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Late sequelae of radiation therapy in cancer of the head and neck with particular reference to the nasopharynx
Late Sequelae of Radiation Therapy in Cancer of the Head and Neck with Particular Reference
to the Nasopharynx
A. J. Ballantyne, MD, Houston, Texas
Radiation therapy, either administered alone or in various combinations with operation and/or chemotherapy, plays an integral and vital role in the treatment of cancer of the head and neck. Although radiation therapy has a necessary destructive effect on the cancer cell, it also has an effect on the normal tissues through which the ionizing radiation passes. The early and late effects of irradiation on the various tissues within the irradiated field depends on the structures involved, rapidity of treatment, total dosage, age of the patient at treatment, length of survival after treatment, and variations in individual tolerance to this therapeutic modality. In the head and neck region the usual acute reactions encountered are erythema of the skin and mucositis. These produce varying degrees of temporary disability of extremely variable duration. In addition, there are numerous changes in blood vessels, bone, and other mesodermal tissues that are not easily recognizable. Most of these changes subside after a time and may be replaced by atrophy and fibrosis. Either because of the-fibrosis or the change in the small and large vessels, late sequelae of radiation therapy do occur and must be recognized as unavoidable and undesirable consequences of treatment. The late sequelae may be either minor or major, depending on the site and the degree of the unfavorable reaction. The minor sequelae in the head and neck region usually consist of atrophy, fibrosis, telangiectasia, xerostomia, dental caries, and varying degrees of stenosis of the nasolachrymal ducts and eustachian tubes. The effect on bone is unpredictable and varies with the age of the patient and the care given to mucosa and teeth in the vicinity of the mandible and maxilla. From the Department of Surgery, Head and Neck Service, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas. Reprint requests should be addressed to A. J. Salbntyne, MD, 6723 Bertner Drive, Houston, Texas 77025. Presented at the Combined Meeting of the James Ewing Society and the Society of Head and Neck Surgeons, New Orleans, Louisiana, March 2529,1975.
Volume 130, October 1075
Major complications arise in the head and neck region because of the frequent necessity for including within the irradiated field such vital structures as spinal cord, brain, eye, middle and inner ear, larynx, and cranial nerves. When radiation therapy includes the eyes, changes in the anterior chamber, the lens, retina, optic nerves, or chiasma, may result. In a series reported by Goepfert, Jesse, and Lindberg [I] combining chemotherapy and radiation for advanced cancer of the paranasal sinuses, four of eleven long-term survivors had unilateral blindness in the ipsilateral field and two of the four had blindness in both eyes. To further complicate the problems, the radiation fields may encompass the pituitary or thyroid glands, and changes in endocrine function may result that affect total body function. Larkins and Martin [2] have described hypopituitarism after extracranial irradiation. In a recent but unpublished paper by Samaan et al [3], fifteen patients who underwent radiation therapy for nasopharyngeal cancer were studied to determine the effect of the radiation on the hypothalamic pituitary axis. Fourteen of the fifteen patients had a hormonal deficiency. Twelve of these patients had evidence of hypothalamic impairment of one or more of the pituitary hormones. Seven patients had indications of primary pituitary failure to secrete one or more hormones with or without an associated hypothalamic lesion. Three patients also showed primary hypothyroidism. Hypothyroidism has been a common finding in patients undergoing extensive irradiation to the neck at this institution, but these patients are not included in the study of Samaan et al [3]. In addition to hypothyroidism, hyperthyroidism in the,presence of panhypopituitarism has been reported by Krishnamurthy and Blahn [4], and one patient with nasopharyngeal cancer in our series was treated for hyperthyroidism but was not studied regarding pituitary function because of accidental death. Wasnich et al [5] have also reported Graves’ ophthalmopathy in patients after external irradiation.
433
Ballantyne
An additional late sequela of the mutagenic effect of irradiation therapy is the development of an unrelated cancer within the irradiated field. Modan et al [6] concluded that risk of both malignant and benign tumors was significantly increased in children irradiated for tinea capitis as compared with normal controls. Development of osteogenic sarcomas after radiotherapy for retinoblastoma has recently been reviewed by Shah, Arlen, and Miller [7], and radiation-induced mesodermal tumors of the central nervous system have been reported by Norwood et al [8]. Our interest in the late sequelae of radiation therapy was stimulated by several recent cases. The first was that of a twenty-five year old male who had an extensive embryonal rhabdomyosarcoma of the orbit, which required operation and subsequent irradiation therapy and chemotherapy consisting of adriamycin, cytoxan, and vincristine. The radiation fields included the lower portion of the frontal lobes on both sides as well as the entire left orbital region. A tumor dose of 6,000 r was delivered to the orbit. Slough of the orbital walls appeared after treatment. Five months after completion of radiation therapy, the patient became comatose; an arteriogram suggested a space-occupying lesion in the left frontal region. At craniotomy, the patient was found to have necrosis of the frontal lobe without evidence of tumor. The two other patients of interest demonstrated the mutagenic effect of radiation. One patient originally seen at the age of nineteen years had had a neuroesthelioma of the ethmoid region treated by radiation therapy; an osteogenic sarcoma developed eleven years later. The other patient underwent treatment for hyperkeratosis of the larynx for a period of two years until finally a diagnosis of well differentiated squamous cell carcinoma of the larynx was obtained. Laryngectomy was recommended but refused, and radiation therapy was instituted. Within four months after completion of therapy, the neck was diffusely infiltrated with spindle cell squamous cell carcinoma from which the patient rapidly expired. One area in the head and neck region that remains exclusively within the province of the radiation therapist is the nasopharynx; a review of patients undergoing treatment for nasopharyngeal cancer may provide some idea as to the frequency of the sequelae that follow radiation therapy. This study in no way was planned to discredit the value of irradiation in treating nasopharyngeal cancer nor to suggest that other means of treatment may be available.
434
The records of 218 patients with lymphoepithelioma or squamous cell carcinoma of the nasopharynx who completed radiation therapy at the M. D. Anderson Hospital between 1948 and 1971 were reviewed. Since follow-up on all patients was not complete and causes of death of those patients expiring outside our institution within one year were difficult to ascertain, the statistics as to sequelae may not truly reflect the frequency of complications. Most patients had some degree of xerostomia and there were many other minor sequelae such as radiation fibrosis, serous otitis, reduction of hearing, dental caries, and occasionally necrosis of the mandible and maxilla. These were not tabulated according to frequency. Radiation fibrosis in the sternocleidomastoid muscle does deserve mention since it is sometimes not recognized as such and may lead to extensive operation or other forms of treatment. The differential diagnosis can usually be made because the area involved is initially quite tender and tends to be nondiscrete and to extend along the sternocleidomastoid muscle. Usually with conservative management the acute phase subsides, and subsequent chronic fibrosis in the specific area may produce some limitation of motion but is not particularly disturbing otherwise. Of the patients having severe complications (Table I), the most frequent major complication is spinal cord myelopathy. This complication has also been reported by Solheim [9], Burns, Jones, and Robertson [IO], Beige et al [II], Jellinger and Sturm [12], Marty and Minckler [13] Nagase et al [14], Yaar, Herishanu, and Lavy [IS], Tan and Khor [16], and Reagan, Thomas, and Colby [17]. Minor degrees of spinal cord change probably occur relatively frequently and may be evidenced by Lehrmitte’s sign, with subsequent disappearance of symptoms. The onset of more severe damage to the spinal cord may be delayed for months or years and may either progress fairly rapidly to a fatal course, progress fairly slowly, or remain relatively arrested. Symptoms usually consist of weakness in one or both extremities and pain that progresses to various degrees of anesthesia. Diagnosis is suspected by the absence of bone destruction on x-ray examination of the cervical spine and by an essentially normal myelogram. Rarely does the cord become completely swollen to produce an abnormal myelogram that suggests tumor, as in the case reported by Marty and Minckler [13]. In the eight patients with cord myelopathy in this series, onset of symptoms varied from eleven months to eleven years, with the majority occurring within
The American Journal of Surgery
Late Sequelae
the first two years. Tumor dosage to the nasopharynx varied from 6,000 to 7,500 r, with a duration of treatment from six to eight weeks. None of the patients had a myelogram that suggested tumor. Permission to examine the spinal cord was obtained from only one patient who died in the hospital; the case report on this patient follows.
Case I. A fifty-three year old white female presented on March 3, 1971 with an extensive lesion of the nasopharynx extending into the nasal cavity. Biopsy revealed poorly differentiated invasive carcinoma. There were no significantly enlarged cervical nodes. Irradiation therapy was administered from March 15, 1971 to May 14,197l utilizing the cobalt 60 and betatron irradiators, with irradiation delivered to both necks, nasopharynx, and nasal cavity using anterior as well as lateral fields. Tumor dose to the nasopharynx using cobalt 60 was 6,500 r plus 1,000 r using betatron. Left hemiparesis was noted on May 23, 1972. Cervical and thoracic myelograms were negative. On July 16, 1972 cervical laminectomy, exploration of the cord, and needle biopsy of the left dorsal aspect of the spinal cord were performed. The patient expired on August 6, 1972 and autopsy revealed no evidence of residual or recurrent tumor, but radiation myelitis was most severe at the lower medulla and the first and upper second cervical vertebrae, with areas of necrosis in the cord. Examples of the other major complications have been infrequently reported. Illustrative case reports of representative examples follow. Case II: Stricture of nasopharynx. On January 21, 1955, a forty-eight year old white male presented with a
mass in the nasopharynx with right upper cervical adenopathy. Biopsy of the nasopharynx revealed grade III squamous cell carcinoma. Radiation therapy was administered from January 27, 1955 to March 18, 1955 using the GE 250 and cobalt 60 irradiators with a tumor dose to the primary of 5,800 r. During the subsequent years, increasing dysphagia with stenosis of the pharynx developed in the patient. In 1965 gastrostomy was performed because of severe dysphagia. An attempt to dilate the stricture resulted in necrosis of the pharyngeal wall, from which the patient expired in 1965. Case III: Necrosis with exsanguinating hemorrhage. A forty-seven year old white male presented with lymphoepithelioma of the nasopharynx with metastasis to right subdigastric nodes on May 21,1968. The patient received a tumor dose of 6,528 r to the nasopharynx using the cobalt 60 irradiator between May 22,1968 and July 10, 1968. On October 24, 1968 the patient had massive bleeding, which was treated by packing. The patient expired in transit to M. D. Anderson Hospital; autopsy at another hospital reported no residual tumor. Case IV: Cranial nerve paralysis. A seventy-four year old white male underwent treatment in March 1968
Volume130, October 1975
TABLE
I
Major
Complications
Completing Therapy
of Radiation Therapy
in 218 Patients
a Course of Radiation
for Squamous
or Lymphoepithelioma
Cell Carcinoma of the Nasopharynx
Complications Fatal Stricture of the pharynx Spinal cord myelopathy Necrosis with fatal hemorrhage Nerve paralysis Brain abscess Radiation-induced cancer* Nonfatal Spinal cord myelopathy Radiation-induced cancert Total
Number of Patients
1 5 3 2 1 1 3 1 17
~-*Osteogenic sarcoma of the maxilla. t Grade I squamous cell carcinoma of hard palate in a twenty-five year old female.
on the betatron and cobalt 60 irradiators for grade III squamous cell carcinoma of the posterior nasopharynx involving the left eustachian tube. Tumor dose of 6,470 r was delivered during a six and a half week period. On June 8, 1970, increased difficulty with swallowing began developing in the patient, and it was noted that the patient had paralysis of the tenth and twelfth cranial nerves. There was no evidence of tumor in the nasopharynx. When examined on August 10, 1970, the patient was suspected of having stricture of the esophagus in the region of the cricoid. The patient’s condition deteriorated and he expired in February 1971. Case V: Brain abscess. A fifty-eight year old white female presented with extensive carcinoma of the nasopharynx and right lateral rectus paralysis on March 27, 1967. Treatment from March 30, 1967 to June 9, 1967 using the cobalt 60 and betatron irradiators consisted of a tumor dose of 6,695 r in seven weeks to the base of the skull and nasopharynx. In September 1969, the patient began having pain in the right ear with drainage. Examination showed a perforation of the right drum with purulent discharge. Tomograms of the temporal bone were reported to be nonrevealing. The patient expired in another hospital on August 28, 1970, and autopsy was reported to show purulent mastoiditis with a brain abscess but no residual tumor. In addition
to these
complications
that can be
reasonably well classified, four patients had bizarre findings in the central nervous system that do not agree with any well recognized pattern. The effect of irradiation on the brain has been reported by Okeda and Shibata [18], Kramer and Lee [19], Wilson, Byfield, and Hanafee [20], and Lampert, Tom, and Rider [21]. One of the patients showing
435
Ballantyne
a
confusing
neurologic
logic consultants radiation,
thought
picture,
which
our neuro-
could be secondary
to ir-
follows.
Case VI. A fifty-six year old white male was administered a tumor dose of 6,268 r to the nasopharynx for a lymphoepithelioma of the nasopharynx with base of the skull involvement, using the cobalt 60 and betatron irradiators from February 20, 1967 to May 11, 1967. On November 20, 1969 the patient underwent frontal craniotomy for marked diminution in vision and was found to have radiation fibrosis in the region of the optic chiasm. When the patient returned for reexamination on August 12, 1974, along with blindness he was found to have weakness of the right arm and leg and hypesthesia of the right leg. He was found to be ataxic. Neurologic examination revealed bilateral atrophy of the optic nerve and pneumoencephalogram showed bilateral atrophy of the frontal lobe.
Comments When
high-dose
irradiation
to the nasopharynx
to cure some of the advanced tumors that occur, particularly those involved with the base of the skull and with cranial nerve palsies, it is necessary to include the hypothalamus, pituitary gland, and base of the brain as well as portions of the upper spinal cord. The major complications that may occur involve the spinal cord, although it is becoming more apparent that disturbances in the hypothalamic-pituitary axis are more common than had previously been thought. Cranial nerve palsies can occur and can be fatal if the tenth and twelfth cranial nerves are involved. At present there seems no way to eliminate these unfortunate sequelae. The clinician who follows patients after irradiation therapy for cancer of the nasopharynx should be alert to the sequelae that may occur and institute proper diagnostic studies to exclude recurrent or metastatic tumor as the cause of symptoms.
is required
Summary Sequlae of radiation therapy may be late in occurring and varied in their manifestations. Although some are untreatable and progressive, the risk of development of some other sequelae can be minimized by careful application of radiotherapy or by ancillary measures, such as dental decay prophylaxis. Some of the serious sequelae secondary to radiation therapy of the nasopharynx have been summarized. These include radiation myelitis, pa-
436
ralysis
of the cranial
ynx, radiation-induced fatal hemorrhage.
nerves,
stricture
cancer,
and
of the pharnecrosis
with
References 1. Goepfert H, Jesse RH, Lindberg RD: Arterial infusion and radiation therapy in the treatment of advanced cancer of the nasal cavity and paranasal sinuses. Am J Surg 126: 464, 1973. 2. Larkins RG, Martin FIR: Hypopituitarism after extracranial irradiation: evidence for hypothalamic origin. 6r Med J l(846): 152, 1973. 3. Samaan NA. Bakdash MM, Caderao JB, Cangir A, Jesse RH, Ballantyne AJ: Hypopituitarism after external irradiation: evidence for both hypothalamic and pituitary origin. In press. 4. Krishnamurthy GT, Blat-d WH: Hyperthyroidism in the presence of panhypopituitarism. W&t J k&d 120: 491, 1974. 5. Wasnich RD. Grumet FC. Payne RO, Kriss JP: Graves’ ophthalopathy following exteinal neck irradiation for nonthyroidal neoplastic disease. J C/in Endocrinol &tab 37: 703, 1973. 6. Modan B, Mart H, Baidatz D. Steinitz R, Levin SG: Radiationinduced head and neck tumours. Lancet 1: 277, 1974. 7. Shah IC, Arlen MA, Miller T: Osteogenic sarcoma developing after radiotherapy for retinoblastoma. Am Surg 40(8): 485, 1974. 8. Norwood CW, Kelly DL, Courtland HD, Alexander E: Irradiation-induced mesodermal tumors of the central nervous system: report of two meningiomas following x-ray treatment for gliomas. Surg Neurol2: 161, 1974. 9. Solheim OP: Radiation injury of the spinal cord. Acta Radio/ [ Ther] (Sfockh) lO(5): 474, October, 1971. 10. Burns RJ, Jones AN, Robertson JS: Pathology of radiation myelopathy. J Neural Neurosurg Psychiatry 35: 888, 1972. Il. Berge G, Brun A, Hakansson GH, Lindgren M. Nordberg UB: Sensitivii to irradiation of the brain stem. Irradiation myeiitis in the treatment of a nasopharynx carcinoma. Cancer 33: 1263, 1974. 12. Jellinger K, Sturm KW: Delayed radiation myelopathy in man. Report of twelve necropsy cases. J Neural Sci 14: 389, 1971. 13. Marty R, Minckler DS: Radiation myelitis simulating tumor. Arch Neural 29: 352, 1973. 14. Nagase T, Tanaka Y, Wada TW, Fujimaki T: Tolerance dose of the spinal cord on radiation myelopathy. Keio J Med 22: 109,1973. 15. Yaar I, Herishanu Y, Lavy S: Radiation myelopathy. Eur Neuroll0: 83, 1973. 16. Tan BC. Khor TH: Radiation myelitis in carcinoma of the nasopharynx. C/in Radio1 20: 329, 1969. 17. Reagan TJ, Thomas JE. Colby MY: Chronic progressive radiation myelopathy. JAMA 202: 106. 1968. 18. Okeda R, Shibata T: Radiation encephalopathy. An autopsy case and some comments on the pathogenesis of delayed radiinecrosis of central nervous system. Acta Pathoi Jap 23: 867. 1973. 19. Kramer S. Lee KF: Complications of radiation therapy: the central nervous system. Semin Roentgen01 9: 75, 1974. 20. Wilson GH, Byfield J. Hanafee WN: Atrophy following radiation therapy for central nervous system neoplasms. Acta Radio/ [ tir] (St&h) 1 l(4): 361, 1972. 21. Lampert P, Tom BA. Rider WD: Disseminated demyelination of the brain following Co60 (gamma) radiation. Arch Pathoi 68: 90, 1959.
The Amerkan Journal01Surgery
to the Nasopharynx
A. J. Ballantyne, MD, Houston, Texas
Radiation therapy, either administered alone or in various combinations with operation and/or chemotherapy, plays an integral and vital role in the treatment of cancer of the head and neck. Although radiation therapy has a necessary destructive effect on the cancer cell, it also has an effect on the normal tissues through which the ionizing radiation passes. The early and late effects of irradiation on the various tissues within the irradiated field depends on the structures involved, rapidity of treatment, total dosage, age of the patient at treatment, length of survival after treatment, and variations in individual tolerance to this therapeutic modality. In the head and neck region the usual acute reactions encountered are erythema of the skin and mucositis. These produce varying degrees of temporary disability of extremely variable duration. In addition, there are numerous changes in blood vessels, bone, and other mesodermal tissues that are not easily recognizable. Most of these changes subside after a time and may be replaced by atrophy and fibrosis. Either because of the-fibrosis or the change in the small and large vessels, late sequelae of radiation therapy do occur and must be recognized as unavoidable and undesirable consequences of treatment. The late sequelae may be either minor or major, depending on the site and the degree of the unfavorable reaction. The minor sequelae in the head and neck region usually consist of atrophy, fibrosis, telangiectasia, xerostomia, dental caries, and varying degrees of stenosis of the nasolachrymal ducts and eustachian tubes. The effect on bone is unpredictable and varies with the age of the patient and the care given to mucosa and teeth in the vicinity of the mandible and maxilla. From the Department of Surgery, Head and Neck Service, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas. Reprint requests should be addressed to A. J. Salbntyne, MD, 6723 Bertner Drive, Houston, Texas 77025. Presented at the Combined Meeting of the James Ewing Society and the Society of Head and Neck Surgeons, New Orleans, Louisiana, March 2529,1975.
Volume 130, October 1075
Major complications arise in the head and neck region because of the frequent necessity for including within the irradiated field such vital structures as spinal cord, brain, eye, middle and inner ear, larynx, and cranial nerves. When radiation therapy includes the eyes, changes in the anterior chamber, the lens, retina, optic nerves, or chiasma, may result. In a series reported by Goepfert, Jesse, and Lindberg [I] combining chemotherapy and radiation for advanced cancer of the paranasal sinuses, four of eleven long-term survivors had unilateral blindness in the ipsilateral field and two of the four had blindness in both eyes. To further complicate the problems, the radiation fields may encompass the pituitary or thyroid glands, and changes in endocrine function may result that affect total body function. Larkins and Martin [2] have described hypopituitarism after extracranial irradiation. In a recent but unpublished paper by Samaan et al [3], fifteen patients who underwent radiation therapy for nasopharyngeal cancer were studied to determine the effect of the radiation on the hypothalamic pituitary axis. Fourteen of the fifteen patients had a hormonal deficiency. Twelve of these patients had evidence of hypothalamic impairment of one or more of the pituitary hormones. Seven patients had indications of primary pituitary failure to secrete one or more hormones with or without an associated hypothalamic lesion. Three patients also showed primary hypothyroidism. Hypothyroidism has been a common finding in patients undergoing extensive irradiation to the neck at this institution, but these patients are not included in the study of Samaan et al [3]. In addition to hypothyroidism, hyperthyroidism in the,presence of panhypopituitarism has been reported by Krishnamurthy and Blahn [4], and one patient with nasopharyngeal cancer in our series was treated for hyperthyroidism but was not studied regarding pituitary function because of accidental death. Wasnich et al [5] have also reported Graves’ ophthalmopathy in patients after external irradiation.
433
Ballantyne
An additional late sequela of the mutagenic effect of irradiation therapy is the development of an unrelated cancer within the irradiated field. Modan et al [6] concluded that risk of both malignant and benign tumors was significantly increased in children irradiated for tinea capitis as compared with normal controls. Development of osteogenic sarcomas after radiotherapy for retinoblastoma has recently been reviewed by Shah, Arlen, and Miller [7], and radiation-induced mesodermal tumors of the central nervous system have been reported by Norwood et al [8]. Our interest in the late sequelae of radiation therapy was stimulated by several recent cases. The first was that of a twenty-five year old male who had an extensive embryonal rhabdomyosarcoma of the orbit, which required operation and subsequent irradiation therapy and chemotherapy consisting of adriamycin, cytoxan, and vincristine. The radiation fields included the lower portion of the frontal lobes on both sides as well as the entire left orbital region. A tumor dose of 6,000 r was delivered to the orbit. Slough of the orbital walls appeared after treatment. Five months after completion of radiation therapy, the patient became comatose; an arteriogram suggested a space-occupying lesion in the left frontal region. At craniotomy, the patient was found to have necrosis of the frontal lobe without evidence of tumor. The two other patients of interest demonstrated the mutagenic effect of radiation. One patient originally seen at the age of nineteen years had had a neuroesthelioma of the ethmoid region treated by radiation therapy; an osteogenic sarcoma developed eleven years later. The other patient underwent treatment for hyperkeratosis of the larynx for a period of two years until finally a diagnosis of well differentiated squamous cell carcinoma of the larynx was obtained. Laryngectomy was recommended but refused, and radiation therapy was instituted. Within four months after completion of therapy, the neck was diffusely infiltrated with spindle cell squamous cell carcinoma from which the patient rapidly expired. One area in the head and neck region that remains exclusively within the province of the radiation therapist is the nasopharynx; a review of patients undergoing treatment for nasopharyngeal cancer may provide some idea as to the frequency of the sequelae that follow radiation therapy. This study in no way was planned to discredit the value of irradiation in treating nasopharyngeal cancer nor to suggest that other means of treatment may be available.
434
The records of 218 patients with lymphoepithelioma or squamous cell carcinoma of the nasopharynx who completed radiation therapy at the M. D. Anderson Hospital between 1948 and 1971 were reviewed. Since follow-up on all patients was not complete and causes of death of those patients expiring outside our institution within one year were difficult to ascertain, the statistics as to sequelae may not truly reflect the frequency of complications. Most patients had some degree of xerostomia and there were many other minor sequelae such as radiation fibrosis, serous otitis, reduction of hearing, dental caries, and occasionally necrosis of the mandible and maxilla. These were not tabulated according to frequency. Radiation fibrosis in the sternocleidomastoid muscle does deserve mention since it is sometimes not recognized as such and may lead to extensive operation or other forms of treatment. The differential diagnosis can usually be made because the area involved is initially quite tender and tends to be nondiscrete and to extend along the sternocleidomastoid muscle. Usually with conservative management the acute phase subsides, and subsequent chronic fibrosis in the specific area may produce some limitation of motion but is not particularly disturbing otherwise. Of the patients having severe complications (Table I), the most frequent major complication is spinal cord myelopathy. This complication has also been reported by Solheim [9], Burns, Jones, and Robertson [IO], Beige et al [II], Jellinger and Sturm [12], Marty and Minckler [13] Nagase et al [14], Yaar, Herishanu, and Lavy [IS], Tan and Khor [16], and Reagan, Thomas, and Colby [17]. Minor degrees of spinal cord change probably occur relatively frequently and may be evidenced by Lehrmitte’s sign, with subsequent disappearance of symptoms. The onset of more severe damage to the spinal cord may be delayed for months or years and may either progress fairly rapidly to a fatal course, progress fairly slowly, or remain relatively arrested. Symptoms usually consist of weakness in one or both extremities and pain that progresses to various degrees of anesthesia. Diagnosis is suspected by the absence of bone destruction on x-ray examination of the cervical spine and by an essentially normal myelogram. Rarely does the cord become completely swollen to produce an abnormal myelogram that suggests tumor, as in the case reported by Marty and Minckler [13]. In the eight patients with cord myelopathy in this series, onset of symptoms varied from eleven months to eleven years, with the majority occurring within
The American Journal of Surgery
Late Sequelae
the first two years. Tumor dosage to the nasopharynx varied from 6,000 to 7,500 r, with a duration of treatment from six to eight weeks. None of the patients had a myelogram that suggested tumor. Permission to examine the spinal cord was obtained from only one patient who died in the hospital; the case report on this patient follows.
Case I. A fifty-three year old white female presented on March 3, 1971 with an extensive lesion of the nasopharynx extending into the nasal cavity. Biopsy revealed poorly differentiated invasive carcinoma. There were no significantly enlarged cervical nodes. Irradiation therapy was administered from March 15, 1971 to May 14,197l utilizing the cobalt 60 and betatron irradiators, with irradiation delivered to both necks, nasopharynx, and nasal cavity using anterior as well as lateral fields. Tumor dose to the nasopharynx using cobalt 60 was 6,500 r plus 1,000 r using betatron. Left hemiparesis was noted on May 23, 1972. Cervical and thoracic myelograms were negative. On July 16, 1972 cervical laminectomy, exploration of the cord, and needle biopsy of the left dorsal aspect of the spinal cord were performed. The patient expired on August 6, 1972 and autopsy revealed no evidence of residual or recurrent tumor, but radiation myelitis was most severe at the lower medulla and the first and upper second cervical vertebrae, with areas of necrosis in the cord. Examples of the other major complications have been infrequently reported. Illustrative case reports of representative examples follow. Case II: Stricture of nasopharynx. On January 21, 1955, a forty-eight year old white male presented with a
mass in the nasopharynx with right upper cervical adenopathy. Biopsy of the nasopharynx revealed grade III squamous cell carcinoma. Radiation therapy was administered from January 27, 1955 to March 18, 1955 using the GE 250 and cobalt 60 irradiators with a tumor dose to the primary of 5,800 r. During the subsequent years, increasing dysphagia with stenosis of the pharynx developed in the patient. In 1965 gastrostomy was performed because of severe dysphagia. An attempt to dilate the stricture resulted in necrosis of the pharyngeal wall, from which the patient expired in 1965. Case III: Necrosis with exsanguinating hemorrhage. A forty-seven year old white male presented with lymphoepithelioma of the nasopharynx with metastasis to right subdigastric nodes on May 21,1968. The patient received a tumor dose of 6,528 r to the nasopharynx using the cobalt 60 irradiator between May 22,1968 and July 10, 1968. On October 24, 1968 the patient had massive bleeding, which was treated by packing. The patient expired in transit to M. D. Anderson Hospital; autopsy at another hospital reported no residual tumor. Case IV: Cranial nerve paralysis. A seventy-four year old white male underwent treatment in March 1968
Volume130, October 1975
TABLE
I
Major
Complications
Completing Therapy
of Radiation Therapy
in 218 Patients
a Course of Radiation
for Squamous
or Lymphoepithelioma
Cell Carcinoma of the Nasopharynx
Complications Fatal Stricture of the pharynx Spinal cord myelopathy Necrosis with fatal hemorrhage Nerve paralysis Brain abscess Radiation-induced cancer* Nonfatal Spinal cord myelopathy Radiation-induced cancert Total
Number of Patients
1 5 3 2 1 1 3 1 17
~-*Osteogenic sarcoma of the maxilla. t Grade I squamous cell carcinoma of hard palate in a twenty-five year old female.
on the betatron and cobalt 60 irradiators for grade III squamous cell carcinoma of the posterior nasopharynx involving the left eustachian tube. Tumor dose of 6,470 r was delivered during a six and a half week period. On June 8, 1970, increased difficulty with swallowing began developing in the patient, and it was noted that the patient had paralysis of the tenth and twelfth cranial nerves. There was no evidence of tumor in the nasopharynx. When examined on August 10, 1970, the patient was suspected of having stricture of the esophagus in the region of the cricoid. The patient’s condition deteriorated and he expired in February 1971. Case V: Brain abscess. A fifty-eight year old white female presented with extensive carcinoma of the nasopharynx and right lateral rectus paralysis on March 27, 1967. Treatment from March 30, 1967 to June 9, 1967 using the cobalt 60 and betatron irradiators consisted of a tumor dose of 6,695 r in seven weeks to the base of the skull and nasopharynx. In September 1969, the patient began having pain in the right ear with drainage. Examination showed a perforation of the right drum with purulent discharge. Tomograms of the temporal bone were reported to be nonrevealing. The patient expired in another hospital on August 28, 1970, and autopsy was reported to show purulent mastoiditis with a brain abscess but no residual tumor. In addition
to these
complications
that can be
reasonably well classified, four patients had bizarre findings in the central nervous system that do not agree with any well recognized pattern. The effect of irradiation on the brain has been reported by Okeda and Shibata [18], Kramer and Lee [19], Wilson, Byfield, and Hanafee [20], and Lampert, Tom, and Rider [21]. One of the patients showing
435
Ballantyne
a
confusing
neurologic
logic consultants radiation,
thought
picture,
which
our neuro-
could be secondary
to ir-
follows.
Case VI. A fifty-six year old white male was administered a tumor dose of 6,268 r to the nasopharynx for a lymphoepithelioma of the nasopharynx with base of the skull involvement, using the cobalt 60 and betatron irradiators from February 20, 1967 to May 11, 1967. On November 20, 1969 the patient underwent frontal craniotomy for marked diminution in vision and was found to have radiation fibrosis in the region of the optic chiasm. When the patient returned for reexamination on August 12, 1974, along with blindness he was found to have weakness of the right arm and leg and hypesthesia of the right leg. He was found to be ataxic. Neurologic examination revealed bilateral atrophy of the optic nerve and pneumoencephalogram showed bilateral atrophy of the frontal lobe.
Comments When
high-dose
irradiation
to the nasopharynx
to cure some of the advanced tumors that occur, particularly those involved with the base of the skull and with cranial nerve palsies, it is necessary to include the hypothalamus, pituitary gland, and base of the brain as well as portions of the upper spinal cord. The major complications that may occur involve the spinal cord, although it is becoming more apparent that disturbances in the hypothalamic-pituitary axis are more common than had previously been thought. Cranial nerve palsies can occur and can be fatal if the tenth and twelfth cranial nerves are involved. At present there seems no way to eliminate these unfortunate sequelae. The clinician who follows patients after irradiation therapy for cancer of the nasopharynx should be alert to the sequelae that may occur and institute proper diagnostic studies to exclude recurrent or metastatic tumor as the cause of symptoms.
is required
Summary Sequlae of radiation therapy may be late in occurring and varied in their manifestations. Although some are untreatable and progressive, the risk of development of some other sequelae can be minimized by careful application of radiotherapy or by ancillary measures, such as dental decay prophylaxis. Some of the serious sequelae secondary to radiation therapy of the nasopharynx have been summarized. These include radiation myelitis, pa-
436
ralysis
of the cranial
ynx, radiation-induced fatal hemorrhage.
nerves,
stricture
cancer,
and
of the pharnecrosis
with
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