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Complications following re-irradiation for head and neck cancer
Complications Following Re-irradiation for Head and Neck Cancer Yukio Ohizumi, MD, Yoshifumi Tamai, MD, Satoshi Imamiya, MD, and Takeshi Akiba, MD Purpose: Re-irradiation may induce serious complications because of overdosage to previously irradiated areas. A few reports do exist that describe the incidence and factors related to late complications. In the present study we analyze complications following re-irradiation for head and neck cancers. Materials and Methods: Between 1984 and 1998, 91 patients presenting with squamous cell carcinoma of the head and neck were re-irradiated with a total dose of 80-144 Gy and overlap fields of 4-128 cm2. Re-irradiation was administered exclusively with external beam irradiation with conventional (n ⫽ 47), hyper- (n ⫽ 10), or hypofractionation (n ⫽ 34). Chemotherapy was combined with the initial course of irradiation (n ⫽ 34) or re-irradiation (n ⫽ 18). Follow-up time ranged from 3 to 84 months. Results: Severe acute reactions occurred in 6.6% of patients. Moreover, incidence was significantly higher (40%) in elderly patients older than 80 years. Severe late complications developed 3-10 months after re-irradiation. The incidence was 13% in 78 patients followed for more than 3 months and 21% in 42 patients with tumor-free status. The complications were observed in 19% of patients previously receiving locoregional irradiation, compared with those receiving local irradiation alone (0%), and in 20% of patients undergoing re-irradiation to the neck, compared with those receiving re-irradiation to the head (3%). These factors were all significant by multivariate analysis. Radiation dose, fractionation method, and overlap area were not significant. Conclusion: Care should be exercised with respect to the potential for acute complications in elderly patients and late complications in those patients having previously received locoregional irradiation and re-irradiation to the neck. (Am J Otolaryngol 2002;23:215-221. Copyright 2002, Elsevier Science (USA). All rights reserved.)
Numerous opportunities exist for re-irradiating cancers of the head and neck regions. In some cases, recurrent tumors can be controlled; however, re-irradiation may induce serious complications as a result of overdoses to previously irradiated areas. In the present investigation, re-irradiation was planned with great care with respect to overlap fields and doses impacting organs at risk. It is currently unclear as to what factors are important with respect to late complications. Radiation dose, overlap field size, overlap site, dose fractionation, combined therapy,
From the Department of Radiation Oncology, Tokai University School of Medicine, Isehara, Japan. Address correspondence to Dr Yukio Ohizumi, Department of Radiation Oncology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 2591193, Japan. E-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 0196-0709/02/2304-0001$35.00/0 doi:10.1053/ajot.2002.124540
and other factors may influence these complications. Of these factors, we were particularly interested in overlap field and overlap site, of which there are only a few reports. In this study, incidence and factors related to the complications were analyzed in cases of head and neck cancer treated by re-irradiation. MATERIALS AND METHODS Between October 1984 and September 1997, 91 patients presenting with squamous cell carcinoma of the head and neck were re-irradiated with a total dose of ⬎80 Gy and overlap fields of ⬎4 cm2. Patients included 68 men and 23 women with an average age of 64 years and a range of 21 to 91 years. Table 1 presents the primary tumor sites and tumor stages. Subjects had been irradiated with external beams of x-rays or gamma rays at a mean dose of 59 Gy (Table 2) at the initial course of radiotherapy. Patients were treated with conventional fractionation (n ⫽ 86), hyperfractionation (n ⫽ 2, 1.2 Gy twice per day) and hypofractionation (n ⫽ 3, ⬎3 Gy daily). Irradiated fields included 31 locals alone, three regional, and 57 locoregionals.
American Journal of Otolaryngology, Vol 23, No 4 (July-August), 2002: pp 215-221
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TABLE 1. Patient Characteristics at the Initial Course of Radiotherapy
TABLE 3. Patient Characteristics at Re-irradiation. Factors
Factors Sex Male Female Primary site Oral cavity Larynx Oropharynx Nasopharynx Hypopharynx Maxillary sinus Stage I II III IV Recurrence Radiation field Local alone Regional alone Locoregional Postoperative radiotherapy Combined chemotherapy
Tumor status Persistent Recurrence Secondary Postoperative status Re-irradiated site and recurrent stage Local T2-3 T4 Regional N2 N3 Loco-regional Re-irradiated field In-field Out-of-field
68 23 27 27 17 8 6 6 9 19 16 37 10 31 3 57 22 34
Field size irradiated with the prescribed dose was 65 ⫾ 41 cm2. Thirty-four patients had undergone chemotherapy before or concurrent with radiotherapy. The chemotherapeutic agents used included cisplatin (n ⫽ 19), 5-fluorouracil (5FU), UFT (a combination of tegafur and uracil), and peplomycin, among others. Half of these agents were administered as combination chemotherapy. Twenty-two patients received postoperative radiotherapy. Following the initial irradiation, 40 patients (44%) underwent salvage operation before re-irradiation, and 21 of these subjects demonstrated recurrence after the salvage operation. One to 175 months (median, 22 months) after the first course of radiotherapy, patients were re-irradiated in the head or neck regions for persistent tumor (n ⫽ 2),
TABLE 2. Radiotherapy Data Factors
No. of Patients
No. of Patients
Range
Mean
First radiation dose 20-85 Gy 59 Gy Interval between radiotherapies 1-175 mo 22 mo Re-irradiation dose 17-78 Gy 55 Gy Total dose 80-144 Gy 114 Gy Overlap field area 4-128 cm2 41 cm2 At re-irradiation: Fractionation Conventional (38) 1.8⬇2.1 Gy/d 55.1 Gy Hyperfractionation (10) 1.2 Gy ⫻ 2/d 58.5 Gy Hypofractionation (21) ⬎2.2 Gy/d 52.3 Gy Combined chemotherapy (13) 53.6 Gy Combined hyperthermia (9) 58.7 Gy NOTE. Figures in parentheses indicate numbers of patients.
2 64 6 19 46 9 37 41 28 13 4 56 35
recurrent tumor (n ⫽ 64), second primary tumors (n ⫽ 6), and postoperative tumor (n ⫽ 19; Table 3). Re-irradiated sites comprised 46 locals, 41 regionals and 4 locoregionals. Malignancies consisted of 9 T2-3s, 37 T4s, 28 N2s, 13 N3s, and 4 TNs, according to the UICC classification.1 Sites related to prior radiation fields were 56 in-field and 35 out-of-field. All patients were treated with external beam irradiation exclusively with cobalt 60 or 4 MV photons. Re-irradiation doses ranged from 17 to 78 Gy at the isocenter (Table 2). The external beam technique was designed to avoid as much as possible overdoses to the spinal cord, brain, eye, larynx, and mandibular bone. Treatment volume was typically determined by adding a safety margin (1-2 cm) to the gross tumor volume. Field size receiving the prescribed dose was 76 ⫾ 61 cm2. Overlap field size was measured from simulation films of the initial course of irradiation and re-irradiation. The overlap areas ranged from 4 to 128 cm2. Overlap sites consisted of 45 heads and 56 necks. Total dosage at the overlap field ranged from 80 to 144 Gy. Conventional fractionated radiotherapy at a daily dose of 1.8-2.1 Gy was administered in 47 patients. Ten patients underwent twice-daily irradiation at a fraction size of 1.2 Gy separated by 6 hours. Thirty-four patients were treated with hypofractionated radiotherapy at a daily dose of 2.2-5.0 Gy. Eighteen patients received chemotherapy at re-irradiation. Cisplatin and/or 5FU were administered in most of these subjects. Nine patients received local hyperthermia at approximately 42°C for about 30 min.
Evaluation and Follow-up Patient follow-up was conducted monthly for the first year and once every 2 months in subsequent years (range, 3-84 months). Radiation oncologists and otolaryngologists or oral surgeons observed tumor response, tumor recurrence, and complica-
COMPLICATIONS FOLLOWING RE-IRRADIATION
tions. Tumor response rates by re-irradiation were 37 percent complete response (CR), 32 percent partial response (PR, indicating ⬎50% tumor volume reduction), and 31 percent no response (NC). Median relapse-free survival, which was defined as the period until tumor appearance for CR or tumor progression for PR or NC, was 7 months. Median overall survival time was nine months. The 5-year relapse-free and overall survival rates were 7% and 11% following re-irradiation, respectively (Fig 1). Severe acute complications were defined as any event involving discontinued radiotherapy or death within 1 month. Those patients displaying acute sequelae or followed within 3 months were excluded with respect to late complications. Seventy-eight patients were evaluated. Grading of late complications was based in accordance with the classifications of RTOG/EORT.2 Cases involving tumor bleeding or necroses were excluded from late complications because of the presence of malignant cells in the lesions.
217
Fig 2. Relationship between relapse-free and complication-free survival following re-irradiation. Complication grade IV (F), III (Œ), II (䊐), I (‚), 0 (E).
Analysis Differences in complication rates were analyzed by the chi-square or Fisher exact test. A logistic regression model was employed for multivariate analysis. A probability value of .05 derived from a 2-sided test was considered significant. For the multivariate model, significant factors determined by univariate analysis were selected and a forward stepwise method was used. The data processing program was SPSS (SPSS Co., Tokyo, Japan).
deterioration of general condition, serious pneumonitis, dyspnea, and 2 instances of intolerable mucositis. Of these cases, 4 patients were older than 80 years. Age greater than 80 years was significantly associated with acute complications (P ⬍ .01). No other factors were significant. Late Complication Rates
RESULTS Acute Complications Severe acute complications were observed in 6 of 91 (6.6%) patients: unknown death,
Late complications of grade 3 and above appeared 3-10 months following re-irradiation (Fig 2). None of these complications caused death. The complication rate was observed in 10 of 78 (13%) patients followed for more than 3 months and in 9 of 42 (21%) patients displaying complete tumor response or postoperative tumor-free status (Table 4).
TABLE 4. Complication Rates
Fig 1. Overall and relapse-free survival following reirradiation for 91 patients with recurrent head and neck cancer.
Complication
Incidence
Percent
Acute Late Follow-up ⬎3 months Grade 2-4 Grade 3-4 Follow-up ⬎1 year Grade 2-4 Grade 3-4 Tumor-free patients Grade 2-4 Grade 3-4
6/91
6.6
19/78 10/78
24 13
11/37 6/37
30 16
15/42 9/42
36 21
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Case Reports of Severe Late Complications A single patient receiving re-irradiation to the nasopharynx (total dose, 137 Gy) exhibited cranial nerve dysfunction (VI to XII). One patient with oropharyngeal cancer developed nonserious paresthesia and muscle weakness; she received a total dose of 55 Gy at the upper cervical spinal cord. Four patients underwent laryngotracheotomy for laryngeal edema (1 of 5 laryngeal cancers with larynx preservation and 3 nonlaryngeal cancers re-irradiated to the larynx). The incidence of severe laryngeal edema was 3 of 8 (38%) patients irradiated to the entire larynx with a total dose of 85-130 Gy (Table 5). Two patients displaying laryngeal or hypopharyngeal cancer developed esophageal stenosis or ulcers and were only able to swallow liquids. A single patient exhibiting an oral floor tumor developed pharyngeal dysfunction, which may have been due to fibrosis; however, this subject had undergone previous surgical intervention. Another patient, developed seizure, headache, facial pain, dizziness, and paresthesia of the trigeminal nerve after radiotherapy dosing of 82.5 Gy directed to the neck and tonsils. This individual recovered from her symptoms with no findings on computed tomography of the brain. The cause was unknown.
head (3%; Table 6). These factors were significant by multivariate analysis. The incidence by overlap field sites is presented in Table 7. Re-irradiation to the neck frequently induced late complications. Anatomical diagnosis indicated a high incidence in the hypopharynx and mesopharynx (50% and 19%, respectively) and low in the oral cavity and larynx (8.7%; Fig 3). Late complications of grade 2 and above were observed in 19 of 78 (24%) patients. Prior radiotherapy to locoregions, overlap fields in the neck, and female sex were significant by multivariate analysis (Table 6). Age and previous chemoradiotherapy were boundary factors by univariate analysis; however, these factors were strongly correlated to the prior irradiation sites. Initial radiation dose, re-irradiation dose, cumulative dose, fractionation methods, and overlap field size were not significant. No relationship was evident between cumulative dose and overlap field size (Fig 4). The prior operation did not influence the rate of severe late complications (8 of 45 with surgery vs 11 of 33 without surgery). Additional factors, including postoperative re-irradiation, combined chemotherapy at re-irradiation, Karnofsky performance status, recurrent stage, and time interval until recurrence, were not significant. DISCUSSION
Factors Related to Late Complications These serious complications did not occur in patients receiving prior radiotherapy exclusively to the primary lesion; however, complications were observed in cases of locoregional irradiation (19%). In addition, complications occurred more frequently in patients re-irradiated to the neck (20%), compared with the
Acute complications due to re-irradiation were serious in elderly patients but not in most other patients. Elderly patients demonstrated a poor general condition; consequently, re-irradiation induced deterioration in the general condition of these patients and serious pneumonia, rather than intolerable acute mucositis. Elderly patients may not be suit-
TABLE 5. Laryngeal Edema Complications
Re-irradiation to whole larynx Laryngeal cancer Non-laryngeal cancer Re-irradiation to partial larynx Laryngeal cancer Non-laryngeal cancer Total
Preserved Larynx
Laryngeal Edema
Other
5 3
1 2
seizure
8 10 26
0 1 4
— esophageal stenosis 2
—
COMPLICATIONS FOLLOWING RE-IRRADIATION
219
TABLE 6. Factors Related to Late Complications Grade 3-4 Variable (No. of patients)
Grade 2-4
Incidence (%)
P
Incidence (%)
0 19
.026*
0 36
⬍.001*
3 20
.038*
12 33
.036*
9 23
.134
16 46
.007*
22 9
.128
37 18
.058
20 8
.171
37 17
.045
10 17
.422
21 30
.359
Prior radiation field Primary alone (25) Primary and node (53) Overlap field Head (33) Neck (45) Sex Male (56) Female (22) Age ⱕ60 (27) ⱖ61 (51) Prior chemotherapy Yes (30) No (48) Fractionation method Conventional/hyperfractionation (48) Hypofractionation (30)
P
NOTE. P values were calculated by the chi-square or Fisher exact test. *Significance by the logistic regression model.
able candidates for re-irradiation or care should be exercised with respect to their general condition during re-irradiation. Late complications appeared relatively early following re-irradiation in this study. Lee et al reported that late complications frequently developed within 1 year after re-irradiation in a large series of re-irradiated nasopharyngeal cancer cases.3 The incidence of severe late complications was 21% in the present investigation; this rate was 9%-41% in previous reports.4-9 The incidence of severe late complications can be influenced by many factors. One of the most important factors in the present study
was the initial course of the radiation field. Previous irradiation exclusively to the primary site did not lead to late complications upon re-irradiation. The previous radiation site to the primary alone or locoregional was related to the first-course irradiation field size or the overlap radiation field size; however, these field sizes did not correlate to the rate of late complications. In contrast, the previous radiation site was related to anatomical diagnosis in that malignancies irradiated exclu-
TABLE 7. Overlap Site and Late Complications No. of Patients Primary Overlap Site
Grade 0
1-2
3-4 (%)
Total
Base of skull, nasopharynx Maxilla, pterygoid, nose Oral cavity, mandible Oropharynx Preserved larynx Hypopharynx Upper neck Middle neck Lower neck Total
6 4 16 2 4 1 6 7 4 50
2 0 2 0 0 0 8 6 0 18
1 (11) 0 (0) 0 (0) 0 (0) 1 (20) 1 (50) 2 (13) 4 (24) 1 (20) 10 (13)
9 4 18 2 5 2 16 17 5 78
Fig 3. Late complications by anatomical diagnosis.
220
Fig 4. Relationship between overlap field and total cumulative radiation dose. Complication grade IV (F), III (Œ), II (䊐), I (‚), 0 (E).
sively to the primary site were primarily laryngeal and oral cancers. Recurrence of these cancers had been previously salvaged before re-irradiation. As a result, complications of laryngeal edema or mandibular necrosis did not occur. An additional factor important in late complications was the site of re-irradiation. We described each anatomical diagnosis. There are several reports of complications associated with re-irradiation for nasopharyngeal cancer. The rate of severe complication was 12.5% in the present study, which is well below the approximately 25% rate documented in other reports.10-12 Encephalopathy may be avoidable by the use of stereotactic radiotherapy. In cases of nasal or intraoral cancers, many patients (83%) had undergone an operation before reirradiation, and the complication rate was low. In instances involving the re-irradiation of laryngeal cancer to preserve the larynx, the incidence of laryngeal edema was lower than that for nonlaryngeal cancers re-irradiated to the larynx. Wang and McIntyre reported no serious complications in early laryngeal cancers re-irradiated at doses ⬎130 Gy.13 Re-irradiation solely to previously locally irradiated larynx may not cause frequent laryngeal edema. In addition, re-irradiation to the neck frequently induced various complications, including esophageal or pharyngeal dysfunction, stenosis of the carotid artery, or myelop-
OHIZUMI ET AL
athy. Consequently, the health care provider should be aware of these complications. Sex was related to a moderate and higher degree of late complications, a conclusion based on the multivariate analysis in this study. No reports exist regarding sex differences in this respect; however, women may exhibit a lower tolerance to re-irradiation than men. No other factors correlated to late complications. The major factors documented are discussed, however. Cumulative dose is considered to be one of the most important factors related to late complications. In nasopharygeal cancer, a higher incidence of late complications has been reported at re-irradiation doses in excess of 60 Gy or total doses greater than 120 Gy.10-12 However, no relationship between dose and complication rate could be demonstrated in the current investigation or in the literature.6,7 Re-irradiation dose is typically determined according to the overlap field size; small overlap areas are irradiated at a higher dose and vice versa (Fig 3). This method may obscure the relationship between complications and radiation dose or overlap field size. Few reports exist that pertain to overlap field; however, Langlois et al documented a high complication rate for large radiation fields.6 With respect to radiotherapy fractionation, hyperfractionation has been reported to reduce late complications.14,15 We found no differences among fractionations, however. Chemotherapy may exacerbate late radiation damage,16-19 although such reports are scarce. Chemotherapy at the time of initial irradiation was significantly related to late complications by univariate analysis, but not by multivariate analysis. Chemotherapy use is also related to anatomical diagnoses. Nasopharyngeal and mesopharyngeal cancers are combined with chemotherapy; laryngeal cancer, in contrast, is not. Further investigation is necessary under controlled conditions in order to clarify the effects of chemotherapy or fractionation. CONCLUSIONS Health care providers should be cautious regarding acute complications in elderly patients. Late complications developed in 10 of 78 (13%) patients followed for more than 3 months as well as in 9 of 42 (21%) patients
COMPLICATIONS FOLLOWING RE-IRRADIATION
with tumor-free status. The factors related to development of late complications were previous irradiation to the locoregional sites and re-irradiation to the neck. Great care should be exercised with respect to radiation field size and site of re-irradiation. REFERENCES 1. International Union Against Cancer (UICC): TNM classification of malignant tumors, (ed 4). Geneva, UICC, 1987 2. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 3. Lee AW, Foo W, Law SC, et al: Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 38:43-52, 1997 4. De Crevoisier R, Bourhis J, Domenge C, et al: Fulldose reirradiation for unresectable head and neck carcinoma: Experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 16:3556-3562, 1998 5. Emami B, Bignardi M, Spector GJ, et al: Reirradiation of recurrent head and neck cancers. Laryngoscope 97:8588, 1987 6. Langlois D, Eschwege F, Kramar A, et al: Reirradiation of head and neck cancers. Presentation of 35 cases treated at the Gustave-Roussy Institute. Radiother Oncol 3:27-33, 1985 7. Levendag PC, Meeuwis CA, Visser AG: Reirradiation of recurrent head and neck cancers: External and/or interstitial radiation. Radiother Oncol 23:6-15, 1992 8. Skolyszewski J, Korseniowski S, Reinfuss M: The reirradiation of recurrences of head and neck cancer. Br J Radiol 53:462-465, 1980 9. Stevens KR Jr, Britsch A, Moss WT: High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys 29:687-698, 1994
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10. Hwang JM, Fu KK, Phillips TL: Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 41:1099-1111, 1998 11. Teo PM, Kwan WH, Chan AT, et al: How successful is high-dose (⬎ or ⫽ 60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 40:897-913, 1998 12. Chua DT, Sham JS, Kwong DL, et al: Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379-386, 1998 13. Wang CC, McIntyre J: Re-irradiation of laryngeal carcinoma—Techniques and results. Int J Radiat Oncol Biol Phys 26:783-785, 1993 14. Benchal M, Bachaud JM, Frangois P, et al: Hyperfractionation in the reirradiation of head and neck cancers. Result of a pilot study. Radiother Oncol 36:203-210, 1995 15. Tercilla OF, Schmidt-Ullrich R, Wazer DE: Reirradiation of head and neck neoplasms using twice-a-day scheduling. Strahlenther Onkol 169:285-290, 1993 16. Spencer SA, Wheeler RH, Peters GE, et al: Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck. Am J Clin Oncol 22:1-5, 1999 17. Weppelmann B, Wheeler RH, Peters GE, et al: Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea, and reirradiation. Int J Radiat Oncol Biol Phys 22:1051-1056, 1992 18. Allal AS, Bieri S, Miralbell R, et al: Combined comcomitant boost radiotherapy and chemotherapy in stage III-IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone. Ann Oncol 8:681-684, 1997 19. Bachaud JM, Cohren-Jonathan E, Alzieu C, et al: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: Final report of a randomized trial. Int J Radiat Oncol Biol Phys 36:999-1004, 1996
Numerous opportunities exist for re-irradiating cancers of the head and neck regions. In some cases, recurrent tumors can be controlled; however, re-irradiation may induce serious complications as a result of overdoses to previously irradiated areas. In the present investigation, re-irradiation was planned with great care with respect to overlap fields and doses impacting organs at risk. It is currently unclear as to what factors are important with respect to late complications. Radiation dose, overlap field size, overlap site, dose fractionation, combined therapy,
From the Department of Radiation Oncology, Tokai University School of Medicine, Isehara, Japan. Address correspondence to Dr Yukio Ohizumi, Department of Radiation Oncology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 2591193, Japan. E-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 0196-0709/02/2304-0001$35.00/0 doi:10.1053/ajot.2002.124540
and other factors may influence these complications. Of these factors, we were particularly interested in overlap field and overlap site, of which there are only a few reports. In this study, incidence and factors related to the complications were analyzed in cases of head and neck cancer treated by re-irradiation. MATERIALS AND METHODS Between October 1984 and September 1997, 91 patients presenting with squamous cell carcinoma of the head and neck were re-irradiated with a total dose of ⬎80 Gy and overlap fields of ⬎4 cm2. Patients included 68 men and 23 women with an average age of 64 years and a range of 21 to 91 years. Table 1 presents the primary tumor sites and tumor stages. Subjects had been irradiated with external beams of x-rays or gamma rays at a mean dose of 59 Gy (Table 2) at the initial course of radiotherapy. Patients were treated with conventional fractionation (n ⫽ 86), hyperfractionation (n ⫽ 2, 1.2 Gy twice per day) and hypofractionation (n ⫽ 3, ⬎3 Gy daily). Irradiated fields included 31 locals alone, three regional, and 57 locoregionals.
American Journal of Otolaryngology, Vol 23, No 4 (July-August), 2002: pp 215-221
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TABLE 1. Patient Characteristics at the Initial Course of Radiotherapy
TABLE 3. Patient Characteristics at Re-irradiation. Factors
Factors Sex Male Female Primary site Oral cavity Larynx Oropharynx Nasopharynx Hypopharynx Maxillary sinus Stage I II III IV Recurrence Radiation field Local alone Regional alone Locoregional Postoperative radiotherapy Combined chemotherapy
Tumor status Persistent Recurrence Secondary Postoperative status Re-irradiated site and recurrent stage Local T2-3 T4 Regional N2 N3 Loco-regional Re-irradiated field In-field Out-of-field
68 23 27 27 17 8 6 6 9 19 16 37 10 31 3 57 22 34
Field size irradiated with the prescribed dose was 65 ⫾ 41 cm2. Thirty-four patients had undergone chemotherapy before or concurrent with radiotherapy. The chemotherapeutic agents used included cisplatin (n ⫽ 19), 5-fluorouracil (5FU), UFT (a combination of tegafur and uracil), and peplomycin, among others. Half of these agents were administered as combination chemotherapy. Twenty-two patients received postoperative radiotherapy. Following the initial irradiation, 40 patients (44%) underwent salvage operation before re-irradiation, and 21 of these subjects demonstrated recurrence after the salvage operation. One to 175 months (median, 22 months) after the first course of radiotherapy, patients were re-irradiated in the head or neck regions for persistent tumor (n ⫽ 2),
TABLE 2. Radiotherapy Data Factors
No. of Patients
No. of Patients
Range
Mean
First radiation dose 20-85 Gy 59 Gy Interval between radiotherapies 1-175 mo 22 mo Re-irradiation dose 17-78 Gy 55 Gy Total dose 80-144 Gy 114 Gy Overlap field area 4-128 cm2 41 cm2 At re-irradiation: Fractionation Conventional (38) 1.8⬇2.1 Gy/d 55.1 Gy Hyperfractionation (10) 1.2 Gy ⫻ 2/d 58.5 Gy Hypofractionation (21) ⬎2.2 Gy/d 52.3 Gy Combined chemotherapy (13) 53.6 Gy Combined hyperthermia (9) 58.7 Gy NOTE. Figures in parentheses indicate numbers of patients.
2 64 6 19 46 9 37 41 28 13 4 56 35
recurrent tumor (n ⫽ 64), second primary tumors (n ⫽ 6), and postoperative tumor (n ⫽ 19; Table 3). Re-irradiated sites comprised 46 locals, 41 regionals and 4 locoregionals. Malignancies consisted of 9 T2-3s, 37 T4s, 28 N2s, 13 N3s, and 4 TNs, according to the UICC classification.1 Sites related to prior radiation fields were 56 in-field and 35 out-of-field. All patients were treated with external beam irradiation exclusively with cobalt 60 or 4 MV photons. Re-irradiation doses ranged from 17 to 78 Gy at the isocenter (Table 2). The external beam technique was designed to avoid as much as possible overdoses to the spinal cord, brain, eye, larynx, and mandibular bone. Treatment volume was typically determined by adding a safety margin (1-2 cm) to the gross tumor volume. Field size receiving the prescribed dose was 76 ⫾ 61 cm2. Overlap field size was measured from simulation films of the initial course of irradiation and re-irradiation. The overlap areas ranged from 4 to 128 cm2. Overlap sites consisted of 45 heads and 56 necks. Total dosage at the overlap field ranged from 80 to 144 Gy. Conventional fractionated radiotherapy at a daily dose of 1.8-2.1 Gy was administered in 47 patients. Ten patients underwent twice-daily irradiation at a fraction size of 1.2 Gy separated by 6 hours. Thirty-four patients were treated with hypofractionated radiotherapy at a daily dose of 2.2-5.0 Gy. Eighteen patients received chemotherapy at re-irradiation. Cisplatin and/or 5FU were administered in most of these subjects. Nine patients received local hyperthermia at approximately 42°C for about 30 min.
Evaluation and Follow-up Patient follow-up was conducted monthly for the first year and once every 2 months in subsequent years (range, 3-84 months). Radiation oncologists and otolaryngologists or oral surgeons observed tumor response, tumor recurrence, and complica-
COMPLICATIONS FOLLOWING RE-IRRADIATION
tions. Tumor response rates by re-irradiation were 37 percent complete response (CR), 32 percent partial response (PR, indicating ⬎50% tumor volume reduction), and 31 percent no response (NC). Median relapse-free survival, which was defined as the period until tumor appearance for CR or tumor progression for PR or NC, was 7 months. Median overall survival time was nine months. The 5-year relapse-free and overall survival rates were 7% and 11% following re-irradiation, respectively (Fig 1). Severe acute complications were defined as any event involving discontinued radiotherapy or death within 1 month. Those patients displaying acute sequelae or followed within 3 months were excluded with respect to late complications. Seventy-eight patients were evaluated. Grading of late complications was based in accordance with the classifications of RTOG/EORT.2 Cases involving tumor bleeding or necroses were excluded from late complications because of the presence of malignant cells in the lesions.
217
Fig 2. Relationship between relapse-free and complication-free survival following re-irradiation. Complication grade IV (F), III (Œ), II (䊐), I (‚), 0 (E).
Analysis Differences in complication rates were analyzed by the chi-square or Fisher exact test. A logistic regression model was employed for multivariate analysis. A probability value of .05 derived from a 2-sided test was considered significant. For the multivariate model, significant factors determined by univariate analysis were selected and a forward stepwise method was used. The data processing program was SPSS (SPSS Co., Tokyo, Japan).
deterioration of general condition, serious pneumonitis, dyspnea, and 2 instances of intolerable mucositis. Of these cases, 4 patients were older than 80 years. Age greater than 80 years was significantly associated with acute complications (P ⬍ .01). No other factors were significant. Late Complication Rates
RESULTS Acute Complications Severe acute complications were observed in 6 of 91 (6.6%) patients: unknown death,
Late complications of grade 3 and above appeared 3-10 months following re-irradiation (Fig 2). None of these complications caused death. The complication rate was observed in 10 of 78 (13%) patients followed for more than 3 months and in 9 of 42 (21%) patients displaying complete tumor response or postoperative tumor-free status (Table 4).
TABLE 4. Complication Rates
Fig 1. Overall and relapse-free survival following reirradiation for 91 patients with recurrent head and neck cancer.
Complication
Incidence
Percent
Acute Late Follow-up ⬎3 months Grade 2-4 Grade 3-4 Follow-up ⬎1 year Grade 2-4 Grade 3-4 Tumor-free patients Grade 2-4 Grade 3-4
6/91
6.6
19/78 10/78
24 13
11/37 6/37
30 16
15/42 9/42
36 21
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Case Reports of Severe Late Complications A single patient receiving re-irradiation to the nasopharynx (total dose, 137 Gy) exhibited cranial nerve dysfunction (VI to XII). One patient with oropharyngeal cancer developed nonserious paresthesia and muscle weakness; she received a total dose of 55 Gy at the upper cervical spinal cord. Four patients underwent laryngotracheotomy for laryngeal edema (1 of 5 laryngeal cancers with larynx preservation and 3 nonlaryngeal cancers re-irradiated to the larynx). The incidence of severe laryngeal edema was 3 of 8 (38%) patients irradiated to the entire larynx with a total dose of 85-130 Gy (Table 5). Two patients displaying laryngeal or hypopharyngeal cancer developed esophageal stenosis or ulcers and were only able to swallow liquids. A single patient exhibiting an oral floor tumor developed pharyngeal dysfunction, which may have been due to fibrosis; however, this subject had undergone previous surgical intervention. Another patient, developed seizure, headache, facial pain, dizziness, and paresthesia of the trigeminal nerve after radiotherapy dosing of 82.5 Gy directed to the neck and tonsils. This individual recovered from her symptoms with no findings on computed tomography of the brain. The cause was unknown.
head (3%; Table 6). These factors were significant by multivariate analysis. The incidence by overlap field sites is presented in Table 7. Re-irradiation to the neck frequently induced late complications. Anatomical diagnosis indicated a high incidence in the hypopharynx and mesopharynx (50% and 19%, respectively) and low in the oral cavity and larynx (8.7%; Fig 3). Late complications of grade 2 and above were observed in 19 of 78 (24%) patients. Prior radiotherapy to locoregions, overlap fields in the neck, and female sex were significant by multivariate analysis (Table 6). Age and previous chemoradiotherapy were boundary factors by univariate analysis; however, these factors were strongly correlated to the prior irradiation sites. Initial radiation dose, re-irradiation dose, cumulative dose, fractionation methods, and overlap field size were not significant. No relationship was evident between cumulative dose and overlap field size (Fig 4). The prior operation did not influence the rate of severe late complications (8 of 45 with surgery vs 11 of 33 without surgery). Additional factors, including postoperative re-irradiation, combined chemotherapy at re-irradiation, Karnofsky performance status, recurrent stage, and time interval until recurrence, were not significant. DISCUSSION
Factors Related to Late Complications These serious complications did not occur in patients receiving prior radiotherapy exclusively to the primary lesion; however, complications were observed in cases of locoregional irradiation (19%). In addition, complications occurred more frequently in patients re-irradiated to the neck (20%), compared with the
Acute complications due to re-irradiation were serious in elderly patients but not in most other patients. Elderly patients demonstrated a poor general condition; consequently, re-irradiation induced deterioration in the general condition of these patients and serious pneumonia, rather than intolerable acute mucositis. Elderly patients may not be suit-
TABLE 5. Laryngeal Edema Complications
Re-irradiation to whole larynx Laryngeal cancer Non-laryngeal cancer Re-irradiation to partial larynx Laryngeal cancer Non-laryngeal cancer Total
Preserved Larynx
Laryngeal Edema
Other
5 3
1 2
seizure
8 10 26
0 1 4
— esophageal stenosis 2
—
COMPLICATIONS FOLLOWING RE-IRRADIATION
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TABLE 6. Factors Related to Late Complications Grade 3-4 Variable (No. of patients)
Grade 2-4
Incidence (%)
P
Incidence (%)
0 19
.026*
0 36
⬍.001*
3 20
.038*
12 33
.036*
9 23
.134
16 46
.007*
22 9
.128
37 18
.058
20 8
.171
37 17
.045
10 17
.422
21 30
.359
Prior radiation field Primary alone (25) Primary and node (53) Overlap field Head (33) Neck (45) Sex Male (56) Female (22) Age ⱕ60 (27) ⱖ61 (51) Prior chemotherapy Yes (30) No (48) Fractionation method Conventional/hyperfractionation (48) Hypofractionation (30)
P
NOTE. P values were calculated by the chi-square or Fisher exact test. *Significance by the logistic regression model.
able candidates for re-irradiation or care should be exercised with respect to their general condition during re-irradiation. Late complications appeared relatively early following re-irradiation in this study. Lee et al reported that late complications frequently developed within 1 year after re-irradiation in a large series of re-irradiated nasopharyngeal cancer cases.3 The incidence of severe late complications was 21% in the present investigation; this rate was 9%-41% in previous reports.4-9 The incidence of severe late complications can be influenced by many factors. One of the most important factors in the present study
was the initial course of the radiation field. Previous irradiation exclusively to the primary site did not lead to late complications upon re-irradiation. The previous radiation site to the primary alone or locoregional was related to the first-course irradiation field size or the overlap radiation field size; however, these field sizes did not correlate to the rate of late complications. In contrast, the previous radiation site was related to anatomical diagnosis in that malignancies irradiated exclu-
TABLE 7. Overlap Site and Late Complications No. of Patients Primary Overlap Site
Grade 0
1-2
3-4 (%)
Total
Base of skull, nasopharynx Maxilla, pterygoid, nose Oral cavity, mandible Oropharynx Preserved larynx Hypopharynx Upper neck Middle neck Lower neck Total
6 4 16 2 4 1 6 7 4 50
2 0 2 0 0 0 8 6 0 18
1 (11) 0 (0) 0 (0) 0 (0) 1 (20) 1 (50) 2 (13) 4 (24) 1 (20) 10 (13)
9 4 18 2 5 2 16 17 5 78
Fig 3. Late complications by anatomical diagnosis.
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Fig 4. Relationship between overlap field and total cumulative radiation dose. Complication grade IV (F), III (Œ), II (䊐), I (‚), 0 (E).
sively to the primary site were primarily laryngeal and oral cancers. Recurrence of these cancers had been previously salvaged before re-irradiation. As a result, complications of laryngeal edema or mandibular necrosis did not occur. An additional factor important in late complications was the site of re-irradiation. We described each anatomical diagnosis. There are several reports of complications associated with re-irradiation for nasopharyngeal cancer. The rate of severe complication was 12.5% in the present study, which is well below the approximately 25% rate documented in other reports.10-12 Encephalopathy may be avoidable by the use of stereotactic radiotherapy. In cases of nasal or intraoral cancers, many patients (83%) had undergone an operation before reirradiation, and the complication rate was low. In instances involving the re-irradiation of laryngeal cancer to preserve the larynx, the incidence of laryngeal edema was lower than that for nonlaryngeal cancers re-irradiated to the larynx. Wang and McIntyre reported no serious complications in early laryngeal cancers re-irradiated at doses ⬎130 Gy.13 Re-irradiation solely to previously locally irradiated larynx may not cause frequent laryngeal edema. In addition, re-irradiation to the neck frequently induced various complications, including esophageal or pharyngeal dysfunction, stenosis of the carotid artery, or myelop-
OHIZUMI ET AL
athy. Consequently, the health care provider should be aware of these complications. Sex was related to a moderate and higher degree of late complications, a conclusion based on the multivariate analysis in this study. No reports exist regarding sex differences in this respect; however, women may exhibit a lower tolerance to re-irradiation than men. No other factors correlated to late complications. The major factors documented are discussed, however. Cumulative dose is considered to be one of the most important factors related to late complications. In nasopharygeal cancer, a higher incidence of late complications has been reported at re-irradiation doses in excess of 60 Gy or total doses greater than 120 Gy.10-12 However, no relationship between dose and complication rate could be demonstrated in the current investigation or in the literature.6,7 Re-irradiation dose is typically determined according to the overlap field size; small overlap areas are irradiated at a higher dose and vice versa (Fig 3). This method may obscure the relationship between complications and radiation dose or overlap field size. Few reports exist that pertain to overlap field; however, Langlois et al documented a high complication rate for large radiation fields.6 With respect to radiotherapy fractionation, hyperfractionation has been reported to reduce late complications.14,15 We found no differences among fractionations, however. Chemotherapy may exacerbate late radiation damage,16-19 although such reports are scarce. Chemotherapy at the time of initial irradiation was significantly related to late complications by univariate analysis, but not by multivariate analysis. Chemotherapy use is also related to anatomical diagnoses. Nasopharyngeal and mesopharyngeal cancers are combined with chemotherapy; laryngeal cancer, in contrast, is not. Further investigation is necessary under controlled conditions in order to clarify the effects of chemotherapy or fractionation. CONCLUSIONS Health care providers should be cautious regarding acute complications in elderly patients. Late complications developed in 10 of 78 (13%) patients followed for more than 3 months as well as in 9 of 42 (21%) patients
COMPLICATIONS FOLLOWING RE-IRRADIATION
with tumor-free status. The factors related to development of late complications were previous irradiation to the locoregional sites and re-irradiation to the neck. Great care should be exercised with respect to radiation field size and site of re-irradiation. REFERENCES 1. International Union Against Cancer (UICC): TNM classification of malignant tumors, (ed 4). Geneva, UICC, 1987 2. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 3. Lee AW, Foo W, Law SC, et al: Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 38:43-52, 1997 4. De Crevoisier R, Bourhis J, Domenge C, et al: Fulldose reirradiation for unresectable head and neck carcinoma: Experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 16:3556-3562, 1998 5. Emami B, Bignardi M, Spector GJ, et al: Reirradiation of recurrent head and neck cancers. Laryngoscope 97:8588, 1987 6. Langlois D, Eschwege F, Kramar A, et al: Reirradiation of head and neck cancers. Presentation of 35 cases treated at the Gustave-Roussy Institute. Radiother Oncol 3:27-33, 1985 7. Levendag PC, Meeuwis CA, Visser AG: Reirradiation of recurrent head and neck cancers: External and/or interstitial radiation. Radiother Oncol 23:6-15, 1992 8. Skolyszewski J, Korseniowski S, Reinfuss M: The reirradiation of recurrences of head and neck cancer. Br J Radiol 53:462-465, 1980 9. Stevens KR Jr, Britsch A, Moss WT: High-dose reirradiation of head and neck cancer with curative intent. Int J Radiat Oncol Biol Phys 29:687-698, 1994
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10. Hwang JM, Fu KK, Phillips TL: Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 41:1099-1111, 1998 11. Teo PM, Kwan WH, Chan AT, et al: How successful is high-dose (⬎ or ⫽ 60 Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 40:897-913, 1998 12. Chua DT, Sham JS, Kwong DL, et al: Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 41:379-386, 1998 13. Wang CC, McIntyre J: Re-irradiation of laryngeal carcinoma—Techniques and results. Int J Radiat Oncol Biol Phys 26:783-785, 1993 14. Benchal M, Bachaud JM, Frangois P, et al: Hyperfractionation in the reirradiation of head and neck cancers. Result of a pilot study. Radiother Oncol 36:203-210, 1995 15. Tercilla OF, Schmidt-Ullrich R, Wazer DE: Reirradiation of head and neck neoplasms using twice-a-day scheduling. Strahlenther Onkol 169:285-290, 1993 16. Spencer SA, Wheeler RH, Peters GE, et al: Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck. Am J Clin Oncol 22:1-5, 1999 17. Weppelmann B, Wheeler RH, Peters GE, et al: Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea, and reirradiation. Int J Radiat Oncol Biol Phys 22:1051-1056, 1992 18. Allal AS, Bieri S, Miralbell R, et al: Combined comcomitant boost radiotherapy and chemotherapy in stage III-IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone. Ann Oncol 8:681-684, 1997 19. Bachaud JM, Cohren-Jonathan E, Alzieu C, et al: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: Final report of a randomized trial. Int J Radiat Oncol Biol Phys 36:999-1004, 1996