HITHOC & the guidelines for management of malignant pleural mesothelioma: Why inclusion matters

Dr. Marcelo Migliore, Dr. Stefan Hoffman and several other thoracic surgeons who spearhead large HITHOC (Hyperthermic intrathoracic chemotherapy) research programs have just authored an editorial for the latest December 2020 issue of the Annals of Translational Medicine.

In this thoughtful article, the authors comment on the absence of any mention or consideration of HITHOC for the treatment of malignant Pleural Mesothelioma (MPM) despite multiple studies showing as survival advantage for patients receiving HITHOC*.

You can read the editorial here.

Migliore et al. point out a couple of things in their arguments for inclusion:

Stating (paraphrasing for brevity) that given the current level of evidence for most of the existing treatments of MPM are rated as weak, it is difficult to understand why HITHOC remains excluded from consideration. This gives the erroneous impression that HITHOC is a new, untried/ untested experimental treatment with little to no evidentiary support. This is false. Even a cursory overview of the data shows this is clearly not the case.


Why is this important, you ask??

Doctors, (at least credible ones), don’t offer or refer patients for treatments that fall outside the approved guidelines. Referring patients for treatments outside of the approved guidelines is considered charlatanism at best, and medical malpractice at worst. It’s akin to giving your patient megavitamin supplements and sending them to a Laetrile clinic, instead of an oncologist. This is particularly unethical when dealing with cancer patients because the direness of their prognosis can make them susceptible to the worst medical scams in our society. But this also means that doctors are hesitant to send their patients for legitimate treatments such as HITHOC because it isn’t “recommended.”

-And.. and it’s not a small AND.. the current “recommended” treatments don’t have strong evidence supporting their use (or a lot of good outcomes.)

Now as the editor of thoracics.org, I am going to take argument this a little bit farther than the authors did in their article.

Migliore and his fellow authors are European.. So they and the majority of their patients don’t fall victim to the “American medical insurance conundrum”, where Americans pay enormous sums of money to insurance carriers who then turn around and deny payment for necessary medical treatments. But, most of my patients are American, so inclusion matters a lot to me, because inclusion or specifically, the lack of inclusion drives a lot of insurance payment decisions.

One of the ways insurance companies save money is by denying payment for any treatment that is considered experimental. (What an insurance company deems experimental can also be controversial but that’s another conversation). Whether that so-called experimental treatment has a high probability of saving or prolonging your life is not important to the insurance company. (In fact, for decades after bone marrow transplant was shown to be a very effective form of treatment for several types of cancers, insurance companies continued to deny coverage – because bone marrow transplant is expensive.)

In fact, this scenario was the basis for a very popular 1997 movie based on the John Grisham novel, “The Rainmaker.

(In the movie, Danny Davito and Matt Damon are in my hometown of Memphis, fighting for a client whose insurance has denied him a life-saving bone marrow transplant. )

As mentioned by the authors in the editorial, the omission of HITHOC from the guidelines suggests that it’s experimental. But as we’ve shown in multiple reviews of the data surrounding HITHOC, it’s been around for over 20 years and has a lot of data to support it’s use.

Even when a treatment isn’t deemed “experimental”, insurance companies don’t have to cover it. They routinely deny payments for treatments that are not part of standard treatment guidelines, so Inclusion in clinical guidelines is the first step to having the treatment included as part of Medical coverage.

In the case of HITHOC, inclusion in the clinical guidelines is critical. Patients with malignant pleural mesothelioma (and other cancers that are treated with HITHOC), don’t have a lot of time – and frankly, without HITHOC, their prognosis, and estimated survival time are both measured in single digits.

Without inclusion – patients never make it from their doctor’s office to the research program. Even if they somehow did find their way there (thru google, word-of-mouth or other means), most patients don’t have the means to pay for it, if insurance won’t help. (Even European programs, which are much more affordable than American programs, HITHOC can cost from 40,000 to 80,000 dollars. In the USA, the cost has been quoted as around a quarter of a million dollars.) So, inclusion matters.


For more information about any of the things we’ve talked about above: (about criteria for recommendations, current malignant pleural mesothelioma guidelines and all things HITHOC)

If you’ve never read a paper reviewing the guidelines for treatment of a medical condition, then you should know a couple of things first.

  • in these papers, multiple strategies or treatment options are listed
  • each of these treatments is then given a letter grade of A, B, or C based on the amount of scientific evidence that it works. (For more about the levels of evidence, see this article on the evidence pyramid).
  • A treatment with a high level of evidence (lots of scientific data, meta-analyses, double-blinded studies with large numbers of participants, etc.) would be ranked as 1A.
  • If we had another treatment, that seemed really effective, but maybe the evidence wasn’t quite as strong for that exact circumstance, it might be listed as 1B. As the supporting evidence for the treatments is reduced, treatments are graded as B, C and X. Level B recommendations are still things we still might consider using for patients, but less so for level C. Level X means that the treatment may actually cause harm. (Level X is often applied to treatments that were used historically, but are later found not to work. This happens quite a bit if you look at treatments used in the 1960’s versus now.)

So the authors are asking for HITHOC be mentioned in these guidelines, to be then ranked based on evidence. Since the evidence is graded, as we explained above, the authors aren’t asking for HITHOC to replace other treatments. They are merely asking for it to be listed as an option.

What are the current guidelines for treatment of MPM?

The current European guidelines for treatment of MPM are here. (In this guideline, they dispense with the standard grades of A, B, C and basically skip to palliative treatments in most cases. For example, they “recommend” talc pleurodesis as the first line surgical treatment – which as readers know, is a palliative treatment based on symptom management only.

The American recommendations also eshew the standard grading nomenclature, but A, B, C are merely substituted with srong, moderate and weak.

What about HITHOC? What is HITHOC?

*Many of those studies have been reviewed here at Thoracics.org: we have a whole section dedicated to cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITHOC).

HITHOC review of the literature (2018)

Author: K Eckland

World of Thoracic Surgery is a blog about the work, research, and practices of thoracic surgeons around the world. It includes case studies, [sometimes] dry research, interviews with thoracic surgeons along with patient perspectives, and feedback.

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