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RE-IRRADIATION OF HEAD AND NECK TUMORS
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RE-IRRADIATION OF HEAD AND NECK TUMORS Benefits and Toxicities Avraham Eisbruch, MD, and Laura Dawson, MD
Most patients with nonresectable, recurrent head and neck malignancies who have previously been irradiated are referred for palliative chemotherapy. Although re-irradiation is not currently considered a standard approach for these patients, it may improve outcome and should be considered for certain patients. This article presents some of the issues that should be considered regarding re-irradiation. RADIOBIOLOGY BACKGROUND
A brief review of the effects of radiation on tumor and normal tissue can introduce the issues involved. The primary target of radiation in the cell is DNA. Most radiation-induced cell death results from radiation-induced DNA damage, which interferes with the reproductive capability of the cell and manifests itself after several cell divisions. The effect of radiation on tumor and normal tissue, therefore, depends on the number of cells actively proliferating and on the length of the cell reproductive cycle. Acute radiation effects occur in tissues that have a high rate of cell turnover: the skin, bone marrow, gastrointestinal mucosa, and hair follicles. Following radiation-induced injury, the rapid proliferation rate of cells in these tissues produces prompt cell repopulation and tissue recovery. In general, late tissue effects manifest as longlasting complications in tissues with slow cell turnover. They include
From the Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
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necrosis of soft tissue, bone, or brain; fibrosis; fistula formation; spinal cord myelitis; and blindness caused by damage to the optic nerve. These late effects are usually irreversible. They depend primarily on the total dose of radiation, the size of the daily radiation fractions, and the volume of irradiated tissue. The development of late effects requires that stem cells have limited proliferative capability. The proliferative requirements of different tissues determine, to a large extent, the effects of irradiation on those tissues. Tissues in which the rate of proliferation is low, such as connective tissue, bone, subcutaneous tissue, and nerves, will be relatively resistant to radiation. Even in such tissues, however, the stem cells may have limited proliferative capacity, and the exhaustion of this capacity seems to cause late organ failure following irradiation. Conventional radiation therapy is delivered in 1.8 to 2.0 Gy daily fractions, 5 fractions weekly, to a total dose of 70 Gy for gross tumor and 50 to 60 Gy for subclinical or microscopic tumor. With lower doses, the probability of tumor control is much reduced. In comparison, using conventional fractionation, the radiation doses associated with a small risk of late toxicities (less than 5% at 5 years) are 50 Gy for spinal cord myelitis, 65 to 70 Gy for bone and muscle necrosis, 60 Gy for brain necrosis, and 50 Gy for optic nerve damage. Increasing the dose of radiation to the normal tissue beyond established limits is associated with a rapidly increasing risk of damage to normal tissue. For any given dose of radiation, the tissue tolerance to radiation will decrease as the irradiated volume increases. This decreased tolerance is considered in the planning of a course of irradiation. For example, after initial treatment of extensive tissue volume at risk for microscopic tumor, an additional high-dose radiation boost is typically delivered to a tight volume around the gross tumor, in an effort to decrease the volume of normal tissue receiving a high dose. The size of the daily radiation fraction also is important in determining late tissue toxicity. Delivery of radiation in small daily fractions allows preferential repair of sublethal injury to cells with a low reproductive capacity compared with cells with a high reproductive capacity, such as tumor cells. The therapeutic ratio of radiation can therefore be improved by using hyperfractionated radiation regimens, that is, radiation delivered in two or more radiation fractions a day, with lower doses per fraction than the standard single daily fraction, over the same treatment time (usually 6 to 8 weeks). The purpose of hyperfractionation is to reduce late tissue toxicity and allow an increased total dose of radiation, which may achieve better tumor control, to be safely delivered to the tumor. REPAIR OVER TIME
A crucial issue associated with re-irradiation is the extent to which normal, previously irradiated tissue can repair radiation damage over time, following the initial course of radiation. The extent of repair and the time required determine the ability to deliver an additional, full
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course of radiation safely to recurrent tumors or to new primary tumors arising in previously irradiated sites. Accurate data concerning the tolerance of previously irradiated late responding tissues to re-irradiation are scant. Some experimental data exist regarding the tolerance of the central nervous system to re-irradiation. Several studies of split-course irradiation of the spinal cord in the rat have been conducted. One study reported that a 15% increase in the radiation dose could be delivered with the same rate of spinal cord myelitis when the irradiation course was divided by a 1-month interval, compared with conventional irradiation.3I Prolonging the interval to 100 days provided no further increase in long-term recovery of the spinal cord.25Other studies of split-course irradiation of the rat cervical cord also demonstrated long-term recovery of spinal cord damage, evidenced by an increased tolerance of the cord as the interval between irradiation courses increased; there was a plateau at an approximately 35% higher tolerable dose, after a 4- to 5- month interval between the irradiation courses." When the long-term recovery was analyzed for late vascular injury in the rat cervical cord, late vascular injury was reduced by 65% when an interval of 7 months was inserted between irradiation courses, compared with a course of irradiation delivering the same total dose in a shorter total time. Van der Kogel and Fawacett reported experiments of irradiation of rat cervical spinal cords in which 10 fractionated treatments were delivered, each fraction delivering approximately 10% of the radiation dose that would induce paralysis from white matter necrosis in 50% of the rats within 6 to 7 months. Re-treatments were given with a variable number of fractions of the same size used for the initial irradiation. They found that after an initial dose representing 65% to 75% of full tolerance, there was an increase in tolerance for re-irradiation representing a 25% to 40% increase above the dose expected to cause paralysis in a continuous regimen.26 The results suggest that when a course of re-irradiation is delivered long after the initial course of irradiation, some capacity of the normal, latereacting tissue to absorb additional radiation is restored. The capacity of various organs to receive additional radiation safely varies, however, and may be related to inherent biological factors and to the size of each organ subunit whose destruction causes clinically significant organ dysfunction. Accurate clinical data regarding these factors are not known for most organs and tissues, so, whenever possible, re-irradiation of critical organs (e.g., brainstem) should respect the standard radiation tolerance limits of those organs, without considering the effects of repair over time. CLINICAL DATA
In patients whose nonresectable, recurrent head and neck cancer is treated with chemotherapy alone, those who have previously received radiation therapy seem to have no higher rate of complications than patients who have not been previously irradiated. Treatment with che-
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motherapy alone is not curative; however, and provides only temporary palliative responses. Airoldi et a1 reported the results of treatment with cisplatin, 80 to 100 mg/m2 bolus every 3 weeks, and 5-fluorouracil (5FU), 750 to 1000 mg/mz continuous infusion over 5 days, in 81 patients with recurrent cancer of the head and neck, 21 of whom had undifferentiated carcinoma of the nasopharynx.' The complete response rate was 12%, the partial response rate was 42%, the stable disease rate was 33%, and the no-response rate was 13%. The results for treating nasopharynx carcinoma with chemotherapy alone were somewhat better than those for treating nasopharyngeal tumors with chemotherapy alone. In patients with non-nasophyngeal tumors treated with chemotherapy alone, the rate of disease-free survival for more than 18 months was only 8%. All of the long-term survivors had a good performance status, a diseasefree interval longer than 12 months following the first treatment, and localized nonbulky recurrences. No severe complications were observed in this series of patients. In comparison, reported series of patients treated with re-irradiation for recurrent head and neck cancer, which vary substantially in patient selection, technical details of radiation treatment, and length of time of recurrence, report 2- to 5-year survival rates of 14% to %YO, with severe complications ranging from zeroz8to 28%.17 Appropriate selection of patients may produce better outcomes with reirradiation than with palliative chemotherapy. In clinical series of re-irradiation, the prevalence and severity of adverse effects differ widely with the modality of radiation (brachytherapy versus external beam radiation), the site irradiated, and the rate of long-term survival. Because the time required for late complications to become clinically apparent ranges from 6 months to 1 or 2 years, series in which many patients do not survive that long will report a relatively low rate of late complications. For example, in six re-treatment series that reported long-term complications, the average rate of fatal complications was 4.5% (range 0-16%), and the average 5-year survival rate was 10% to 21%.9,15, 17,zo, 28 Fatal complications may arise from tissue and tumor necrosis causing carotid artery rupture, brain (usually temporal lobe) necrosis, aspiration caused by cranial nerve paralysis, pharyngeal dysmotility or fibrosis, or narcotic overdose in patients with severe pain resulting from tissue destruction. Stevens et a1 recommended re-irradiation only for patients showing minimal clinical evidence of late normal-tissue radiation effects following the first course of irradiation.21The appearance of the skin in the previously irradiated area was used as an indicator of radiation effects. Skin with marked fibrosis, edema, telangiectasis, or atrophy suggested either a previous high local dose or individual sensitivity to late effects of radiation. Patients with moderate or severe normal-tissue radiation effects were not re-irradiated. Patients accepted for re-irradiation had flexible, nonfibrotic, nonedematous skin and intact, nonulcerated mucosal surfaces. Approximately one half to two thirds of patients evaluated for re-irradiation were selected for re-irradiation. The 5-year actuarial survival in this series was 37% for patients with new tumors and 17%
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for patients with recurrent tumors. Although locoregional tumor control within the irradiated volume was achieved in 23 of 85 patients, only 12 were alive and without evidence of disease at 5 years, underscoring the high risk of metastatic disease and death from unrelated conditions in these patients. The total radiation dose delivered to the volume of overlap with the original and subsequent radiation fields (including brachytherapy) ranged from 69 to 180 Gy. Severe adverse effects from re-irradiation were observed in 9% of the patients; however, it is possible that in some of these patients the fatal tissue necrosis and hemorrhage from carotid artery rupture may have been the result of tumor recurrence rather than the direct effect of radiation. There were no correlations between the cumulative dose of radiation or the time interval between the two irradiation courses and the risk of severe adverse effects. Similarly, other authors have not found a significant correlation between tissue necrosis and cumulative radiation d0se.l" 18, 32 Patients re-irradiated more than 1 year after initial irradiation have tumor control rates that are significantly better compared with those for patients irradiated after shorter intervals.l8P 32 These observations are expected: tumors that achieve a brief period of control following the first irradiation course are assumed to include a substantial number of clonogenic tumor cells that are resistant to radiation. Because these tumors grow back quickly, it is less likely that tumor control would be achieved with re-irradiation. On the other hand, tumors that recur following a longer interval may contain a smaller number of radioresistant cells. Weichselbaum et a1 demonstrated the existence of radioresistant tumor cells in head and neck squamous cell cancer that recurred after a curative course of i r r a d i a t i ~ nIn . ~this ~ study, the radiobiological parameters of human head and neck squamous cell carcinoma cell lines cultured from patients who suffered local failure after a curative course of irradiation were consistent with radioresistance when compared with the parameters of tumor cells cultured from head and neck cancer patients before radiotherapy. In general, series of re-irradiation report a significantly lower rate of local tumor control than tumors of similar stage and size treated with primary irradiation. Possible explanations of these findings are that recurrent tumors are inherently more aggressive, that radioresistant cells may emerge following initial radiation, and that a less aggressive treatment (lower radiation doses and decreased irradiated volumes) is commonly used at re-irradiation. LARYNX AND NASOPHARYNX RE-IRRADIATION
In the larynx and the nasopharynx, re-irradiation of tumors is more successful, and the rate of complications is lower, than in other sites of the head and neck. Wang et a1 reported on 20 patients with recurrent laryngeal cancer treated with re-irradiation.28Most of these patients had early tumors at recurrence and were treated with relatively small irradiation field sizes limited to the larynx, sparing the arytenoids as
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much as possible. A high dose (65 to 66 Gy) was delivered at reirradiation. The 5-year actuarial local control rate was 6l%, which rose to 93% when surgical salvage for re-irradiation failures was included. No significant radiation sequelae, such as severe arytenoid edema, chondronecrosis, or functionless larynx, were encountered, suggesting a high resistance of the cartilaginous larynx to re-irradiation with high cumulative doses. The investigators concluded that early tumors with good prognostic factors for local control, such as T1 or T2 lesions, should be considered for re-irradiation. On the other hand, larger tumors that would require larger irradiation fields have lower tumor control rates and higher complication risks. Following re-irradiation, the options for surgical salvage may be limited by the radiation effects on normal tissues. Patients presenting with advanced tumors at recurrence should therefore undergo laryngectomy rather than re-irradiation. Another site amenable for re-irradiation is the nasopharynx. The feasibility of re-irradiation at this site is especially important, because the tumors arising in the nasopharynx are generally nonresectable. A major factor in effective irradiation of nasopharyngeal carcinomas is incorporating brachytherapy, most often using radioactive cesium sources placed in the nasopharyngeal cavity. Radiation doses around brachytherapy implants are characterized by a rapid fall-off of dose away from the sources. Using brachytherapy, therefore, a high radiation dose can be delivered to the mucosa of the nasopharynx and to tumors lying immediately beneath the mucosa, while normal structures such as the optic nerve and chiasm, temporal brain, and temporomandibular joints receive little dose. The efficacy of brachytherapy, however, is limited to tumor cells lying close to the mucosa. Most series reporting the use of brachytherapy incorporated it into a program that included external irradiation. In general, series that used re-irradiation of nasopharyngeal cancer using brachytherapy as a major component of the treatment program reported better locoregional control rates and fewer complications than series using external irradiation alone. This difference reflects the advantage of brachytherapy in distributing the physical dose, but it may also represent a selection bias because larger tumors would more likely be treated with external radiation alone, requiring that relatively large volumes of normal tissue be irradiated. Series reporting re-irradiation for nasopharyngeal cancer typically report local disease control rates of 15% to 60% and late complication rates of 6% to 37?40.~,'~, 16, The largest series of patients treated with re-irradiation for recurrent nasopharyngeal carcinoma was reported from Hong Kong by Lee et al.16 Of 654 patients, only 6% of re-irradiated patients were suitable for treatment with brachytherapy alone, and 82% were treated with external beam radiation alone or with external beam radiation combined with brachytherapy. The method of irradiation significantly affected the risk of late complications, which was higher with external beam radiation alone. Overall, 26% of patients developed symptomatic late complications, for an actuarial complication-free rate of 52% at 5 years. The most common late complication was trismus, caused by radiation effects on
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the temporomandibular joint and the masseter muscles, which occurred in approximately 15%of patients. Other complications included deafness caused by late effects of radiation on the inner ear and eighth nerve or by otitis (in 8% of patients), endocrine dysfunction, cranial neuropathy, and temporal lobe necrosis (in approximately 3% of patients), and a relatively low risk of soft tissue necrosis and bone necrosis (in about 1% of patients). In early tumors, which would be stage T1 at recurrence, the actuarial local failure-free rate at 5 years was 45% for patients treated with combined brachytherapy and external beam radiation and 30% for patients treated with brachytherapy alone or with external beam radiation alone. The actuarial late complication-free rate at 5 years was 60% in patients treated with brachytherapy alone or with brachytherapy combined with external beam radiation and 40% in patients treated with external beam radiation alone. A higher rate of complications arising from brain or nerve damage was reported in a series of nasopharyngeal tumors treated with re-irradiation by Chua et al.7 Patients who received external beam radiation with or without brachytherapy had a 33% incidence of cranial neuropathies or brain stem damage, a 16% incidence of temporal lobe necrosis and hearing impairment, a 13% incidence of visual impairment, and a 13% incidence of endocrine dysfunction. All these rates were significantly lower in patients with early tumors treated with brachytherapy alone. Similarly, in a series from a different hospital in Hong K0ng,2~ radiation-induced temporal lobe encephalopathy was reported in 20% of the patients, most of whom were treated with external beam radiation alone. The higher incidence of temporal lobe damage found in this series may be explained by the frequent use of computed tomographic (CT) scans during patient follow-up, the inclusion of radiologically evident but clinically asymptomatic cases, and the use of higher re-irradiation doses delivered mainly by external beam radiation. These investigators concluded that patients for re-irradiation should be stringently selected, taking into consideration the overall poor salvage rate and the high risk of complications. In this series, patients with early stage tumors at presentation, with no infiltration of the skull base or cranial nerves, with a long interval following the previous radiation treatment, and patients with a good performance status had favorable risk-to-benefit ratios. In series of patients treated with re-irradiation in the United States, tumor histology has been identified as a significant prognostic factor: the outcome of patients with undifferentiated carcinoma or lymphoepithelioma was significantly better than that of patients with other tumor histologies.12,2o BRACHYTHERAPY
Although the placement of intracavitary brachytherapy sources in the nasopharyngeal cavity seems to improve the rate of local control and reduce the rate of complications, anatomic constraints usually pre-
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vent the use of this technique in other sites in the head and neck. Brachytherapy sources, however, can be inserted directly into the tumor, delivering a high local radiation dose that falls off rapidly and spares neighboring organs. The most common technique places nylon catheters, which are afterloaded with radioactive iridium (Ir-192) wire sources,8’ 14, 17-19 in the tumor. Radiation delivered by interstitial implants is usually supplemented with external irradiation. The dose of radiation delivered to the vicinity of the implant is higher than can be achieved safely with external radiation and is associated with improved rates of tumor control. However, there is a high risk of local damage to tissue adjacent to the implant. Most series of re-irradiation using interstitial implants report a high rate of soft tissue necrosis and fistula in the vicinity of the implanted tumor. Levendag et a1 reported a series of patients re-irradiated with external beam radiation alone and a subsequent series of patients irradiated with interstitial implants, with or without additional external irradiati~n.’~ The patients receiving interstitial implants had better rates of local control (50%) than those receiving external reirradiation (29%). A higher rate of local severe complications (33%), however, was observed in patients treated with interstitial implants. Other investigators report similar experience. A similar high rate of necrosis and fistula was observed by Fontanesi et al, who used interstitial irradiation alone to treat 23 recurrent or second primary head and neck tumors in previously irradiated areas.* Although local control was seen in 21 of 23 patients at a median follow-up of 10 months, severe complications occurred in 48% of the patients. In this series, the rate of dose delivery from the implant seemed to have a significant effect on the complication rate, with lower dose rates having significantly fewer complications. It is possible that technical improvements of the implants may reduce these complications. For example, Pommier et a1 reported a series of patients treated with brachytherapy for recurrent pharyngeal wall squamous cell carcinoma in previously irradiated fields.19No severe complications were observed in this series. The investigators attribute the absence of complications to the small target volume treated with brachytherapy, which limited the high dose delivered to neighboring soft tissues. STEREOTACTIC RADIOTHERAPY
Another method of limiting the volume of normal tissue exposed to re-irradiation is the use of stereotuctic radiosurgery, a method of delivering high dose radiation to a precisely defined target, commonly with a single high dose fraction. The high accuracy of radiation delivery makes this technique attractive for patients with recurrent tumors, usually smaller than 4 cm, that can be irradiated with very tight margins and limited exposure of neighboring tissue. A limited experience in using radiosurgery to treat locally recurrent nasopharyngeal cancer and recurrent cancer in other sites at the base of skull has been reported.”
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The small patient numbers and limited follow-up in these series leave the outcome and exact role of this technique in recurrent cancer still unclear. The delivery of a single large radiation fraction, as is common in stereotactic radiosurgery, has biologic disadvantages, with respect to normal tissue tolerance, compared with fractionated irradiation. The emergence of fractionated stereotactic radiosurgery is expected to improve the therapeutic ratio of this technique, particularly for tumors in previously irradiated areas.
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HYPERFRACTIONATION
Hyperfractionated irradiation in patients who have received irradiation in the past is an attractive strategy which may lower the high rate of late tissue complications. Benchalal et a1 have used this strategy in 19 patients with head and neck cancer who were previously irradiated.3 Hyperfractionation consisted of two daily fractions of 1.2 Gy spaced by 6- to 8-hour intervals, to a dose range of 45.6 to 60 Gy. Overall, no lethal complications were observed, but locoregional control rates were disappointing: all patients with gross disease presented with local failure within the re-irradiated volume. It is possible that the use of higher radiation doses, facilitated by hyperfractionation, could improve these results. CHEMORADIOTHERAPY
The addition of chemotherapy to radiation seems promising in improving local control and survival in primarily irradiated head and neck tumors, particularly when chemotherapy is given concurrently with radiati~n.~ These findings, and the general lack of overlapping late tissue toxicities of radiation and chemotherapy, make the combination of radiation and chemotherapy an attractive treatment strategy for tumors in previously irradiated head and neck areas. Trials of concurrent chemotherapy and re-irradiation use chemotherapy agents that are active and commonly used in the treatment of primary head and neck tumors. Chemotherapy regimens include the combinations of cisplatin, 11, 22, 27, 30 or paclitaxel.6 In these studies, the 5-fluorouracil, hydroxyurea,lO, acute toxicity of combined radiation and chemotherapy does not seem to be excessive compared with the toxicity expected following similar treatment in patients who had not been irradiated in the past. Assessment of the late toxicities in these regimens is difficult because of the 11, 22 wide range of radiation doses employed.lO, In other series of concurrent chemotherapy and radiation, the total radiation doses were relatively low, in the range that would be expected to provide palliation but not cure.6,30 Weppelman et a1 delivered radiation doses of 40 to 48 Gy concurrently with 5-FU and hydroxyurea,3° and Buchele et a1 delivered twice weekly paclitaxel concurrently with
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30 to 46 Gy irradiation.6 Vokes et a1 reported a trial of concomitant chemotherapy including 5-FU, hydroxyurea, and cisplatin, and high dose radiation (73-75 Gy) to gross disease.27Acute toxicities were related mainly to chemotherapy. The 1-year local control rate for patients who had been previously irradiated was 64'7'0, and the median survival was 12 months. These results suggest that such an approach, combining both aggressive chemotherapy and high dose irradiation, may translate into better outcomes in patients with recurrent malignancies.
SUMMARY
Most patients with head and neck cancer that recurs after irradiation should be treated with curative surgery. In patients whose tumors are nonresectable, or if surgery would cause unacceptable morbidity, a trial of curative re-irradiation may be considered. Taking into account the overall poor prognosis of these patients and the high rate of late tissue toxicity, especially soft tissue necrosis, fistula formation, and potential nerve damage, patients should be carefully selected. Several sites, notably the larynx and nasopharynx, can be re-irradiated with a relatively high rate of locoregional tumor control. In other sites, several criteria may be used to select patients for curative re-irradiation: limited tumor size, a relatively long period since previous irradiation (a suitable, though arbitrary, minimal time period may be 1year), good performance status, and lack of evidence of skin or soft tissue damage (skin fibrosis, atrophy or telangiectasis) by the previous irradiation course. Even when these selection criteria are used, the prognosis is poor, and long-term survival rates are low even if locoregional tumor control is achieved. Innovative strategies and techniques, including aggressive combined chemoradiation, hyperfractionation, and limiting the extent of irradiated tissues by using conformal irradiation, may improve locoregional control rates. It should be emphasized, however, that the only chance for achieving locoregional control and cure is through the delivery of a full dose of radiation, similar to the dose required for primary tumors. The delivery of a low radiation dose, commonly practiced to avoid complications, is expected to achieve palliation only.
References 1. Airoldi M, Bumma C, Cortesina G , et al: Long term survival following chemotherapy for recurrent head and neck cancer: Patient characteristics. Acta Otorhinolaryngologica Italica 14603409, 1994 2. Bajada C, Selch M, De Salles A, et a1 Application of stereotactic radiosurgery to the head and neck region. Acta Neurochir Suppl (Wein) 623114117, 1994 3. Benchalal M, Bachaud Jh4,Francois P, et al: Hyperfractionationin the reirradiation of head and neck cancers. Radiother Oncol36203-210, 1995 4. Brizel D, Albers M, Fisher SR, et a1 Hyperfractionated irradiation with or without
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concurrent chemotherapy for locally advanced head and neck cancer, N Engl J Med 3381798-1804,1998 5. Buatti JM, Friedman WA, Bova FJ: Linac radiosurgery for locally recurrent nasopharyngeal carcinoma: Rationale and techniques. Head Neck 171419,1995 6. Buchele T, Becker A, Sandner A, et a1 Reirradiation concomitant with paclitaxel in recurrent squamous cell carcinoma of the head and neck-a phase 1/11 study [abstract]. Int J Radiat Oncol Biol Phys 42 (suppl):226, 1998 7. Chua DlT, Sham JST, Kwong DLW, et a1 Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379-386, 1998 8. Fontanesi J, Hetzler D, Ross J: Effect of dose rate on local control and complications in the reirradiation of head and neck tumors with interstitial iridium-192. Int J Radiat Oncol Biol Phys 17365-369,1989 9. Fu KK, Newman H, Philipps T L Treatment of locally recurrent carcinoma of the nasopharynx. Radiology 117425431, 1975 10. Gandia D, Wibault P, Guillot T, et al: Simultaneous chemoradiotherapy as salvage treatment in locoregional recurrences of squamous head and neck cancer. Head Neck 158-15, 1993 11. Hartsell WF, Thomas CR, Murthy AK, et a1 Pilot study for the evaluation of simultaneous cisplatin/5-fluorouracil infusion and limited radiation therapy in regionally recurrent head and neck cancer. Am J Clin Oncol17338-343,1994 12. Hwang JM, Fu KK, Phillips TL: Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 41:10991111,1998 13. Kaplan ID, Adler JR, Hicks WL: Radiosurgery for palliation of base of skull recurrences from head and neck cancers. Cancer 701980-1984,1992 14. Langlois D, Hoffstetter S, Malissard L, et a1 Salvage irradiation of oropharynx and mobile tongue by iridium brachytherapy. Int J Radiat Oncol Biol Phys 145349-853,1988 15. Lee AWM, Law SCK, Foo W, et a 1 Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976-1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 26773-782,1993 16. Lee AWM, Foo W, Law SCK, et a1 Reirradiation of recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 38:43-52, 1997 17. Levendag PC, Meeuwis CA, Visser AG: Reirradiation of recurrent head and neck cancer: External and/or interstitial radiation therapy. Radiother Oncol 236-14, 1992 18. Mazeron JJ, Langlois D, Glaubiger D Salvage reirradiation of oropharyngeal cancers using iridium 192 wire implants: 5 year results of 70 cases. Int J Radiat Oncol Biol Phys 13957-962, 1987 19. Pommier P, Bolot G, Martel I, et al: Salvage brachytherapy of posterior pharyngeal wall squamous cell carcinoma in a previously irradiated area. Int J Radiat Oncol Biol Phys 3853-58,1997 20. Pryzant RM,Wendt CD, Delclos L, et al: Retreatment of nasopharyngeal cancer in 53 patients. Int J Radiat Oncol Biol Phys 22941-947, 1992 21. Stevens KR, Britch A, Moss WT: High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys 29:687498, 1994 22. Tan EH, Adelstein DJ, Saxton JP, et al: Concurrent chemoradiotherapy for salvage in relapsed squamous cell head and neck cancer. Cancer Invest 15:422428, 1997 23. Teo PML, Kwan WH, Chan ATC, et a1 HOWsuccessful is high-dose (>60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 40:897-913,1998 24. van der Kogel AJ, Sissing HA, Zoetelief J. Effects of x-rays and neutrons on repair and regeneration in the rat spinal cord. Int J Radiat Oncol Biol Phys 82095-2097, 1983 25. van der Kogel AJ: Radiation induced damage in the central nervous system, an interpretation of target cell responses. Br J Cancer 53 (suppl 7): 207-217, 1986 26. van der Kogel, AJ: Central nervous system radiation injury in small animal models. In Gutin PH, Leibel SA, Sheling GE (eds): Radiation Injury to the Nervous System. New York, Raven Press, New York, 1991, pp 91-111
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27. Vokes EE, Haraf DJ, Mick R, et a l Intensified concomitant chemoradiotherapy with and without filgastim for poor-prognosis head and neck cancer. J Clin Oncol 1223512359, 1994 28. Wang CC, McIntyre J: Reirradiation of laryngeal carcinoma: Techniques and results. Int J Radiat Oncol Biol Phys 26783-785, 1993 29. Weichselbaum RR, Beckett MA, Schwartz J L Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy. Int J Radiat Oncol Biol Phys 15~575-579,1988 30. Weppelman B, Wheeler RH, Peters GE, et a1 Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea and reirradiation. Int J Radiat Oncol Biol Phys 22:1051-1056,1992 31. White A, Horansey S: Time dependent repair of radiation damage in the rat spinal cord after x-rays. Eur J Cancer 16957-962, 1980 32. Yan JH, Hu YH, Gu XZ: Radiation therapy of recurrent nasopharyngeal carcinomaReport of 219 patients. Acta Radiologica Oncology 2223-28, 1983
Address reprint requests to A. Eisbruch, MD Department of Radiation Oncology University of Michigan Hospitals Ann Arbor, MI 48109 e-mail [email protected]
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RE-IRRADIATION OF HEAD AND NECK TUMORS Benefits and Toxicities Avraham Eisbruch, MD, and Laura Dawson, MD
Most patients with nonresectable, recurrent head and neck malignancies who have previously been irradiated are referred for palliative chemotherapy. Although re-irradiation is not currently considered a standard approach for these patients, it may improve outcome and should be considered for certain patients. This article presents some of the issues that should be considered regarding re-irradiation. RADIOBIOLOGY BACKGROUND
A brief review of the effects of radiation on tumor and normal tissue can introduce the issues involved. The primary target of radiation in the cell is DNA. Most radiation-induced cell death results from radiation-induced DNA damage, which interferes with the reproductive capability of the cell and manifests itself after several cell divisions. The effect of radiation on tumor and normal tissue, therefore, depends on the number of cells actively proliferating and on the length of the cell reproductive cycle. Acute radiation effects occur in tissues that have a high rate of cell turnover: the skin, bone marrow, gastrointestinal mucosa, and hair follicles. Following radiation-induced injury, the rapid proliferation rate of cells in these tissues produces prompt cell repopulation and tissue recovery. In general, late tissue effects manifest as longlasting complications in tissues with slow cell turnover. They include
From the Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 13 * NUMBER 4 AUGUST 1999
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necrosis of soft tissue, bone, or brain; fibrosis; fistula formation; spinal cord myelitis; and blindness caused by damage to the optic nerve. These late effects are usually irreversible. They depend primarily on the total dose of radiation, the size of the daily radiation fractions, and the volume of irradiated tissue. The development of late effects requires that stem cells have limited proliferative capability. The proliferative requirements of different tissues determine, to a large extent, the effects of irradiation on those tissues. Tissues in which the rate of proliferation is low, such as connective tissue, bone, subcutaneous tissue, and nerves, will be relatively resistant to radiation. Even in such tissues, however, the stem cells may have limited proliferative capacity, and the exhaustion of this capacity seems to cause late organ failure following irradiation. Conventional radiation therapy is delivered in 1.8 to 2.0 Gy daily fractions, 5 fractions weekly, to a total dose of 70 Gy for gross tumor and 50 to 60 Gy for subclinical or microscopic tumor. With lower doses, the probability of tumor control is much reduced. In comparison, using conventional fractionation, the radiation doses associated with a small risk of late toxicities (less than 5% at 5 years) are 50 Gy for spinal cord myelitis, 65 to 70 Gy for bone and muscle necrosis, 60 Gy for brain necrosis, and 50 Gy for optic nerve damage. Increasing the dose of radiation to the normal tissue beyond established limits is associated with a rapidly increasing risk of damage to normal tissue. For any given dose of radiation, the tissue tolerance to radiation will decrease as the irradiated volume increases. This decreased tolerance is considered in the planning of a course of irradiation. For example, after initial treatment of extensive tissue volume at risk for microscopic tumor, an additional high-dose radiation boost is typically delivered to a tight volume around the gross tumor, in an effort to decrease the volume of normal tissue receiving a high dose. The size of the daily radiation fraction also is important in determining late tissue toxicity. Delivery of radiation in small daily fractions allows preferential repair of sublethal injury to cells with a low reproductive capacity compared with cells with a high reproductive capacity, such as tumor cells. The therapeutic ratio of radiation can therefore be improved by using hyperfractionated radiation regimens, that is, radiation delivered in two or more radiation fractions a day, with lower doses per fraction than the standard single daily fraction, over the same treatment time (usually 6 to 8 weeks). The purpose of hyperfractionation is to reduce late tissue toxicity and allow an increased total dose of radiation, which may achieve better tumor control, to be safely delivered to the tumor. REPAIR OVER TIME
A crucial issue associated with re-irradiation is the extent to which normal, previously irradiated tissue can repair radiation damage over time, following the initial course of radiation. The extent of repair and the time required determine the ability to deliver an additional, full
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course of radiation safely to recurrent tumors or to new primary tumors arising in previously irradiated sites. Accurate data concerning the tolerance of previously irradiated late responding tissues to re-irradiation are scant. Some experimental data exist regarding the tolerance of the central nervous system to re-irradiation. Several studies of split-course irradiation of the spinal cord in the rat have been conducted. One study reported that a 15% increase in the radiation dose could be delivered with the same rate of spinal cord myelitis when the irradiation course was divided by a 1-month interval, compared with conventional irradiation.3I Prolonging the interval to 100 days provided no further increase in long-term recovery of the spinal cord.25Other studies of split-course irradiation of the rat cervical cord also demonstrated long-term recovery of spinal cord damage, evidenced by an increased tolerance of the cord as the interval between irradiation courses increased; there was a plateau at an approximately 35% higher tolerable dose, after a 4- to 5- month interval between the irradiation courses." When the long-term recovery was analyzed for late vascular injury in the rat cervical cord, late vascular injury was reduced by 65% when an interval of 7 months was inserted between irradiation courses, compared with a course of irradiation delivering the same total dose in a shorter total time. Van der Kogel and Fawacett reported experiments of irradiation of rat cervical spinal cords in which 10 fractionated treatments were delivered, each fraction delivering approximately 10% of the radiation dose that would induce paralysis from white matter necrosis in 50% of the rats within 6 to 7 months. Re-treatments were given with a variable number of fractions of the same size used for the initial irradiation. They found that after an initial dose representing 65% to 75% of full tolerance, there was an increase in tolerance for re-irradiation representing a 25% to 40% increase above the dose expected to cause paralysis in a continuous regimen.26 The results suggest that when a course of re-irradiation is delivered long after the initial course of irradiation, some capacity of the normal, latereacting tissue to absorb additional radiation is restored. The capacity of various organs to receive additional radiation safely varies, however, and may be related to inherent biological factors and to the size of each organ subunit whose destruction causes clinically significant organ dysfunction. Accurate clinical data regarding these factors are not known for most organs and tissues, so, whenever possible, re-irradiation of critical organs (e.g., brainstem) should respect the standard radiation tolerance limits of those organs, without considering the effects of repair over time. CLINICAL DATA
In patients whose nonresectable, recurrent head and neck cancer is treated with chemotherapy alone, those who have previously received radiation therapy seem to have no higher rate of complications than patients who have not been previously irradiated. Treatment with che-
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motherapy alone is not curative; however, and provides only temporary palliative responses. Airoldi et a1 reported the results of treatment with cisplatin, 80 to 100 mg/m2 bolus every 3 weeks, and 5-fluorouracil (5FU), 750 to 1000 mg/mz continuous infusion over 5 days, in 81 patients with recurrent cancer of the head and neck, 21 of whom had undifferentiated carcinoma of the nasopharynx.' The complete response rate was 12%, the partial response rate was 42%, the stable disease rate was 33%, and the no-response rate was 13%. The results for treating nasopharynx carcinoma with chemotherapy alone were somewhat better than those for treating nasopharyngeal tumors with chemotherapy alone. In patients with non-nasophyngeal tumors treated with chemotherapy alone, the rate of disease-free survival for more than 18 months was only 8%. All of the long-term survivors had a good performance status, a diseasefree interval longer than 12 months following the first treatment, and localized nonbulky recurrences. No severe complications were observed in this series of patients. In comparison, reported series of patients treated with re-irradiation for recurrent head and neck cancer, which vary substantially in patient selection, technical details of radiation treatment, and length of time of recurrence, report 2- to 5-year survival rates of 14% to %YO, with severe complications ranging from zeroz8to 28%.17 Appropriate selection of patients may produce better outcomes with reirradiation than with palliative chemotherapy. In clinical series of re-irradiation, the prevalence and severity of adverse effects differ widely with the modality of radiation (brachytherapy versus external beam radiation), the site irradiated, and the rate of long-term survival. Because the time required for late complications to become clinically apparent ranges from 6 months to 1 or 2 years, series in which many patients do not survive that long will report a relatively low rate of late complications. For example, in six re-treatment series that reported long-term complications, the average rate of fatal complications was 4.5% (range 0-16%), and the average 5-year survival rate was 10% to 21%.9,15, 17,zo, 28 Fatal complications may arise from tissue and tumor necrosis causing carotid artery rupture, brain (usually temporal lobe) necrosis, aspiration caused by cranial nerve paralysis, pharyngeal dysmotility or fibrosis, or narcotic overdose in patients with severe pain resulting from tissue destruction. Stevens et a1 recommended re-irradiation only for patients showing minimal clinical evidence of late normal-tissue radiation effects following the first course of irradiation.21The appearance of the skin in the previously irradiated area was used as an indicator of radiation effects. Skin with marked fibrosis, edema, telangiectasis, or atrophy suggested either a previous high local dose or individual sensitivity to late effects of radiation. Patients with moderate or severe normal-tissue radiation effects were not re-irradiated. Patients accepted for re-irradiation had flexible, nonfibrotic, nonedematous skin and intact, nonulcerated mucosal surfaces. Approximately one half to two thirds of patients evaluated for re-irradiation were selected for re-irradiation. The 5-year actuarial survival in this series was 37% for patients with new tumors and 17%
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for patients with recurrent tumors. Although locoregional tumor control within the irradiated volume was achieved in 23 of 85 patients, only 12 were alive and without evidence of disease at 5 years, underscoring the high risk of metastatic disease and death from unrelated conditions in these patients. The total radiation dose delivered to the volume of overlap with the original and subsequent radiation fields (including brachytherapy) ranged from 69 to 180 Gy. Severe adverse effects from re-irradiation were observed in 9% of the patients; however, it is possible that in some of these patients the fatal tissue necrosis and hemorrhage from carotid artery rupture may have been the result of tumor recurrence rather than the direct effect of radiation. There were no correlations between the cumulative dose of radiation or the time interval between the two irradiation courses and the risk of severe adverse effects. Similarly, other authors have not found a significant correlation between tissue necrosis and cumulative radiation d0se.l" 18, 32 Patients re-irradiated more than 1 year after initial irradiation have tumor control rates that are significantly better compared with those for patients irradiated after shorter intervals.l8P 32 These observations are expected: tumors that achieve a brief period of control following the first irradiation course are assumed to include a substantial number of clonogenic tumor cells that are resistant to radiation. Because these tumors grow back quickly, it is less likely that tumor control would be achieved with re-irradiation. On the other hand, tumors that recur following a longer interval may contain a smaller number of radioresistant cells. Weichselbaum et a1 demonstrated the existence of radioresistant tumor cells in head and neck squamous cell cancer that recurred after a curative course of i r r a d i a t i ~ nIn . ~this ~ study, the radiobiological parameters of human head and neck squamous cell carcinoma cell lines cultured from patients who suffered local failure after a curative course of irradiation were consistent with radioresistance when compared with the parameters of tumor cells cultured from head and neck cancer patients before radiotherapy. In general, series of re-irradiation report a significantly lower rate of local tumor control than tumors of similar stage and size treated with primary irradiation. Possible explanations of these findings are that recurrent tumors are inherently more aggressive, that radioresistant cells may emerge following initial radiation, and that a less aggressive treatment (lower radiation doses and decreased irradiated volumes) is commonly used at re-irradiation. LARYNX AND NASOPHARYNX RE-IRRADIATION
In the larynx and the nasopharynx, re-irradiation of tumors is more successful, and the rate of complications is lower, than in other sites of the head and neck. Wang et a1 reported on 20 patients with recurrent laryngeal cancer treated with re-irradiation.28Most of these patients had early tumors at recurrence and were treated with relatively small irradiation field sizes limited to the larynx, sparing the arytenoids as
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much as possible. A high dose (65 to 66 Gy) was delivered at reirradiation. The 5-year actuarial local control rate was 6l%, which rose to 93% when surgical salvage for re-irradiation failures was included. No significant radiation sequelae, such as severe arytenoid edema, chondronecrosis, or functionless larynx, were encountered, suggesting a high resistance of the cartilaginous larynx to re-irradiation with high cumulative doses. The investigators concluded that early tumors with good prognostic factors for local control, such as T1 or T2 lesions, should be considered for re-irradiation. On the other hand, larger tumors that would require larger irradiation fields have lower tumor control rates and higher complication risks. Following re-irradiation, the options for surgical salvage may be limited by the radiation effects on normal tissues. Patients presenting with advanced tumors at recurrence should therefore undergo laryngectomy rather than re-irradiation. Another site amenable for re-irradiation is the nasopharynx. The feasibility of re-irradiation at this site is especially important, because the tumors arising in the nasopharynx are generally nonresectable. A major factor in effective irradiation of nasopharyngeal carcinomas is incorporating brachytherapy, most often using radioactive cesium sources placed in the nasopharyngeal cavity. Radiation doses around brachytherapy implants are characterized by a rapid fall-off of dose away from the sources. Using brachytherapy, therefore, a high radiation dose can be delivered to the mucosa of the nasopharynx and to tumors lying immediately beneath the mucosa, while normal structures such as the optic nerve and chiasm, temporal brain, and temporomandibular joints receive little dose. The efficacy of brachytherapy, however, is limited to tumor cells lying close to the mucosa. Most series reporting the use of brachytherapy incorporated it into a program that included external irradiation. In general, series that used re-irradiation of nasopharyngeal cancer using brachytherapy as a major component of the treatment program reported better locoregional control rates and fewer complications than series using external irradiation alone. This difference reflects the advantage of brachytherapy in distributing the physical dose, but it may also represent a selection bias because larger tumors would more likely be treated with external radiation alone, requiring that relatively large volumes of normal tissue be irradiated. Series reporting re-irradiation for nasopharyngeal cancer typically report local disease control rates of 15% to 60% and late complication rates of 6% to 37?40.~,'~, 16, The largest series of patients treated with re-irradiation for recurrent nasopharyngeal carcinoma was reported from Hong Kong by Lee et al.16 Of 654 patients, only 6% of re-irradiated patients were suitable for treatment with brachytherapy alone, and 82% were treated with external beam radiation alone or with external beam radiation combined with brachytherapy. The method of irradiation significantly affected the risk of late complications, which was higher with external beam radiation alone. Overall, 26% of patients developed symptomatic late complications, for an actuarial complication-free rate of 52% at 5 years. The most common late complication was trismus, caused by radiation effects on
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the temporomandibular joint and the masseter muscles, which occurred in approximately 15%of patients. Other complications included deafness caused by late effects of radiation on the inner ear and eighth nerve or by otitis (in 8% of patients), endocrine dysfunction, cranial neuropathy, and temporal lobe necrosis (in approximately 3% of patients), and a relatively low risk of soft tissue necrosis and bone necrosis (in about 1% of patients). In early tumors, which would be stage T1 at recurrence, the actuarial local failure-free rate at 5 years was 45% for patients treated with combined brachytherapy and external beam radiation and 30% for patients treated with brachytherapy alone or with external beam radiation alone. The actuarial late complication-free rate at 5 years was 60% in patients treated with brachytherapy alone or with brachytherapy combined with external beam radiation and 40% in patients treated with external beam radiation alone. A higher rate of complications arising from brain or nerve damage was reported in a series of nasopharyngeal tumors treated with re-irradiation by Chua et al.7 Patients who received external beam radiation with or without brachytherapy had a 33% incidence of cranial neuropathies or brain stem damage, a 16% incidence of temporal lobe necrosis and hearing impairment, a 13% incidence of visual impairment, and a 13% incidence of endocrine dysfunction. All these rates were significantly lower in patients with early tumors treated with brachytherapy alone. Similarly, in a series from a different hospital in Hong K0ng,2~ radiation-induced temporal lobe encephalopathy was reported in 20% of the patients, most of whom were treated with external beam radiation alone. The higher incidence of temporal lobe damage found in this series may be explained by the frequent use of computed tomographic (CT) scans during patient follow-up, the inclusion of radiologically evident but clinically asymptomatic cases, and the use of higher re-irradiation doses delivered mainly by external beam radiation. These investigators concluded that patients for re-irradiation should be stringently selected, taking into consideration the overall poor salvage rate and the high risk of complications. In this series, patients with early stage tumors at presentation, with no infiltration of the skull base or cranial nerves, with a long interval following the previous radiation treatment, and patients with a good performance status had favorable risk-to-benefit ratios. In series of patients treated with re-irradiation in the United States, tumor histology has been identified as a significant prognostic factor: the outcome of patients with undifferentiated carcinoma or lymphoepithelioma was significantly better than that of patients with other tumor histologies.12,2o BRACHYTHERAPY
Although the placement of intracavitary brachytherapy sources in the nasopharyngeal cavity seems to improve the rate of local control and reduce the rate of complications, anatomic constraints usually pre-
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vent the use of this technique in other sites in the head and neck. Brachytherapy sources, however, can be inserted directly into the tumor, delivering a high local radiation dose that falls off rapidly and spares neighboring organs. The most common technique places nylon catheters, which are afterloaded with radioactive iridium (Ir-192) wire sources,8’ 14, 17-19 in the tumor. Radiation delivered by interstitial implants is usually supplemented with external irradiation. The dose of radiation delivered to the vicinity of the implant is higher than can be achieved safely with external radiation and is associated with improved rates of tumor control. However, there is a high risk of local damage to tissue adjacent to the implant. Most series of re-irradiation using interstitial implants report a high rate of soft tissue necrosis and fistula in the vicinity of the implanted tumor. Levendag et a1 reported a series of patients re-irradiated with external beam radiation alone and a subsequent series of patients irradiated with interstitial implants, with or without additional external irradiati~n.’~ The patients receiving interstitial implants had better rates of local control (50%) than those receiving external reirradiation (29%). A higher rate of local severe complications (33%), however, was observed in patients treated with interstitial implants. Other investigators report similar experience. A similar high rate of necrosis and fistula was observed by Fontanesi et al, who used interstitial irradiation alone to treat 23 recurrent or second primary head and neck tumors in previously irradiated areas.* Although local control was seen in 21 of 23 patients at a median follow-up of 10 months, severe complications occurred in 48% of the patients. In this series, the rate of dose delivery from the implant seemed to have a significant effect on the complication rate, with lower dose rates having significantly fewer complications. It is possible that technical improvements of the implants may reduce these complications. For example, Pommier et a1 reported a series of patients treated with brachytherapy for recurrent pharyngeal wall squamous cell carcinoma in previously irradiated fields.19No severe complications were observed in this series. The investigators attribute the absence of complications to the small target volume treated with brachytherapy, which limited the high dose delivered to neighboring soft tissues. STEREOTACTIC RADIOTHERAPY
Another method of limiting the volume of normal tissue exposed to re-irradiation is the use of stereotuctic radiosurgery, a method of delivering high dose radiation to a precisely defined target, commonly with a single high dose fraction. The high accuracy of radiation delivery makes this technique attractive for patients with recurrent tumors, usually smaller than 4 cm, that can be irradiated with very tight margins and limited exposure of neighboring tissue. A limited experience in using radiosurgery to treat locally recurrent nasopharyngeal cancer and recurrent cancer in other sites at the base of skull has been reported.”
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The small patient numbers and limited follow-up in these series leave the outcome and exact role of this technique in recurrent cancer still unclear. The delivery of a single large radiation fraction, as is common in stereotactic radiosurgery, has biologic disadvantages, with respect to normal tissue tolerance, compared with fractionated irradiation. The emergence of fractionated stereotactic radiosurgery is expected to improve the therapeutic ratio of this technique, particularly for tumors in previously irradiated areas.
5*13
HYPERFRACTIONATION
Hyperfractionated irradiation in patients who have received irradiation in the past is an attractive strategy which may lower the high rate of late tissue complications. Benchalal et a1 have used this strategy in 19 patients with head and neck cancer who were previously irradiated.3 Hyperfractionation consisted of two daily fractions of 1.2 Gy spaced by 6- to 8-hour intervals, to a dose range of 45.6 to 60 Gy. Overall, no lethal complications were observed, but locoregional control rates were disappointing: all patients with gross disease presented with local failure within the re-irradiated volume. It is possible that the use of higher radiation doses, facilitated by hyperfractionation, could improve these results. CHEMORADIOTHERAPY
The addition of chemotherapy to radiation seems promising in improving local control and survival in primarily irradiated head and neck tumors, particularly when chemotherapy is given concurrently with radiati~n.~ These findings, and the general lack of overlapping late tissue toxicities of radiation and chemotherapy, make the combination of radiation and chemotherapy an attractive treatment strategy for tumors in previously irradiated head and neck areas. Trials of concurrent chemotherapy and re-irradiation use chemotherapy agents that are active and commonly used in the treatment of primary head and neck tumors. Chemotherapy regimens include the combinations of cisplatin, 11, 22, 27, 30 or paclitaxel.6 In these studies, the 5-fluorouracil, hydroxyurea,lO, acute toxicity of combined radiation and chemotherapy does not seem to be excessive compared with the toxicity expected following similar treatment in patients who had not been irradiated in the past. Assessment of the late toxicities in these regimens is difficult because of the 11, 22 wide range of radiation doses employed.lO, In other series of concurrent chemotherapy and radiation, the total radiation doses were relatively low, in the range that would be expected to provide palliation but not cure.6,30 Weppelman et a1 delivered radiation doses of 40 to 48 Gy concurrently with 5-FU and hydroxyurea,3° and Buchele et a1 delivered twice weekly paclitaxel concurrently with
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30 to 46 Gy irradiation.6 Vokes et a1 reported a trial of concomitant chemotherapy including 5-FU, hydroxyurea, and cisplatin, and high dose radiation (73-75 Gy) to gross disease.27Acute toxicities were related mainly to chemotherapy. The 1-year local control rate for patients who had been previously irradiated was 64'7'0, and the median survival was 12 months. These results suggest that such an approach, combining both aggressive chemotherapy and high dose irradiation, may translate into better outcomes in patients with recurrent malignancies.
SUMMARY
Most patients with head and neck cancer that recurs after irradiation should be treated with curative surgery. In patients whose tumors are nonresectable, or if surgery would cause unacceptable morbidity, a trial of curative re-irradiation may be considered. Taking into account the overall poor prognosis of these patients and the high rate of late tissue toxicity, especially soft tissue necrosis, fistula formation, and potential nerve damage, patients should be carefully selected. Several sites, notably the larynx and nasopharynx, can be re-irradiated with a relatively high rate of locoregional tumor control. In other sites, several criteria may be used to select patients for curative re-irradiation: limited tumor size, a relatively long period since previous irradiation (a suitable, though arbitrary, minimal time period may be 1year), good performance status, and lack of evidence of skin or soft tissue damage (skin fibrosis, atrophy or telangiectasis) by the previous irradiation course. Even when these selection criteria are used, the prognosis is poor, and long-term survival rates are low even if locoregional tumor control is achieved. Innovative strategies and techniques, including aggressive combined chemoradiation, hyperfractionation, and limiting the extent of irradiated tissues by using conformal irradiation, may improve locoregional control rates. It should be emphasized, however, that the only chance for achieving locoregional control and cure is through the delivery of a full dose of radiation, similar to the dose required for primary tumors. The delivery of a low radiation dose, commonly practiced to avoid complications, is expected to achieve palliation only.
References 1. Airoldi M, Bumma C, Cortesina G , et al: Long term survival following chemotherapy for recurrent head and neck cancer: Patient characteristics. Acta Otorhinolaryngologica Italica 14603409, 1994 2. Bajada C, Selch M, De Salles A, et a1 Application of stereotactic radiosurgery to the head and neck region. Acta Neurochir Suppl (Wein) 623114117, 1994 3. Benchalal M, Bachaud Jh4,Francois P, et al: Hyperfractionationin the reirradiation of head and neck cancers. Radiother Oncol36203-210, 1995 4. Brizel D, Albers M, Fisher SR, et a1 Hyperfractionated irradiation with or without
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concurrent chemotherapy for locally advanced head and neck cancer, N Engl J Med 3381798-1804,1998 5. Buatti JM, Friedman WA, Bova FJ: Linac radiosurgery for locally recurrent nasopharyngeal carcinoma: Rationale and techniques. Head Neck 171419,1995 6. Buchele T, Becker A, Sandner A, et a1 Reirradiation concomitant with paclitaxel in recurrent squamous cell carcinoma of the head and neck-a phase 1/11 study [abstract]. Int J Radiat Oncol Biol Phys 42 (suppl):226, 1998 7. Chua DlT, Sham JST, Kwong DLW, et a1 Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379-386, 1998 8. Fontanesi J, Hetzler D, Ross J: Effect of dose rate on local control and complications in the reirradiation of head and neck tumors with interstitial iridium-192. Int J Radiat Oncol Biol Phys 17365-369,1989 9. Fu KK, Newman H, Philipps T L Treatment of locally recurrent carcinoma of the nasopharynx. Radiology 117425431, 1975 10. Gandia D, Wibault P, Guillot T, et al: Simultaneous chemoradiotherapy as salvage treatment in locoregional recurrences of squamous head and neck cancer. Head Neck 158-15, 1993 11. Hartsell WF, Thomas CR, Murthy AK, et a1 Pilot study for the evaluation of simultaneous cisplatin/5-fluorouracil infusion and limited radiation therapy in regionally recurrent head and neck cancer. Am J Clin Oncol17338-343,1994 12. Hwang JM, Fu KK, Phillips TL: Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 41:10991111,1998 13. Kaplan ID, Adler JR, Hicks WL: Radiosurgery for palliation of base of skull recurrences from head and neck cancers. Cancer 701980-1984,1992 14. Langlois D, Hoffstetter S, Malissard L, et a1 Salvage irradiation of oropharynx and mobile tongue by iridium brachytherapy. Int J Radiat Oncol Biol Phys 145349-853,1988 15. Lee AWM, Law SCK, Foo W, et a 1 Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976-1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 26773-782,1993 16. Lee AWM, Foo W, Law SCK, et a1 Reirradiation of recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 38:43-52, 1997 17. Levendag PC, Meeuwis CA, Visser AG: Reirradiation of recurrent head and neck cancer: External and/or interstitial radiation therapy. Radiother Oncol 236-14, 1992 18. Mazeron JJ, Langlois D, Glaubiger D Salvage reirradiation of oropharyngeal cancers using iridium 192 wire implants: 5 year results of 70 cases. Int J Radiat Oncol Biol Phys 13957-962, 1987 19. Pommier P, Bolot G, Martel I, et al: Salvage brachytherapy of posterior pharyngeal wall squamous cell carcinoma in a previously irradiated area. Int J Radiat Oncol Biol Phys 3853-58,1997 20. Pryzant RM,Wendt CD, Delclos L, et al: Retreatment of nasopharyngeal cancer in 53 patients. Int J Radiat Oncol Biol Phys 22941-947, 1992 21. Stevens KR, Britch A, Moss WT: High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys 29:687498, 1994 22. Tan EH, Adelstein DJ, Saxton JP, et al: Concurrent chemoradiotherapy for salvage in relapsed squamous cell head and neck cancer. Cancer Invest 15:422428, 1997 23. Teo PML, Kwan WH, Chan ATC, et a1 HOWsuccessful is high-dose (>60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 40:897-913,1998 24. van der Kogel AJ, Sissing HA, Zoetelief J. Effects of x-rays and neutrons on repair and regeneration in the rat spinal cord. Int J Radiat Oncol Biol Phys 82095-2097, 1983 25. van der Kogel AJ: Radiation induced damage in the central nervous system, an interpretation of target cell responses. Br J Cancer 53 (suppl 7): 207-217, 1986 26. van der Kogel, AJ: Central nervous system radiation injury in small animal models. In Gutin PH, Leibel SA, Sheling GE (eds): Radiation Injury to the Nervous System. New York, Raven Press, New York, 1991, pp 91-111
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27. Vokes EE, Haraf DJ, Mick R, et a l Intensified concomitant chemoradiotherapy with and without filgastim for poor-prognosis head and neck cancer. J Clin Oncol 1223512359, 1994 28. Wang CC, McIntyre J: Reirradiation of laryngeal carcinoma: Techniques and results. Int J Radiat Oncol Biol Phys 26783-785, 1993 29. Weichselbaum RR, Beckett MA, Schwartz J L Radioresistant tumor cells are present in head and neck carcinomas that recur after radiotherapy. Int J Radiat Oncol Biol Phys 15~575-579,1988 30. Weppelman B, Wheeler RH, Peters GE, et a1 Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea and reirradiation. Int J Radiat Oncol Biol Phys 22:1051-1056,1992 31. White A, Horansey S: Time dependent repair of radiation damage in the rat spinal cord after x-rays. Eur J Cancer 16957-962, 1980 32. Yan JH, Hu YH, Gu XZ: Radiation therapy of recurrent nasopharyngeal carcinomaReport of 219 patients. Acta Radiologica Oncology 2223-28, 1983
Address reprint requests to A. Eisbruch, MD Department of Radiation Oncology University of Michigan Hospitals Ann Arbor, MI 48109 e-mail [email protected]