which allows people to propose their use as standard of care with very limited data, and to then be astonished when societal payers do not cover the often substantive costs. At law the onus of proof is on the prosecution: I dont see why this is any different in medicine.

The Ashya King Dilemma:

Fact, Fictions, and Failures in Medical Decision Making

The Ashya King case is a study in the unfortunate inaccessibility to the general public, and even to popular medical media reporting sources, of quality medical information for making informed evidence-based decisions. It was misreported (for example, it was claimed, incorrectly, that Southampton General Hospital did not have facilities for the new proton beam therapy (PBT); it has), misunderstood (five-year old Ashya King has medulloblastoma (MB), a primary brain tumor, requiring both whole-brain and spine irradiation or other treatment as well as chemotherapy, in order to minimize tumor leakage and escape into the cerebral-spinal fluid (CSF), and so focal-based radiotherapies have no appreciable advantage [1]) and misreasoned (see below) by virtually all parties involved. Indeed, experts in proton beam therapy at a press conference in London convened by the Science Media Centre (SMC) offered their view that the advantages of using a beam of protons rather than conventional x rays were minimal in this type of cancer (medulloblastoma), which in fact stands a good chance of cure if treated with conventional whole-brain/spinal radiotherapy in line with currently well defined protocols [2]; that fact is not seriously in dispute as the evidence reviewed shows. So I am not much concerned with the popular distortions, nor the media fury surrounding the tortured lines of the Ashya King narrative, but my primary focus is: what are the facts?

The answer to all these questions, as I demonstrate below, is No.

Proton Beam Therapy: Myth and Reality

There are three main advantages claimed for using protons instead of (conventional) photons in radiotherapy:

- Protons may reduce late side effects by sparing normal tissue,

- if indeed there are reduced adverse effects, then escalation of the radiation dose resulting in potentially better tumor control might be possible;

- Protons may reduce the risk of secondary malignancy.

But although advantage of protons over photons have been suggested in several treatment planning studies, but there are in fact no robust randomized controlled studies demonstrating true superiority of proton-based therapies over photon-based ones.

Thus, although it is often claimed that proton beam therapy (PBT) was able to spare the cochleae and hypothalamus better than conventional photon-based therapy from the posterior fossa boost treated to 30.6 Gy, nonetheless, such cochlea sparing in 23 children treated with proton therapy did not result in any clinical relevant benefits: it did not reduced ototoxicity and did not correlate with predicted dose to the auditory apparatus for proton-treated patients [3,4].

In addition, compared the risks of radiogenic secondary cancers and cardiac mortality in 17 pediatric medulloblastoma patients treated with either passively scattered proton beam therapy (PBT) or field-in-field conventional photon craniospinal irradiation (CSI), it was found that although despite perceived advantages of lowered risk for these potential harms (secondary cancers and cardiac mortality) in a large clinically representative sample in the United States, the magnitude of superiority in fact depended strongly on the status of the patients' anatomical development so interpretation must continue to be guarded and we can not yet draw general conclusions about superiority [5]. Nor do we can confidence from other studies, including a case report from the same team which also found that proton therapy confers lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient [6], since with only one lone pediatric patient being used for radiogenic second cancer risk estimation, the results lack all generalizability.

In fact, we have unsettling cautions: researchers at the University of Oxford have suggested in their studies that physical and radiobiological factors were shown to combine to give a higher risk of tumor recurrence under certain dose reduction schedules typically otherwise motivated for photon (rather than proton) therapy in “low-risk” patients undergoing proton beam therapy (PBT) [7], and that furthermore, without knowing more about the relative biological effectiveness (RBE)involved in the individual medulloblastoma context, the therapeutic ratio achieved may actually be reversed, especially in the case of fast-growing tumors with high α/β ratios situated in the CNS. What needs to be understood here is that higher α/β ratios entail that tumor response is less sensitive to the amount of radiation administered with each fraction, so that a lower radiation dose per treatment can typically be used, while lower tumor α/β ratios, entail that a larger dose of radiation per treatment can provide improved efficacy in terms of tumor control. The point the investigators are driving home is that in cases of fast-growing medulloblastoma tumors with high α/β ratios, proton beam therapy may lead, unintentionally, to higher risk of tumor recurrence, and hence in these not at all uncommon circumstances, proton beam therapy (PBT) may turn out to be inferior in terms of oncological safety (risk of tumor recurrence).

Furthermore, we must always remember that although prospective clinical trials using proton beam therapy (PBT) are now being increasingly conducted, very few are randomized controlled trials (RCTs) comparing proton beam therapy directly with conventional photon therapy, and there continues to be a notable scarcity of prospective data from clinical trials showing true clinically relevant benefits for proton radiotherapy despite its theoretical advantages, and without robust cross-confirmed prospective RCTs, it remains premature to accept the often overly optimistic current hyperbole of proton superiority in outcome, safety and toxicity. Nor, it must also be remembered, can we forget or overlook that improvements in photon techniques continue to be made, also enabling safe dose escalation so that any claimed advantage differential of proton over photon is typically of an increasingly narrower margin.

In this connection, I note that the conclusion of an evidence-based review by the American Society of Radiation Oncology (ASTRO)'s Emerging Technology Committee Proton Task Force [8], the largest and most robust critical appraisal of the evidence available, was that "In pediatric CNS malignancies there is a suggestion from the literature that PBT is superior to photon approaches but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients protons appear to offer a dosimetric benefit over photons but more clinical data are needed", conclusions that are in large agreement with those of a previous systematic review [9]: "The evidence on clinical efficacy of proton therapy relies to a large extent on non-controlled studies, and thus is associated with low level of evidence according to standard heath technology assessment and evidence based medicine criteria".

Finally, proton beam therapy (PBT) must be assessed separately for each malignancy context: the facts of its efficacy and safety for one cancer do not imply comparable ones for another cancer. Thus, in recent (2013) results of a Phase I trial of the long term cosmetic outcomes of proton beam radiotherapy conducted at Massachusetts General Hospital and reported at ASTRO 2013 [10], it was found that overall cosmesis judged by physicians was good/excellent for only 62 % of proton beam therapy patients compared to 94% for patients treated with conventional photon radiotherapy, and that the incidences of skin toxicities were also greater for the proton beam therapy group, with telangiectasia at 69% with proton beam therapy compared to just 16 % for conventional photon therapy, and pigmentation change standing at 54% versus 22% and late skin toxicity at 61.5 % versus 18% for proton beam therapy versus conventional photon based therapy, respectively. Thus, in this context proton beam therapy led to higher rates of long-term telangiectasia, skin color changes, and skin toxicities.

Where We Stand

Thus, to this day, clinical data is still required to substantiate that any gains found dosimetrically actually translate into true clinically relevant improvements in patient outcome, and note that because proton beam therapy needs a correction factor (relative biological effectiveness or RBE) to relate proton doses to photon doses, it currently uses a generic value, confounding easy comparisons. But note what we are NOT saying: although we demonstrate that the evidence base for proton beam therapy warranting clinical deployment over photon-based radiotherapies is immature and insufficiently robust to found clinical recommendations, nonetheless proton beam therapy does exhibit a number of potential advantages, that - once mature methodologically high quality RCT data arrives - may justify its relative favor as a radiotherapeutic intervention in the future. That day may yet come. But that day is not now.

The Evidence-Based Answers

So we can answer our three questions first posed above, as follows:

The fault is not with the loving and dedicated - but misguided and unguided, through no fault of their own - parents seeking the best treatment for their child, but rather with the medical community's continued inability to convey the practical implications of complex systematic reviews and critical appraisals in a form intelligible to the lay public to assist in making the best evidence-based medical decisions, and with the tendency of popular medical media reporting to provide breezy and readable, but ultimately naive and uncritical, coverage of these complex and important issues.

References

Dear Constantine, 

Many thanks for your brilliant contribution! Your analysis highlights some problems that goes far beyond the Ashya King case and it would be appropriate to continue discussing these problems:

1. Inability to adequately and credibly deliver justification of the specialist's / hospital's approach to treat malignancies (culture still prevails that patient listens and nods and agrees unconditionally with whatever the specialist has to say). 

2. Lack of solid clinical efficacy data to support the specialist's decision for a certain therapy to start or deny.

3. Lack of common sense. In theory, any prescribed treatment (medication or procedural) requires a certain history of clinical validation. However, when there is no sufficient validation one tends to go ahead prescribing procedures anyway without necessarily consider the fundamental biological consequences (not FDA-regulated?). 

4. It seems to me that there is no standard to define when clinical data become sufficient to justify treatment. Procedural prescriptions take place without the context of a clinical trial and patients are given false hope and die subsequently by the treatment rather than by the disease itself.

5. In my humble opinion, the emphasis to clinical data has overwhelmed the requirement to think biology: Killing any malignancy by radiation or chemotherapy is not only causing harm to the malignancy but also to the rest of the body, too often with damning consequences while still recorded as successfully treated.

6. Clinical evidence from the past may or may not pass unbiased and modern statistic scrutiny.