RRP ISA Survey Results

    Dr Steven Gray on MMC

    MMC Issues

    From: Dr Steven Gray's e-mail (posted with permission)
    Date: 19 Jan 2001

    [Ed. note: Dr. Gray, who is now deceased, was one of the most highly respected otolaryngologists of his time. His clarity of mind and  compassionate heart made a profound impression on many people. This was originally presented in two separate e-mails. Without taking any other literary liberties, we have brought the two e-mails together in one article.]


    My name is Steven Gray, I am a laryngologist who because of a disability from my autoimmune disease am now doing only research. I practiced laryngology for 12 years before stopping which occurred in 1998. I was very active with RRP care because I did a fellowship in pediatric otolaryngology and my practice focused on pediatric and adult laryngology issues. I have been very familiar with these issues. I currently am funded through NIH to do research on vocal fold scarring. We also are currently involved in an IRB multi-institutional study using Mitomycin C in the larynx. I have been active in the RRP community in previously years, but not recently. . . . Marshall Smith and Harlan Muntz, both very good physicians who do a lot of RRP work, saw your note and knowing of my expertise in the area, asked me to respond to you. Although I am not sure I qualify as an expert in laryngeal scarring, I do have laryngeal scarring in my own vocal folds as a result of many laryngeal operations and it has become an interest and passion of mind. I am not sure our profession has anyone who could rightly be called an expert in this area. It is the goal of most surgeons to not be an expert in this area, because hopefully your patients are not getting scar from your operations. Nevertheless, because of my personal interest in it, I have learned more about it than perhaps others. 

    Let me start by saying that most scar has as it source a surgical or traumatic injury. That starts the wound healing process by which scar is formed. Despite medications and other coexisting conditions, it is surgery that has the strongest correlation with scar. Once a surgery injury has been received, there are many things that can make wound healing and scar worse. But still, it is surgery that is the start of the process....

    ....You mention the use of Mitomycin C, an agent with which we have a lot of experience here. If Mitomycin is used at the same time as Cidofovir and surgery, I can see problems. Mitomycin prevents normal healing. It blocks DNA synthesis and blocks RNA synthesis and blocks the cellular machinery to make proteins. Proteins are required for wound repair. Fibroblast mitosis and migration are required for wound repair. This is all blocked by Mitomycin C. It is also likely that Mitomycin preferentially inhibits fibroblast activities more than epidermal cell growth or epithelialization. This means that wound repair is probably more inhibited than the inhibition of the skin of the larynx growing back over the wound. In some cases this may be desirable. But in the larynx, where a thinner vibrating portion of the vocal fold in not desirable, it is probably not advantageous.

    For good vocal fold activities, we need a relative thick layer of the vocal fold called the "lamina propria" which is kind of soft and gelantinous in composition. This allows easy vibration of the folds. This area is biologically quite active in producing certain proteins helpful in vibration. Active and prodigious protein production is the key for a healthy lamina propria layer.

    Last year a study was presented at the American BronchoEsophagology Association showing that dogs receiving vocal fold surgery and Mitomycin C injections into the vocal folds at the time of surgery had "worse" results than dogs receiving only surgery. Worse results were determined by stiffness or scarring of the vocal folds and also by how well the vocal folds vibrated. A caution was given to surgeons that although Mitomycin C may be useful for the treatment of scarring in certain laryngeal conditions, the use of Mitomycin C injection directly into the vocal folds may result in worse vibratory properties of the vocal folds (meaning worse voice). We have done further research in this area and presented our early results of that research at the neurolaryngology study section last year showing marked inhibition of protein production following Mitomycin C injections. Protein production drops by over 50% in some cases. This effect is probably temporary ( maybe a month or two). But while the tissue is in a healing state, a month or two of decreased protein production may be enough to result in a permanently different and thinner tissue. ( The finding of the dog study).

    Regarding the dog studies you cited showing MMC being useful in treating stenosis: Indeed they were very good articles and the authors deserve a pat on the back and our thanks for doing this good early research on MMC. It is their work that got most of us interested in MMC. However, in looking at their work, it is still relatively short term research. This is not a criticism of their work. Only an limitation to how far we can extend their conclusions and how to apply their results. You will notice that in one of the articles cited, that the difference between the MMC treated group and the control is quite large and dramatic, but with each week that passes, the difference between the two groups becomes less. If enough time passes, do the two groups end up the same? The research doesn't extend out far enough. I believe that the two groups will still be different at a year. But I suspect the difference between the two groups at a year will not be nearly as large as it was at one month or 3 months. Now, again these are my thoughts and are not based on any study. These studies are underway by us and other groups.

    .... Mitomycin C is currently being researched more in properly designed IRB studies for the use of treating laryngeal and airway scarring, but these conditions are usually areas where a thinner, atrophic tissue depleted of proteins is the desired outcome, such as laryngeal webs or stenosis.

    Use of Mitomycin C injections, under the current formulations that it is prepared, given as direct injections into the vibrating or membranous portion of the vocal folds, is possibly with some risk as shown above. Further studies need to define this better. It is possible that further studies of Mitomycin C will find that it is a great help in vocal fold surgery, and perhaps our concern about its effect on voice will be completely unfounded. On the other hand, we may find that direct injections of Mitomycin C poses a significant voice risk. At this time we simply do not know. Incidentally, our research shows that topical application results in greater protein suppression than injection. 

    Since labeling on Mitomycin C does not list it is indicated for use in the larynx or vocal folds, and it does not yet represent standard of care in today's laryngology practice (it would still be considered experimental) I would suspect that IRB human research form which patients sign for use of Mitomycin C or Cidofovir mention possible voice effects.

    Given the above findings and the cautions that both the reporting investigative teams suggested, I find it a little curious why you feel that the Cidofovir is responsible for the scarring [Ed. note: Clark Rosen, MD  confirmed Cidofovir can cause scarring at the 2003 AAO RRP mini-symposium and also at the RRP Focus Group prior to the 2002 AAO meeting]. Indeed it is possible that Cidofovir played a role, it is just that there are no reports from anyone else that it is a problem, whereas even though Mitomycin C has been used in many less patients than Cidofovir, already we are concerned about its potential effect on the voice and vocal fold vibration. Mitomycin C has a limited time effect. 

    I have no doubt that Cidofovir may cause an intense area of necrosis. But just as in burns, if the burn or area of damage is confined to the epithelial layer, the degree of scarring is much less than if the injury also involves the underlying lamina propria or connective tissue. 3rd degree burns result in much worse scar than 2nd degree burns. Theoretically, RRP is confined to the epithelial cells, so the area of necrosis should be confined to the epithelial layer. Nevertheless, I totally agree with you, that the combination of Cidofovir and surgery, (surgery causing the base of tissue injury and wound repair and Cidofovir inducing an additional epithelial necrosis) may set the stage for a more aggressive wound repair process (more scarring). Surgeons may need to be more cognizant that the combination of the two may predispose people towards a more aggressive wound repair response. It is intriguing to consider the potential effect of incidental or accidental topical application of Mitomycin C (remember that topical application is more potent than direct injection) on this. Basically you would have a surgically injured site, with overlying epithelial necrosis, now combined with a very potent inhibitor of wound repair. This could certainly lead to a prolonged wound repair process due to the MMC but also due to the fact that you are delaying epithelial coverage of the wound due to the epithelial necrosis. So you have an open wound that is healing slowly. In my mind that sets all the right parameters for a membranous fold that will heal with a contracted, thin lamina propria.

    It may be that a few more months, as the effect of Mitomycin or Cidofovir gets more distant, may show some improvement in a voice that has been adversely affected by the use of MMC. As one gets farther out from the injury, voice exercises that are not injurious may be useful. Voice exercises have not been shown to improve scarred vocal folds- that study has not been done. But vocal exercises, theoretically, may be helpful in the tissue remodeling process that goes on in scar maturation for up a year after the start of wound healing. A randomized, prospective, observational study of 58 patients showing that vocal function exercises were statistically significant (better) in improving the voice across a mixed population of people with voice problems is in press in the Journal of Speech and Hearing Research.

    Perhaps the most important item is that I believe that the next few years will result in significant improvements in methods to treat scar. Our research group is extremely involved in this, but so are many other groups. Findings from any of these groups (including large corporations, small biotech firms) would be helpful to you ( and maybe me). The area of connective tissue scarring has been recognized by many to be extremely lucrative if something is discovered to improve or treat scarring. Scarring is a big problem for many people (think of the people who have been burned or severe traumatic injuries (or joint contractures). So a lot of research is going on. Our own group will likely start an IRB proposal to address some of the solutions for scarring which are being proposed by certain research groups within the next year. But I would not jump the gun. I really think that waiting just a couple of years more will allow you to be treated with methods that are not currently available. 

    I think what we are beginning to experience is that we now have at our disposal some very powerful tools. Individually they are very useful, but perhaps when combined, their individuals good effects and strengths may result in potentially deleterious conditions or consequences.

    Is MMC useful? I think the data is showing that it is. Good studies showing efficacy are still lacking? Reports of studies in progress and anecdotal reports seem to indicate a very useful role. However, it probably isn't as wonderful at "curing" scarring as we initial thought. Currently it is probably best used in conditions where you truly want to block the wound repair process and you hope to achieve a smaller, atrophic or non-existant piece of tissue. So areas of stenosis, webs, granulation tissue, these may be conditions that doctors are thinking are the best treated with MMC. However, I remind us that this is still conjecture by me and many physicians may think differently about this, and I certainly would not argue with them- we simply don't have the data yet.

    Regarding sharing this with others. I will leave that up to you....I need to caution again that much of these messages are how "I" put this together. It is not "truth" nor do we have strong evidence based on well designed studies supporting some of the ideas here. These are educated opinions based on studies and knowledge that we have available. Have I put all this stuff about scarring and vocal folds together correctly?- Only time will tell. Likely I (we) am (are) right on some items and wrong on others. Next, I am concerned that by mass mailing this to everyone we may be suggesting a standard of care. I don't want this to sound like or be an indictment for any physician who disagrees with me or chooses to practice differently. As indicated, we lack any studies to define a standard of care with scarring.

    Dr. Steven D. Gray 
    Charles and Alice Hetzel Presidential Chair 
    University Hospital 
    Salt Lake City, Utah