Radioresistant Glottic Cancer
Alexander Osborn, M.D.
February 22, 2007

Our patient is a 53-year-old man who presented to the Michael E. DeBakey VA Medical Center with three months of hoarseness. He denied any other symptoms such as weight loss, dyspnea, stridor, and otalgia.

His past medical and social history were significant for a 30-pack-year history of cigarette smoking that he quit 20 years ago. The tobacco use was coupled with five to six drinks of alcohol a day.

On physical exam, his exam was notable for a left true vocal cord mass, which did involve the anterior commissure. There was decreased cord mobility; however, the cord was not fixed. There was also noted to be no subglottic extension of the tumor.

The patient was taken to the OR, and direct laryngoscopy and biopsy were performed. The biopsy was positive for squamous cell carcinoma. He underwent a CT, which confirmed our clinical finding that there were no metastatic lymph nodes in this patient. Accordingly, he underwent radiotherapy; a fairly standard treatment at the VAMC, 66 Gy divided into 33 fractions of 2 Gy each. After he completed his radiation therapy, he was lost to follow-up in our clinic until five months later, when he presented again with recurrent hoarseness. Exam revealed an exophytic lesion. He was taken to the OR, and a repeat biopsy was performed. Squamous cell carcinoma was found, and he underwent a total laryngectomy. He is now four months out from his laryngectomy, and he is doing fairly well with no evidence of disease. He speaks through a TEP prosthesis, and overall seems to doing well.

First, I will mention the incidence of recurrent therapy for T1 and T2 lesions. Although there is a range in the published literature, these numbers came from a review in the Otolaryngology Clinics of North America. The rate of recurrence is anywhere from 7% to 19% and 12% to 33% in T1 and T2 lesions, respectively.

Let us look at what makes a tumor resistant to radiation therapy. First I will spend a little bit of time talking about the way radiation works to kill cells. Radiation causes double-strand breaks in DNA, an overwhelming number of which causes apoptosis or programmed cell death. When the radiation hits a cell, some of its effect is direct, namely the DNA itself will be directly ionized forming a DNA radical, basically a free-radical DNA molecule. This breaks the backbone of the DNA molecules and causes a break. More commonly, however, ionizing radiation will ionize water and create a hydroxyl radical, which then interacts with the DNA, again forming a DNA radical. DNA radicals can be scavenged by cellular free radical scavengers, and if that occurs, the DNA radical is eliminated and actually the backbone of the DNA molecule fits back together and the DNA damage is resolved. If, however, that radical reacts with molecular oxygen, that radical undergoes peroxidation, and the break in the backbone is stabilized and can no longer be simply repaired. Thus, for DNA to be effectively damaged by ionizing radiation, there has to be an adequate supply of molecular oxygen. Cells can become naturally resistant to radiation if they are in a low oxygen environment, and that is what often happens to these tumors as they outgrow their blood supply: certain parts of the tumor may be operating at minimal oxygen concentration, and thus these are inherently or naturally resistant to radiation.

If we look at tumor and treatment characteristics that are associated with resistance to radiation, these are the characteristics that we find. Tumors that involve the anterior commissure are more resistant to radiation, as are bulky tumors, tumors with decreased cord mobility, and tumors that extend to the subglottis or supraglottis. The patient in our case presentation had decreased cord mobility and anterior commissure involvement, and extension into the subglottis. The way you deliver radiation also determines how a tumor reacts. Longer courses with more lower dose fractions are less effective than shorter courses with higher dose fractions, even though the total dose may be equal. One thing I want to point out about these physical characteristics is that I don’t feel there is something special about the positions themselves. What extension these areas represent is perhaps a more aggressive tumor biology and so tumors that are more aggressive or more advanced are going to be more resistant. Thus, you could argue that extension is reflection of the molecular makeup of these tumors.

One of the first attempts at analyzing the molecular makeup of radioresistant versus radiosensitive tumors was this effort in 1991. The authors looked at 29 tumors, half of which were sensitive to radiation and half of which were resistant to radiation. They simply looked at the DNA content of these tumors. What they found was that 5 of these 29 tumors had more than the normal copy of DNA. All five of those aneuploloid tumors were radioresistant. This was not a very sensitive test, but it was a highly specific test. More recently, people have started to look at molecular markers. One of the more active areas of investigation is the Bcl-2 marker. Apoptosis occurs when cytochrome C is released from the mitochondria, and this release of cytochrome C is promoted by the Bax‑Bak complex. Bcl-2 inhibits the action of this complex, inhibiting cytochrome C release, and inhibiting cell death. So, basically Bcl-2 is an anti-apoptotic protein; therefore, it stands to reason that tumors in which Bcl-2 is overexpressed might be more resistant to apoptosis and, therefore, more resistant to radiation. In a pilot study performed by a group in England, a number of molecular markers were examined: the P53 tumor suppressor, the P16 and P21 CDK inhibitors and two members of the apoptosis pathway. Only Bcl-2 was found in this pilot study to be significantly differentially expressed in radioresistant versus radiosensitive tumors. This group developed a rather large tumor bank consisting of 124 matched samples of resistant and sensitive tumors. They looked at Bcl-2 expression and found a statistically significant difference in its expression between resistant and sensitive tumors. This study brings up an interesting idea that as more markers are found using gene expression arrays, and radioresistant and radiosensitive tumors are compared to one another, then more markers will be found and, eventually, you might be able to come up with a panel of markers which one day might actually give a very high sensitivity or very high specificity for tumors that will be radioresistant.

I would like to talk about one more marker; the COX-2 protein. The same authors, using the same tissue bank, found COX-2 was differentially expressed in sensitive and resistant tumors. Although the sensitivity and specificity, seen in this table, does not make COX-2 especially useful as a clinical marker of resistance, it does bring up the idea that if we could perhaps use COX-2 inhibitors, we might get more resistant tumors to become sensitive to radiation. This hypothesis has essentially been attempted in in-vivo, in mouse xenograft models. Seen in this figure are two sets of animals. One has been implanted with a COX-2 positive tumor material, and one with COX-2 negative tumor material. These black lines represent animals that have been treated with radiation and either placebo or a COX-2 inhibitor. This is a measure of tumor volume over time. You can see that tumors grow more slowly if a COX-2 inhibitor is added to the treatment regimen of these animals. These animals were treated with radiation and COX-2 inhibitors, and their tumors grew more slowly than those that were treated with radiation alone. This effect is abolished if the tumor does not have any COX-2 overexpression. This lays the foundation for clinical trials in the future, wherein patients would be given COX-2 inhibitors as an adjunct therapy to their radiation in order to enhance radiosensitivity.

I am going to move on how to we treat recurrent and radioresistant tumors. We have currently three main forms of treatment: endoscopic laser removal, open organ preservation surgery, and total laryngectomy. There are some criteria that have been laid out historically and then tested over time to help us decide who is eligible for these organ preservation therapies and who should get a total laryngectomy in the case of recurrence. These criteria were initially defined by Miller in 1970, and as I said, tested later on. These are criteria. The contralateral cord has to be free of tumor, and the arytenoid also has to be free of tumor. Subglottic extension in the resistant tumors should be no greater than 5mm. The cartilage should not be invaded. The mobility of the affected cord can be reduced, but it cannot be fixed. The recurrence should be at the site of original disease. Because of the compromised glottic function and the long rehabilitation that is required after organ preservation surgery, these additional criteria were proposed: good pulmonary function, few comorbidities, and a willingness to undergo a long rehabilitation, which can, in some cases, be as long as 6 to 9 months in learning to swallow again. Because of the long rehabilitation and other criteria, an age less than 75 years is preferred.

Just a quick overview of the two different types of open organ preservation surgery. The more commonly used method is the supracricoid partial laryngectomy with either hyoidoepiglottopexy or a supracricoid hyoidopexy. You can see that the thyroid cartilage and vocal cords are removed, and then the hyoid bone has been taken down and fixed to the cricoid cartilage. This is a view from the top. You are looking down the airway here, and these are the arytenoids pexied forward in this picture. This has two purposes: one is to close the airway and provide more airway protection here, and the second it to provide a phonating surface here along the arytenoid. The other type of open organ preservation surgery is this vertical hemilaryngectomy, originally described in the early 1950s. The thyroid cartilage is split anteriorly to the midline and laid open, and then the lesion is removed. The top part of the thyroid cartilage is then sutured down to the inferior remaining portion, and the mucosa is reapproximated. When this mucosa is reapproximated, it can be buckled or sometimes a fascial graft is placed underneath in order to provide a protruding surface for the opposite cord to phonate against.

I am going to spend a minute now talking about how these patients do. Basically, is organ preservation surgery a good option for people with recurrent disease? I was unable to find a good head to head study that took patients that were eligible for partial laryngectomy and then randomized them either into partial or total laryngectomy arms. There are, however, in the literature, a few studies that compare the oncologic outcomes of patients who are eligible for partial laryngectomy to those outcomes of patients who were not eligible and received total laryngectomy. This is a review of 43 cases from Memorial Sloan-Kettering that shows that the overall survival of patients who received a partial laryngectomy is better than patients who receive a total laryngectomy. This is not because the partial laryngectomy is a better operation, but rather because these patients have less advanced tumor at that time or the tumor may be less aggressive, and so it is easily treated. The take-home point of this study is that partial laryngectomy is, however, a good option because it does provide good overall survival and disease specific survival for a select group of patients, namely patients with early recurrent disease. This is shown here, when survival is stratified by stage at recurrence. Patients with T1 and T2 staged recurrent lesions survive longer than patients with recurrent T3 and T4 lesions. These results were mirrored in a large study of 112 patients at MD Anderson where again, patients who are eligible for conservation surgery had better survival than patients who were not. Again, disease-specific survival was better for patients who are eligible for conservation surgery versus total laryngectomy. Another interesting finding brought up in this study was that the rate of complication was actually higher in patients who had a total laryngectomy than patients who had a conservative surgery, and that complication was largely due to pharyngocutaneous fistula.

So, partial laryngectomy seems to be a viable option for patients with low-T stage recurrences. It is also psychologically a very appealing alternative for patients. Despite the psychological appeal, however, a study I would like to mention compared the quality of life between partial laryngectomy and total laryngectomy patients. There are two quality of life questionnaires as well as a voice-handicapped index questionnaire that can be given to partial and total laryngectomy patients. What these authors found was that patients, in a testament to the adaptability of the human spirit, having received a partial or total laryngectomy, seemed to score very similarly on these quality of life questionnaires. The only significant difference was in the categories of smell and tastes, where, of course, partial laryngectomy patients reported a higher quality of life than total laryngectomy patients.

I was unable to find a good head-to-head study that compared different types of organ preservation procedures. The closest was a compilation review of 23 papers and 552 cases of organ preservation procedure via open partial laryngectomies or endoscopic laser treatments. One thing I should mention is that the criteria for endoscopic laser treatment are essentially the same as that of an open or partial laryngectomy; however, there is an additional criteria, in that the entire tumor must be able to be visualized endoscopically. If that is not possible, then the option of endoscopic laser treatment should not be undertaken. In this review of all these papers, open procedures achieved 90% ultimate control compared to 83% for endoscopic laser procedures. That was balanced with the endoscopic treatments rarely needing a tracheostomy and their relatively rapid swallowing rehabilitation. You just need to keep in mind that this is not a head-to-head study. These are done at different centers by different authors, so take the results with a grain of salt. I think it would be a little bit of a stretch to say that open procedures are that much better than endoscopic laser procedures.

Lastly, with organ preservation surgery, I wanted to address the possibility that patients who have been treated with radiation are more likely to have postoperative complications. This is true in this study that analyzed patients undergoing supracricoid partial laryngectomy after radiation versus supracricoid partial laryngectomy as the initial therapy for their tumor. The results are that patients who had been treated with radiation experienced early post-op complications more often; however, late complications and medical complications are not significantly different, nor are the times to decannulation or swallowing. Radiotherapy in and of itself is not really a contraindication to doing these organ preservation surgeries. We just have to be aware of the possibility for more complications in the presence of radiation.

Briefly, I will talk about management of the neck in recurrent glottic cancer. This is a study on how we manage the clinically negative neck in the patients with recurrence at the primary sites. One of the early studies found that 3% of patients that had their primary lesions cured by radiation would recur in the neck. If patients had a recurrent tumor at the primary site, the incidence of failure of the neck rose sharply to 1 in 5. So, the authors of this paper recommended that all patients with recurrent glottic cancer at the primary site undergo neck dissection. This recommendation has been refined somewhat over the years. I will mention two studies. One was a prospective study that analyzed patients with original T1 or T2 lesions that were treated with radiation. All the patients included in the study had recurrent cancer, their neck was clinically negative at the time of recurrence, and they all underwent bilateral neck dissection along with their salvage laryngectomy. What the authors found was that 10% of the T1 recurrences and 28% of the T2 recurrences had disease in the neck upon microscopic examination. Looking at the characteristics of the patients with neck recurrence, they found that only 3 or fewer nodes were found, they were all ipsilateral, they were all at level 2 or level 3, and most importantly, they were only in patients that had T3 or T4 lesions on recurrence. So, the authors state that the patients with T3 and T4 lesions at recurrence undergo an ipsilateral neck dissection. A similar study, again at MD Anderson, had somewhat different results. Namely, they found cases of bilateral neck disease. Thus the recommendations of this study were for bilateral neck dissection in rT3 and rT4 lesions.

Last, I will talk a little bit about surveillance. How do we monitor our patients after they have undergone radiation? How do we find recurrences, and how do we diagnose them? Two studies by a group in the Netherlands have analyzed the follow-up protocol used in Europe for patients who have had radiation therapy for early glottic cancer. The regimen consists of 17 visits over the first 5 years and 22 visits over 10 years. They found all the patients that had recurrences and they divided them into 3 categories. Twenty percent of the patients were found on routine visits, and they were without symptoms. This is the population that screening is supposed to find: the asymptomatic patient who comes into your clinic for a routine checkup and you see a suspicious lesion on the glottis. However, most of the patients have symptoms and had recurrence found on a routine visit, or they have symptoms of recurrence such as hoarseness or dysphagia and they scheduled an extra visit. They called the clinic and said, “I am having some trouble swallowing,” or “I am having hoarseness,” and they come in before the next appointment because they were worried. So 80% of the patients in this study that had symptoms at the time their recurrence was found. In the study they found that there was no difference really in survival overall, or disease-specific survival, between the groups. So, it did not really matter when or how the recurrence was found. The patients that were found on routine screening without symptoms did not really have an advantage over these patients that were found with symptoms. Now, this is not to imply that our post radiotherapy patient should just be sent off and asked to follow up on a PRN basis. I think that there are a number of reasons that we should follow patients routinely, not the least of which is for their peace of mind or our peace of mind. Also, at least at the VAMC, a number of our patients continue to smoke after their primary lesion is treated. Routine follow-up visits give us the chance to aggressively counsel them against smoking and promote smoking cessation. Additionally, in looking at the patients that had symptoms of recurrence and had recurrence diagnosed at a routine visit, it is impossible to say when they would have come to clinic if they did not have a visit scheduled. They may have waited much longer and waited until the tumors were far more advanced. Unfortunately, it is going to be difficult to do a good prospective study, because I think it would be difficult recruiting patients into a study where we tell them up front that “We are not going to follow you as often. We are going to rely on you to tell us when you have cancer coming back.” So, as far as optimizing our follow-up routine, it seems at least that the one used in Europe detects cancers in a prompt enough fashion and confers good outcomes on patients. However, we do need to tailor that routine based on our patient population. At the VAMC, as I mentioned, a lot of our patients require more frequent follow-up. If they routinely miss routine visits or they need smoking cessation counseling, they may need more aggressive follow-up routines at least during the first 3 years, when most recurrences occur.

The protocol for diagnosing recurrent tumors has also been studied. At the VAMC, we tend to take our patients to the OR if they have a suspicious lesion. We ask them to repeat a direct laryngoscopy and biopsy. This means of diagnosis has been analyzed by a study by a European group. You can see that with 131 patients with suspicious lesions, this is the kind of path that they had to take in order to end up with a final diagnosis. Fifty-one patients were found to have recurrence on the first laryngoscopy; 78 patients were negative, and ultimately, about half of these were disease-free and the other half were found to have recurrence. So, there is about a 50% false-negative rate on the first pass when the method of direct laryngoscopy with biopsy alone was used to come to a diagnosis. Furthermore, if you look at the number of actual trips to the OR that is required in order to categorize these patients, many of them had to undergo multiple laryngoscopies to arrive to a final diagnosis, positive or negative. This brings up the point that we should probably, if it is available to us, use adjunct means of diagnosis like CT or PET CT coupled with direct laryngoscopy in order to decrease the number of trips to the OR.

I will summarize. We have talked about new ways that are on the horizons for us to predict responses to radiation therapy. We have looked at the outcomes of people with partial laryngectomies, and it seemed be a valid option for select group of patients with recurrent cancer. With advanced stage recurrences, neck dissection either ipsilateral or bilateral should be part of the salvage operation. There is room improvement in the way we surveil and diagnose recurrence.

Case Presentation:

E.C. is a 63 year-old man who presented to the VAMC with three months of hoarseness. He denied weight loss, dyspnea, stridor, otalgia, and throat pain.

His past medical history was positive for hypertension and HLD. Currently medications include Metoprolol and Lipitor. There is no known history of drug abuse. Social history consists of a 30 pack a year tobacco use; however he quit 20 years ago. He currently drinks 5 or 6 alcoholic beverages daily.

Upon physical examination, his ears showed EAC clear with no effusion or perforation. His nose was moist mucosa with no anterior masses. Oral care/oropharynx: soft floor of mouth and base of tongue, no lesions. HP/L: left true vocal cord mass involving the anterior commisure and extending into ventricle, decreased cord mobility, no subglottic extension. Neck: no lymphadenopathy

Subsequent biopsy of the lesion was positive for squamous cell carcinoma. A CT scan of the neck was negative for metastatic nodes.

The patient underwent 66 Gy radiotherapy in 2 Gy fractions, and he was subsequently lost to follow-up. He presented with the complaint of hoarseness five months after completing his chemotherapy. Subsequent exam revealed a LTVC lesion and biopsy confirmed recurrence of squamous cell carcinoma. The patient underwent total laryngectomy and is doing well four months post-op.

Bibliography:

Alpen EL. Radiation Biophysics, 2 nd ed. San Diego: Academic Press, 1998.

Biller HF, Barnhill FR Jr, Ogura JH, Perez CA. Hemilaryngectomy following radiation failure for carcinoma of the vocal cords. Laryngoscope 1970;80:249-252.

Brouwer J, Bodar EJ, DeBree R, Langendijk JA, Castelijns JA, Hoekstra OS, Leemans CR. Detecting recurrent laryngeal carcinoma after radiotherapy: Room for improvement. Eur Arch Otol Rhinol Laryngol 2004;261:417-422.

Chen MF, Chang JT, Tsang NM, Liao CT, Chen WC. Radiotherapy of early-stage glottic cancer: Analysis of factors affecting prognosis. Ann Otorhinolaryngol 2003;112:904-911.

Condon LT, Ashman JN, Ell SR, Stafford ND, Greenman J, Cawkwell L. Overexpression of Bci-2 in squamous cell carcinoma of the larynx: A marker of radioresistance. Int J Cancer 2002;100:472-475.

Ganly I, Patel SG, Matsuo J, Singh B, Kraus DH, Boyle JO, Wong RJ, Shaha AR, Lee N, Shah JP. Results of surgical salvage after failure of definitive radiation therapy for early-stage squamous cell carcinoma of the glottic larynx. Arch Otolaryngol Head Neck Surg 2006;132:59-66.

Holsinger FC, Funk E, Roberts DB, Diaz EM Jr. Conservation laryngeal surgery versus total laryngectomy for radiation failure in laryngeal cancer. Head Neck 2006;28:779-784.

Holsinger FC, Laccourreye O, Weinstein GS, Diaz EM Jr, McWhorter AJ. Technical refinements in the supracricoid partial laryngectomy to optimize functional outcomes. J Am Coll Surg 2005;201:809-820.

Kadish S. Can I treat this small larynx lesion with radiation alone? Update on the radiation management of early (T1 and T2) glottic cancer. Otolaryngol Clin North Am 2005;38:1-9.

Le QT, Fu KK, Kroll S, Ryu JK, Quivey JM, Meyler TS, Krieg RM, Phillips TL. Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma. Int J Radiat Oncol Biol Phy 1997;39:115-126.

Mendenhall WM, Parsons JT, Brant TA, Stringer SP, Cassisi NJ, Million RR. Is elective neck treatment indicaed for T2N0 squamous cell carcinoma of the glottic larynx? Radiother Oncol 1989;14:199-202.

Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB. Management of T1-T2 glottic carcinomas. Cancer 2004;100:1786-1792.

Montgomery WW. Surgery of the Larynx, Trachea, Esophagus, and Neck. Philadelphia: Saunders/Elsevier Science Press, 2002.

Motamed M, Laccourreye O, Bradley PJ. Salvage conservation laryngeal surgery after irradiation failure for early laryngeal cancer. Laryngoscope 2006;116:451-455.

Nix P, Lind M, Greenman J, Stafford N, Cawkwell L. Expression of Cox-2 protein in radioresistant laryngeal cancer. Ann Oncol 2004;15:797-801.

Nix P, Cawkwell L, Patmore H, Greenman J, Stafford N. Bci-2 expression predicts radiotherapy failure in laryngeal cancer. Br J Cancer 2005;92:2185-2189.

Nix PA, Greenman J, Cawkwell L, Stafford ND. Defining the criteria for radioresistant laryngeal cancer. Clin Otolaryngol Allied Sci 2004;29:705-708.

Pellini R, Manciocco V, Spriano G. Functional outcome of supracricoid partial laryngectomy with cricohyoidopexy: Radiation failure vs. previously untreated cases. Arch Otolaryngol Head Neck Surg 2006;132:1221-1225.

Pyo H, Choy H, Amorino GP, Kim JS, Cao Q, Hercules SK, DuBois RN. A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2. Clin Cancer Res 2001;7:2998-3005.

Ritoe SC, Verbeek AL, Krabbe PF, Kaanders JH, van den Hoogen FJ, Marres HA. Screening for local and regional cancer recurrence in patients curatively treated for laryngeal cancer: Definition of a high-risk group and estimation of the lead time. Head Neck 2006 Nov 22 epub.

Ritoe SC, Krabbe PF, Kaanders JH, van den Hoogen FJ, Verbeek AL, Marres HA. Value of routine follow-up for patients cured of laryngeal carcinoma. Cancer 2004;101:1382-1389.

Sewnaik A, van den Brink JL, Wieringa MH, Meeuwis CA, Kerrebijn JD. Surgery for recurrent laryngeal carcinoma after radiotherapy: Partial laryngectomy or total laryngectomy for a better quality of life? Otolaryngol Head Neck Surg 2005;132:95-98.

Walter MA, Peters GE, Peiper SC. Predicting radioresistance in early glottic squamous cell carcinoma by DNA content. Ann Otol Rhinol Laryngol 1991;100:523-526.

Wax MK, Touma BJ. Management of the N0 neck during salvage laryngectomy. Laryngoscope 1999;109:4-7.

Wein RO, Weber RS. The current role of vertical partial laryngectomy and open supraglottic laryngectomy. Curr Probl Cancer 2005;29:201-214.

Willis S, Day CL, Hinds MG, Huang DC. The Bci-2-regulated apoptotic pathway. J Cell Sci 2003;116:4053-4056.

Yao M, Roebuck JC, Holsinger FC, Myers JN. Elective neck dissection during salvage laryngectomy. Am J Otolaryngol 2005;26:388-392.

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