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Hyperbaric Oxygen Therapy
OtolaryngologyHead and Neck Surgery
Letters to the Editor 703
Volume 116 N u m b e r 6 Part 1
ing. Tumor recurrence often presents with intralaryngeal and extralaryngeal spread with multicentric tumor loci surrounded by dense fibrosis, rendering exact T staging very difficult. 5 Moreover, the decision as to whether a tumor should be treated by primary surgery or primary radiotherapy is established according to the initial T staging. For these reasons, it seemed adequate to consider the initial T staging even for tumor recurrence.
Dr. reed. P. Zbiiren University Clinic of Oto-Rhino-Laryngology Head and Neck Surgery Inselspital CH-3010 Bern Switzerland 23]8/81199
REFERENCES 1. Spiessl B, Beahrs OH, Hermanek P, et al. TNM atlas: illustrated guide to the TNM/pTNM classification of malignant tumors. 3rd ed. Berlin: Springer, 1992. 2. Becket M, Zb~en R L~ing H, Stoupis C, Porcellini B, Vock R Neoplastic invasion of the laryngeal cartilage: comparison of MR imaging and CT with histopathologic correlation. Radiology 1995;194:661-9. 3. ZbSren P, Becker M, L~ing H. Pretherapeutic staging of laryngeal cancer: clinical findings, computed tomography and magnetic resonance imaging versus histopathology. Cancer 1996;77:1263-73. 4. Hosal N, Onerci M, Turan E. Peristomal recurrence. Am J Otolaryngol 1993;14:206-8. 5. Brandenburg JH, Gondon KG, Frank TW. Coronal section of larynges from radiation therapy failures: a clinical-pathologic study. Otolaryngol Head Neck Surg 1986;95:213-8.
Hyperbaric Oxygen Therapy To the Editor." We have read with interest the recent article by Bradfield et al.1 wherein the authors present four case reports of patients who had aggressive progression of squamous cancers after exposure to hyperbaric oxygen therapy (HBO). The problem with such anecdotal reports is that whereas four cases are reported, we are not told how many other cases were successfully treated by HBO without progression of tumor. Note that each patient had intravenous antibiotics as well as HBO. Would anyone suggest that the administration of intravenous antibiotics should be avoided because these four patients' diseases progressed after their administration? We do not discount that valid concerns regarding HBO and tumor growth have led to studies and previous case reports. Our group has published two papers in this regard. 2,3 The first of these surveyed practitioners of HBO in regard to their experience in treating patients with an intercurrent or past history of malignancy. The vast majority of survey respondents had not seen a case of malignancy reactivated or accelerated by HBO. In this survey only 7% of the respondents had concerns that HBO might have carcinogenic or growth-accelerating properties. Our second publication is a review of all previous discov-
erable publications related to this topic. In this paper we discussed 24 references: 12 clinical reports, 11 animal studies, and 1 that was both an animal study and a clinical report. Three clinical reports suggested a positive cancer-growth enhancement, whereas 10 clinical reports showed no cancergrowth enhancement. Two animal studies suggested a positive cancer-enhancing effect, and 10 animal studies showed no such effect. (The report that included both animals and human beings was counted in both groups). The vast majority of published reports showed no cancer-growth enhancement by HBO exposure. Those studies that did show growth enhancement were refuted by larger subsequent studies, were mixed studies, or were highly anecdotal. We also discussed three potential mechanisms whereby HBO might potentially demonstrate carcinogenic or growthenhancing properties: (1) by nourishing the tumor, (2) by causing immune suppression, and (3) by causing toxicity mediated through free radical formation. It is a natural concern that HBO, which is often indicated as an adjunct to stimulate neovascularization and growth of healing tissues, could do the same for malignant tissues. However, it has been known since Warburg's 4 publication in the 1930s that one characteristic that sets malignant tissues apart from benign tissues is a preference for anaerobic pathways of glycolysis, even in the presence of oxygen. For this reason, the simple addition of a high concentration of molecular oxygen is unlikely to stimulate malignant growth by heightened metabolism. Immune suppression is a powerful risk factor for malignancy, as demonstrated by the high incidence of cancer in organ transplant recipients on long-term, continuous regimens of immune suppression: HBO has been shown to be immunosuppressive in some animal trials. However, in human subjects Feldmeier et al5 showed no effect of HBO on immune competence when these subjects were exposed to 20 daily HBO treatments. Concerns that HBO can cause toxicity because of a drastic increase in free radicals are also valid. Free radicals have been implicated as risk factors for a number of deleterious and degenerative conditions, including cancer. Recent publications have shown that HBO does not increase the deleterious effects of free radical damage. 6 Kaelin et al.7 have shown a significant increase in the activity of the free radical scavenger snperoxide dismutase in animals exposed to HBO. Such an enhancement of free radical scavenger activity may well be the dominant effect of HBO in this circumstance, and deleterious free radical effects may actually decrease under HBO conditions. It should also be noted that at least 5 of the 24 references we reviewed actually showed decreased growth of the primary or decreased likelihood of metastasis after HBO exposure. More than 2000 patients received HBO in the reports that showed a neutral or inhibitory effect on their growth, whereas only a total of 82 patients (including those in this report) received HBO in publications suggesting enhanced tumor growth.
OtolaryngologyHead and NeckSurgery June 1997
704 Letters to the Editor
Finally, if we scrutinize the patients presented in the present publication, a negative outcome is not entirely surprising. Two of the four had T4 tumors to begin with. Another had squamous cell cancer of the larynx and supraglottic larynx metastatic to an intrathyroid lymph node as well as metastatic papillary thyroid cancer. This patient also had his radiation interrupted for 6 weeks because of pneumonia. Such interruptions are known to markedly decrease beneficial effectiveness of radiation therapy. This patient had already had a recurrence before the initiation of HBO. The final patient had three recurrences in the neck before HBO. All in all this group represents a high-risk group in whom recurrent/progressive disease is not unexpected. In regard to the rapidity of tumor growth, we have all seen patients, often near the end of their disease, develop rapid progression. In part this probably represents a collapse of normal host defense mechanisms. In part it certainly represents the survival of tumor clones that are resistant to therapy. Although the authors do not claim that HBO was causative for tumor recurrence or progression in the four cases presented, they certainly imply that this is their concern. We propose that the weight of the available literature including these case reports fails to demonstrate a carcinogenic or tumor-growth enhancement effect by HBO.
John J. Feldmeier, DO Wayne S. Court, PhD, MD Department of Radiation Oncology Karmanos Cancer Institute Wayne State University Grace Hospital 6071 W. Outer Dr. Detroit, MI 48235 David A. Davoh, CHT
Barbara Stegmann, MD Richard D. Heimbach, AID Paul T Sheffield, PhD Department of Hyperbaric Medicine Southwest Texas Methodist Hospital san Antonio, TX 23/8178464
REFERENCES 1. Bradfield JJ~ Kinsella JB, Mader JT, Bridges EW, Calhoun Kid. Rapid progression of head and neck squamous carcinoma after hyperbaric oxygen. Otolaryngol Head Neck Surg 1996;114:7937. 2. Feldmeier JJ, Heimbach RD, Davolt DA, Brakora MJ. Hyperbaric oxygen and the cancer patient: a survey of practices, patterns. Undersea Hyperbaric Medicine 1993;20:337-45. 3. Feldmeier JJ, Heimbaeh RD, Davolt DA, Brakora M J, Sheffield PJ, Porter AT. Does hyperbaric oxygen have a cancer causing or promoting effect? A review of the pertinent literature. Undersea Hyperbaric Medicine 1994;21:467-75. 4. Warburg O; Dickens F, trans. The metabolism of tumors. London: Constable & Co Ltd, 1930. 5. Feldmeier JJ, Boswell RN, Brown M, Shaffer R The effects of hyperbaric oxygen on the immunological status of healthy human subjects. In: Kindwall ER ed. Proceedings of the Eighth International Congress on Hyperbaric Medicine. San Pedro, Calif.: Best Publishing Co, 1987:41-6 6. Zamboni WA, Roth AC, Russel RC, Nemiroff PM, Casas L, Smoot EC. The effects of acute hyperbaric oxygen therapy on axial pattern skin flap survival when administered during and after total ischemia. J Reconstr Microsurg 1989;5:343-7. 7. Kaelin CM, Im JJ, Myers RAM, Manson PN, Hoopes JE. The effects of hyperbaric oxygen on free flap in rats. Arch Surg 1990; 125:607-9.
T h e J o u r n a l is c o n s i d e r i n g p r i n t i n g a special p u b l i c a t i o n c o n t a i n i n g historical articles about our specialty w h i c h w e r e published in m u l t i p l e issues in 1996. We are soliciting interest in such a publication. I f you w o u l d be interested in purchasing a special limited-edition, consolidated publication, please write the Editor, or call (210)490-2805.
Letters to the Editor 703
Volume 116 N u m b e r 6 Part 1
ing. Tumor recurrence often presents with intralaryngeal and extralaryngeal spread with multicentric tumor loci surrounded by dense fibrosis, rendering exact T staging very difficult. 5 Moreover, the decision as to whether a tumor should be treated by primary surgery or primary radiotherapy is established according to the initial T staging. For these reasons, it seemed adequate to consider the initial T staging even for tumor recurrence.
Dr. reed. P. Zbiiren University Clinic of Oto-Rhino-Laryngology Head and Neck Surgery Inselspital CH-3010 Bern Switzerland 23]8/81199
REFERENCES 1. Spiessl B, Beahrs OH, Hermanek P, et al. TNM atlas: illustrated guide to the TNM/pTNM classification of malignant tumors. 3rd ed. Berlin: Springer, 1992. 2. Becket M, Zb~en R L~ing H, Stoupis C, Porcellini B, Vock R Neoplastic invasion of the laryngeal cartilage: comparison of MR imaging and CT with histopathologic correlation. Radiology 1995;194:661-9. 3. ZbSren P, Becker M, L~ing H. Pretherapeutic staging of laryngeal cancer: clinical findings, computed tomography and magnetic resonance imaging versus histopathology. Cancer 1996;77:1263-73. 4. Hosal N, Onerci M, Turan E. Peristomal recurrence. Am J Otolaryngol 1993;14:206-8. 5. Brandenburg JH, Gondon KG, Frank TW. Coronal section of larynges from radiation therapy failures: a clinical-pathologic study. Otolaryngol Head Neck Surg 1986;95:213-8.
Hyperbaric Oxygen Therapy To the Editor." We have read with interest the recent article by Bradfield et al.1 wherein the authors present four case reports of patients who had aggressive progression of squamous cancers after exposure to hyperbaric oxygen therapy (HBO). The problem with such anecdotal reports is that whereas four cases are reported, we are not told how many other cases were successfully treated by HBO without progression of tumor. Note that each patient had intravenous antibiotics as well as HBO. Would anyone suggest that the administration of intravenous antibiotics should be avoided because these four patients' diseases progressed after their administration? We do not discount that valid concerns regarding HBO and tumor growth have led to studies and previous case reports. Our group has published two papers in this regard. 2,3 The first of these surveyed practitioners of HBO in regard to their experience in treating patients with an intercurrent or past history of malignancy. The vast majority of survey respondents had not seen a case of malignancy reactivated or accelerated by HBO. In this survey only 7% of the respondents had concerns that HBO might have carcinogenic or growth-accelerating properties. Our second publication is a review of all previous discov-
erable publications related to this topic. In this paper we discussed 24 references: 12 clinical reports, 11 animal studies, and 1 that was both an animal study and a clinical report. Three clinical reports suggested a positive cancer-growth enhancement, whereas 10 clinical reports showed no cancergrowth enhancement. Two animal studies suggested a positive cancer-enhancing effect, and 10 animal studies showed no such effect. (The report that included both animals and human beings was counted in both groups). The vast majority of published reports showed no cancer-growth enhancement by HBO exposure. Those studies that did show growth enhancement were refuted by larger subsequent studies, were mixed studies, or were highly anecdotal. We also discussed three potential mechanisms whereby HBO might potentially demonstrate carcinogenic or growthenhancing properties: (1) by nourishing the tumor, (2) by causing immune suppression, and (3) by causing toxicity mediated through free radical formation. It is a natural concern that HBO, which is often indicated as an adjunct to stimulate neovascularization and growth of healing tissues, could do the same for malignant tissues. However, it has been known since Warburg's 4 publication in the 1930s that one characteristic that sets malignant tissues apart from benign tissues is a preference for anaerobic pathways of glycolysis, even in the presence of oxygen. For this reason, the simple addition of a high concentration of molecular oxygen is unlikely to stimulate malignant growth by heightened metabolism. Immune suppression is a powerful risk factor for malignancy, as demonstrated by the high incidence of cancer in organ transplant recipients on long-term, continuous regimens of immune suppression: HBO has been shown to be immunosuppressive in some animal trials. However, in human subjects Feldmeier et al5 showed no effect of HBO on immune competence when these subjects were exposed to 20 daily HBO treatments. Concerns that HBO can cause toxicity because of a drastic increase in free radicals are also valid. Free radicals have been implicated as risk factors for a number of deleterious and degenerative conditions, including cancer. Recent publications have shown that HBO does not increase the deleterious effects of free radical damage. 6 Kaelin et al.7 have shown a significant increase in the activity of the free radical scavenger snperoxide dismutase in animals exposed to HBO. Such an enhancement of free radical scavenger activity may well be the dominant effect of HBO in this circumstance, and deleterious free radical effects may actually decrease under HBO conditions. It should also be noted that at least 5 of the 24 references we reviewed actually showed decreased growth of the primary or decreased likelihood of metastasis after HBO exposure. More than 2000 patients received HBO in the reports that showed a neutral or inhibitory effect on their growth, whereas only a total of 82 patients (including those in this report) received HBO in publications suggesting enhanced tumor growth.
OtolaryngologyHead and NeckSurgery June 1997
704 Letters to the Editor
Finally, if we scrutinize the patients presented in the present publication, a negative outcome is not entirely surprising. Two of the four had T4 tumors to begin with. Another had squamous cell cancer of the larynx and supraglottic larynx metastatic to an intrathyroid lymph node as well as metastatic papillary thyroid cancer. This patient also had his radiation interrupted for 6 weeks because of pneumonia. Such interruptions are known to markedly decrease beneficial effectiveness of radiation therapy. This patient had already had a recurrence before the initiation of HBO. The final patient had three recurrences in the neck before HBO. All in all this group represents a high-risk group in whom recurrent/progressive disease is not unexpected. In regard to the rapidity of tumor growth, we have all seen patients, often near the end of their disease, develop rapid progression. In part this probably represents a collapse of normal host defense mechanisms. In part it certainly represents the survival of tumor clones that are resistant to therapy. Although the authors do not claim that HBO was causative for tumor recurrence or progression in the four cases presented, they certainly imply that this is their concern. We propose that the weight of the available literature including these case reports fails to demonstrate a carcinogenic or tumor-growth enhancement effect by HBO.
John J. Feldmeier, DO Wayne S. Court, PhD, MD Department of Radiation Oncology Karmanos Cancer Institute Wayne State University Grace Hospital 6071 W. Outer Dr. Detroit, MI 48235 David A. Davoh, CHT
Barbara Stegmann, MD Richard D. Heimbach, AID Paul T Sheffield, PhD Department of Hyperbaric Medicine Southwest Texas Methodist Hospital san Antonio, TX 23/8178464
REFERENCES 1. Bradfield JJ~ Kinsella JB, Mader JT, Bridges EW, Calhoun Kid. Rapid progression of head and neck squamous carcinoma after hyperbaric oxygen. Otolaryngol Head Neck Surg 1996;114:7937. 2. Feldmeier JJ, Heimbach RD, Davolt DA, Brakora MJ. Hyperbaric oxygen and the cancer patient: a survey of practices, patterns. Undersea Hyperbaric Medicine 1993;20:337-45. 3. Feldmeier JJ, Heimbaeh RD, Davolt DA, Brakora M J, Sheffield PJ, Porter AT. Does hyperbaric oxygen have a cancer causing or promoting effect? A review of the pertinent literature. Undersea Hyperbaric Medicine 1994;21:467-75. 4. Warburg O; Dickens F, trans. The metabolism of tumors. London: Constable & Co Ltd, 1930. 5. Feldmeier JJ, Boswell RN, Brown M, Shaffer R The effects of hyperbaric oxygen on the immunological status of healthy human subjects. In: Kindwall ER ed. Proceedings of the Eighth International Congress on Hyperbaric Medicine. San Pedro, Calif.: Best Publishing Co, 1987:41-6 6. Zamboni WA, Roth AC, Russel RC, Nemiroff PM, Casas L, Smoot EC. The effects of acute hyperbaric oxygen therapy on axial pattern skin flap survival when administered during and after total ischemia. J Reconstr Microsurg 1989;5:343-7. 7. Kaelin CM, Im JJ, Myers RAM, Manson PN, Hoopes JE. The effects of hyperbaric oxygen on free flap in rats. Arch Surg 1990; 125:607-9.
T h e J o u r n a l is c o n s i d e r i n g p r i n t i n g a special p u b l i c a t i o n c o n t a i n i n g historical articles about our specialty w h i c h w e r e published in m u l t i p l e issues in 1996. We are soliciting interest in such a publication. I f you w o u l d be interested in purchasing a special limited-edition, consolidated publication, please write the Editor, or call (210)490-2805.