REIRRADIATION WITH INTENSITY-MODULATED RADIOTHERAPY IN RECURRENT HEAD AND NECK CANCER

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1 ORIGINAL ARTICLE REIRRADIATION WITH INTENSITY-MODULATED RADIOTHERAPY IN RECURRENT HEAD AND NECK CANCER Felix Zwicker, MD, 1,2 Falk Roeder, MD, 1,2 Henrik Hauswald, MD, 1 Christian Thieke, MD, PhD, 2 Carmen Timke, MD, 1,2 Wolfgang Schlegel, PhD, 3 Juergen Debus, MD, PhD, 1,2 Marc W. Münter, MD, 1 Peter E. Huber, MD, PhD 1,2 1 Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. F.Zwicker@dkfz.de 2 Clinical Cooperation Unit Radiation Oncology, DKFZ, Heidelberg, Germany 3 Department of Medical Physics, DKFZ, Heidelberg, Germany Accepted 23 September 2010 Published online 31 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. In this retrospective investigation we analyzed outcome and toxicity after intensity-modulated reirradiation of recurrent head and neck cancer. Methods. Thirty-eight patients with local recurrent head and neck cancer were evaluated. The median dose of initial radiotherapy was 61 Gy. Reirradiation was carried out with step-and-shoot intensity-modulated radiotherapy (median dose: 49 Gy). Results. Median overall survival was 17 months, and the 1- and 2-year overall survival rates were 63% and 34%. The 1- and 2-year local control rates were 57% and 53%. Distant spread occurred in 34%, and reirradiation induced considerable late toxicity in 21% of the patients. Thirty-two percent showed increased xerostomia after reirradiation. The risk for xerostomia was significantly higher for cumulative mean doses of 45 Gy to parotid glands. Considering median cumulative maximum doses of 53 Gy to the spinal cord and 63 Gy to the brainstem, no late toxicities were observed. Conclusions. Reirradiation with intensity-modulated radiotherapy in recurrent head and neck cancer is feasible with acceptable toxicity and yields encouraging rates of local control and overall survival. VC 2011 Wiley Periodicals, Inc. Head Neck 33: , 2011 Keywords: recurrent head and neck cancer; reirradiation; intensity-modulated radiotherapy; late toxicity; xerostomia The local failure rate in advanced head and neck cancer after primary treatment with surgery and adjuvant irradiation or with definitive chemoradiation is 30% to 50%. 1,2 More than 50% of the patients with recurrent head and neck cancer die as a direct consequence of locoregionally recurrent disease, even though salvage treatment is performed. 3 In the situation of recurrent disease, salvage treatment is difficult because of a commonly advanced tumor Correspondence to: F. Zwicker M. W. Münter and P. E. Huber share senior authorship for this work. VC 2011 Wiley Periodicals, Inc. classification and altered normal tissue structure caused by previous multimodal treatment. Surgery is an effective treatment option, 4 but often the recurrent tumor is not resectable because of infiltration of critical structures such as the base of the scull, arterial vessels, or the jaw. Many of the patients are not suitable for surgery because of their poor performance status. Chemotherapy is another possibility but does not achieve long-term local control in general. With a median survival of 5 to 10 months, 5,6 with platinumbased chemotherapy, this option can be considered as a palliative approach. In contrast, reirradiation alone or in combination with chemotherapy may constitute a treatment approach with curative intent in patients with recurrent head and neck cancer not amendable by surgery. However, because of the previous irradiation of the head and neck area, an enhanced late toxicity rate has to be accepted after reirradiation. Therefore a balance has to be determined between reduction of treatment volume and dose to spare toxicity and gain local control probability. In the past, reirradiation was often performed with 2-dimensional (2D) or 3- dimensional (3D) radiation techniques. With these techniques, reirradiation with doses of 60 to 65 Gy yielded 2-year overall survival (OS) rates of 15% to 33%, 7 12 but resulted also in severe toxicity including treatment-related deaths in up to 17% of the patients. 7 Pryzant et al 13 found rapidly increasing rates of late toxicity, especially in terms of neurologic impairment, if cumulative lifetime doses of more than 100 Gy were applied. Today, intensity-modulated radiotherapy (IMRT) is a well established method for the definitive treatment of head and neck cancer. Acute and late toxicity can be reduced by sparing normal tissue without compromising local control. 14 Theoretically, IMRT should offer similar advantages in the situation of recurrent Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December

2 tumors, especially because of the high conformity regarding the target volume and the optimized sparing of adjacent previously irradiated organs at risk. However, reports about the use of IMRT in recurrent head and neck cancer are rare To evaluate the clinical benefit of IMRT in this situation, we report our experience using this treatment approach for patients with recurrent head and neck cancer in our institution. In addition to the analysis of local control, survival, and acute and late toxicity, special attention was paid to the incidence of xerostomia after reirradiation dependent on the cumulative dose to the parotid glands, because of its significant impact on the patient s quality of life. Table 1. Patient characteristics. Characteristic Years No. of patients % Age Median 59 Range Sex Male Female Primary tumor site Nasopharynx Oropharynx 5 12 Hypopharynx 4 11 Larynx 2 5 Nasal and paranasal sinus 9 24 Parotid gland 1 3 Cervical esophagus 1 3 Paraspinal soft tissue 1 3 Histology Squamous cell Undifferentiated Adeno 1 3 Adenoid cystic 7 18 Chordoma 1 3 Primary stage, TNM T T T T N N N N3 0 0 M Recurrent stage, TNM r-tx 1 3 r-t1 2 5 r-t2 3 8 r-t r-t r-n r-n r-n2 3 8 r-n3 0 0 r-m MATERIALS AND METHODS Between 2000 and 2008, we performed reirradiation using IMRT in 38 consecutive patients with histologic study proven locally recurrent head and neck cancer without distant metastases, who had previously been treated with external beam radiotherapy. The median age was 59 years (range, years). Twenty-seven patients (71%) were male, and 11 (29%) were female. Before retreatment, restaging usually consisted of CT or MRI of the head and neck area, radiography or CT of the chest, and ultrasonography of the abdomen. For tumor classification, the sixth edition of the Union Internationale Centre le Cancer classification system for head and neck cancers was used. 18 Detailed information on primary and recurrent classification of malignant tumors, lymph node and distant metastases (TNM), tumor localization and histologic subtypes are shown in Table 1. The median time interval between the initial treatment and reirradiation was 43 months. Salvage surgery was performed in 13 patients (34%) before reirradiation and resulted in clear margins in 2 cases, close or positive margins in 8, and gross residual disease in 3 cases. Concurrent systemic therapy during reirradiation was given in 19 patients (50%) at the discretion of the treating physician and included various agents (cisplatin, carboplatin, 5-fluorouracil, cetuximab). Reirradiation was defined as overlap of at least 70% between initial and retreatment target volumes. The median total dose of the primary irradiation was 61 Gy (with only 1 patient receiving 36 Gy and all others within a range of Gy) with single doses of 1.8 to 2.5 Gy. In all cases, the initial radiation treatment was documented either by simulation films with corresponding treatment data in case of conventional techniques or 3D isodose plots and dose-volumehistography information in case of 3D or IMRT techniques. The maximum doses of organs at risk such as brainstem or spinal cord and the mean doses to the parotid glands were carefully estimated from the available information. Cumulative lifetime doses were calculated by use of the dose volume histography information from the reirradiation plans. For the calculations of maximum lifetime doses in brainstem and spinal cord, the maximum doses from the single plans were simply added, although this might have resulted in an overestimation because accurate information about the localization of the maximum doses were not available for some of the initial treatment plans. On the basis of the assumption that both parotid glands were of similar volumes, we calculated the cumulative mean dose of both parotid glands as 1 organ for each patient by adding the mean doses of both parotid glands of both treatment plans. Patients were fixed in the supine position by individual scotch-cast masks and whole-body vacuum pillows. Patient positioning in our institution has been described in detail previously. 18 Planning CT and MRI scans were performed in treatment position with slice thickness of 3 mm with intravenous contrast. The clinical target volume included the gross tumor 1696 Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December 2011

3 volume, with a safety margin of 0.5 to 1 cm. No elective irradiation of uninvolved nodal regions was performed, except in 1 patient. A safety margin for the planning target volume (PTV) was added according to our institutional standards. Inverse treatment planning was performed using KonRad developed at the German Cancer Research Center (DKFZ), which is connected to the 3D-planning program VIRTUOS to calculate and visualize the 3D dose distribution. The IMRT treatment planning process has been described in detail previously. 19,20 Considering brainstem and spinal cord, special attempts were made during the planning process to keep the cumulative physical dose below 60 and 50 Gy. However, if adequate target coverage could not be achieved without exceeding those limits, a violation was accepted in small areas at the surface. In such cases, the limits had to be maintained assuming a 50% dose tolerance recovery from the initial treatment course. In contrast, the cumulative doses stated in our report were calculated without assuming any dose tolerance recovery by simply adding the physical doses of both treatment courses. Stereotactic setup was used in all cases. IMRT with 5 to 9 beams was carried out by a step-and-shoot technique with 6 megavolt photons with use of a linear accelerator (Siemens, Concord, CA). Patient positioning was verified by a kv In-Room CT-Scanner on rails. Reirradiation was applied in conventional fractionation (single dose Gy, 5 times a week) to a median dose of 49 Gy (range, Gy). The resulting median cumulative lifetime dose of initial radiotherapy and reirradiation was 111 Gy (range, Gy). Patients were followed up by clinical investigation in combination with CT or MRI every 3 months. No patient was lost to follow-up. The median follow-up time was 15 months (range, 1 87). Eleven patients (29%) were still alive at the time of analysis with a mean follow up time of 29 months. Acute and late toxicity was scored according to the Common Terminology Criteria for Adverse Events (version 3) of the Radiation Therapy Oncology Group (RTOG) and of the European Organization for Research and Treatment of Cancer. 21 Severe radiation related toxicity was defined as grade 3 late toxicity. Late toxicities without total loss of function but severe impact on the patient quality of life, like severe limitations of dietary intake caused by fibrosis, strictures, or stiffness of the temporomandibular joint, severe impairment of cranial nerves, brain necrosis or osteonecrosis, spinal cord or brainstem injury, or major vascular complications, were also counted as severe radiation-induced late toxicity. Xerostomia was defined according to clinical Common Terminology Criteria for Adverse Events RTOG/ the European Organization for Research and Treatment of Cancer criteria (version 3): grade 1 for minor (slight dryness of mouth; good response on stimulation by eating), grade 2 for moderate (moderate dryness of mouth; poor response on stimulation by eating) and grade 3 for total loss of function (complete dryness of mouth; no response on stimulation by eating). No grade 4 or 5 events were detected. Increase of xerostomia was defined as clinical change before and after reirradiation. Changes were determined and documented during the follow-up visits of the patient in a clinical interview. The endpoints of this retrospective analysis were local control, locoregional control, distant metastasis free survival, and overall survival. Local control after reirradiation was defined as absence of infield tumor progression or recurrence. Locoregional control was defined as absence of tumor progression or recurrence in the head and neck area independent of its correlation to the radiation fields. All time-to-event-data were calculated from the first day of reirradiation until the last follow up or until death with the Kaplan-Meier method. Differences in subgroups were tested for statistical significance by the log-rank test. Relationships between distinct parameters, like xerostomia rates, were tested for significance by the chisquare test. Differences were considered statistically significant for a p value of.05. Statistical analyses were performed with STATISTICA (Version 6, Stat- Soft, Tulsa, OK) or SIGMAPLOT (Version10, Systat Software, Chicago, IL). RESULTS First course of radiation was performed in 7 cases with 2D and in 17 cases with 3D planned radiotherapy. In 5 cases a combination of 2D and sequential 3D boost radiation was performed. In 9 cases IMRT was used. The second course irradiation was performed in all cases (n ¼ 38) with step and shoot IMRT. Survival and Patterns of Recurrence. The median time interval between the initial treatment and reirradiation was 43 months. The median actuarial overall survival for the entire cohort was 17 months, with 1-, 2-, and 3-year actuarial overall survival rates of 63%, 34%, and 34%, respectively (Figure 1). Local failure was found in 16 patients, resulting in actuarial 1-, 2-, and 3-year local control rates of 57%, 53% and 44%, respectively (Figure 2). The corresponding rates for locoregional control (including outfield failures in the head and neck area) were 50%, 45%, and 38%, respectively (Figure 3). In total only 4 outfield recurrences were observed after reirradiation. Distant metastases were found in 13 patients and occurred in lung (n ¼ 4), liver (n ¼ 2), brain (n ¼ 2), distant lymph nodes (n ¼ 2), or multiple sites (n ¼ 3). The resulting 1-, 2-, and 3-year distant metastasis free survival rates were 72%, 67%, and 67%, respectively (Figure 4). For an example of dose distribution in reirradiation, see Figure 5. Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December

4 FIGURE 1. Kaplan-Meier estimation of overall survival for all treated patients. Acute Toxicity. Three patients (8%) had development of grade 3 mucositis, and 4 patients (11%) had grade 3 skin reactions. One patient had development of necrosis of a soft tissue flap (grade 4) during reirradiation, but surgical revision could be postponed, and reirradiation was finished without treatment break. One patient died as a result of acute arterial bleeding (grade 5) 2 weeks after finishing the reirradiation course. Temporary loss of taste or smell (grade 3) was reported by 2 patients (5%) each. No grade 3 acute hematologic toxicity was observed. For detailed information about acute toxicity, see Table 2. Late Toxicity. Severe late toxicities were documented in 8 patients (20%), with 3 patients showing more than 1 side effect. In particular, severe late toxicities were found, such as total unilateral hearing loss in 1 patient, severe reirradiation-induced xerostomia in 2 patients, severe impairment of dietary intake in 4 FIGURE 3. Kaplan-Maier estimation of locoregional control for all treated patients. patients, and impairment of cranial nerves in 3 patients. No brainstem or spinal cord injuries and no brain necrosis or osteonecrosis was observed. One patient had acute intraoral hemorrhage and needed a transfusion and an intraoral intervention 7 months after reirradiation without tumor progression on imaging. For detailed information about late toxicity, see Table 2. Because of its impact on patient quality of life, special attention was paid to the occurrence of xerostomia after reirradiation. Forty-five percent of the patients had xerostomia after reirradiation in general, but only 11 patients (31%) showed an increase of xerostomia compared with their status before reirradiation. We then calculated the cumulative mean dose of both parotid glands as 1 organ for each patient by adding the mean dose of the initial treatment and the reirradiation treatment for each parotid gland and averaging the result to get the cumulative mean dose FIGURE 2. Kaplan-Maier estimation of local control for all treated patients. FIGURE 4. Kaplan-Meier estimation of distant metastases free survival for all treated patients Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December 2011

5 FIGURE 5. Dose distribution of step-and-shoot IMRT reirradiation with 5 coplanar beams for a patient with recurrent squamous cell cancer of the oropharynx/tongue. The median dose prescription was 50.4 Gy (100%) to the PTV with 1.8 Gy single dose. PTV (red), spinal cord (yellow), and right/left parotid glands (blue) are shown as outlines. The dashed yellow line shows the 95% and the green line the 50% isodose line. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] of both parotid glands, assuming an equal volume of both parotid glands. The median cumulative mean dose of both parotid glands of all 38 patients was 44.8 Gy. Patients with xerostomia after reirradiation showed an average cumulative mean dose of both parotid glands of 54.7 Gy, whereas patients without xerostomia had an average cumulative mean dose of both parotid glands of 35.5 Gy. Patients with a cumulative mean dose of both parotid glands of 45 Gy showed a significantly increased risk of 75% for developing xerostomia after reirradiation compared with 26% in patients with a cumulative mean dose of both parotid glands of 45 Gy (p ¼.0041; Table 3). The median maximum dose to the brainstem was 39 Gy during primary radiation treatment and 23 Gy during reirradiation. Assuming the same localization for the maximum doses during the 2 courses of radiation therapy, we found a median cumulative maximum dose of 62.7 Gy. In 10 cases (26%), the cumulative maximum dose ranged between 60 and 70 Gy, and in 11 cases (29%) more than 70 Gy were reached. The median maximum dose to the spinal cord was 35.8 Gy during primary irradiation and 16.5 Gy during reirradiation. The median cumulative maximum dose of both radiation courses was 53.4 Gy. In 17 cases (45%), the cumulative maximum dose ranged between 50 and 60 Gy; in 7 cases (18%), between 60 and 65 Gy. No late toxicities have been observed so far for these regions. For detailed information regarding the distribution of dose to organs at risk, see Table 3. DISCUSSION Treatment of locally recurrent head and neck cancer after previous radiotherapy is challenging. Complete surgical removal is an attractive option 4 but is often limited because of tumor infiltration into vital structures such as major vessels, nerves, or skull base. However, even after salvage surgery, adjuvant treatment including reirradiation has been shown to improve progression free survival in a recent trial. 22 In patients not amenable to surgery, chemotherapy alone is frequently used as salvage therapy. This approach is feasible in most cases but achieves only median survival rates of 5 to 10 months 5,6 and should be considered as a palliative option. Because by definition these patients have a localized recurrence of their disease, the preferable treatment should include a major local treatment component. Because radiotherapy is used as the major local treatment in Table 2. Acute and late toxicity. No. of patients (%) by grade Toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute toxicity Mucositis 17 (45%) 13 (34%) 3 (8%) 0 (0%) 1 (3%) Skin reaction 22 (58%) 5 (13%) 4 (11%) 1 (3%) 0 (0%) Hematotoxicity 4 (11%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) Taste 9 (24%) 5 (13%) 2 (5%) 0 (0%) 0 (0%) Smell 7 (18%) 4 (11%) 2 (5%) 0 (0%) 0 (0%) Late toxicity Hearing defect right 1 (3%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) Hearing defect left 1 (3%) 2 (5%) 1 (3%) 0 (0%) 0 (0%) Xerostomia Before reirradiation 4 (11%) 0 (0%) 4 (11%) 0 (0%) 0 (0%) After reirradiation 7 (20%) 4 (11%) 6 (17%) 0 (0%) 0 (0%) Progress of xerostomia 11 (31%) Severe toxicity Trismus 3 (8%) Cranial nerve damage 3 (8%) Esophageal stenosis 1 (3%) Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December

6 Table 3. Distribution of maximum and median doses in organs at risk. Organ at risk SD Range Clinical side effects Median of maximum doses, Gy Spinal cord none Primary irradiation Reirradiation Cumulative Brainstem none Primary irradiation <2 60 Reirradiation <2 45 Cumulative <2 86 Median of mean doses, Gy Right parotid gland Primary irradiation <2 70 Reirradiation <2 32 Cumulative <2 91 Left parotid gland Primary irradiation <2 70 Reirradiation <2 30 Cumulative <2 86 Mean of CMDBP, Gy All patients < % xerostomias (grade 1 3) Patients with xerostomia % xerostomias (CMDBP 45 Gy) Patients without xerostomia < % xerostomias (CMDBP <45 Gy) p ¼.006 p ¼.0041 Abbreviation: CMDBP, cumulative mean dose of both parotid glands as 1 organ. primary head and neck cancer not amenable to surgery, increasing interest has been paid in the use of reirradiation for nonresectable local recurrence in patients with head and neck cancer. For example, two phase II trials using conventional or 3D conformal radiation techniques were conducted by the RTOG to investigate the value of reirradiation with concurrent chemotherapy in this setting. 11,12 In these trials, a split course radiation regimen (median dose 60 Gy) in combination with 5-fluorouracil/hydroxyurea or cisplatin/taxol was used. With these approaches, the investigators reported 2-year overall survival rates of 17% and 26%, respectively, and emphasized the importance of adding a local treatment modality. On the other hand, they reported significant treatmentrelated side effects with 28% to 31% grade 4/5 toxicities, including 7% to 8% treatment-related deaths. The delivery of reirradiation with conventional or 3D conformal techniques is often limited by the tolerance of surrounding organs at risk and therefore may result in either a higher risk for severe side effects or in insufficient target coverage. In contrast, IMRT has demonstrated superior target coverage and improved sparing of organs at risk in many sites of the body, especially in the head and neck region. 23 Therefore, it is conceivable that IMRT should offer dosimetric advantages in re-treating these patients with radiation therapy. In our series, a total of 38 patients have been treated for locally recurrent head and neck cancer using IMRT in all cases with a median dose of 49 Gy, resulting in a median cumulative lifetime dose of 111 Gy. With this approach, we reached a median actuarial overall survival of 17 months and 2-year overall survival and 2-year locoregional control rates of 34% and 45%, respectively. Despite the known dosimetric advantages of IMRT compared with other radiation techniques, only few studies have focused on the use of IMRT as salvage radiotherapy techniques in recurrent head and neck cancer. Sulman et al 15 treated 74 patients with a median dose of 60 Gy and reported excellent results with a median overall survival of 25 months and 2-year overall survival and 2- year locoregional control rates of 58% and 64%, respectively. Lee et al 16 found a median overall survival of 15 months in a cohort of 105 patients treated with IMRT (median dose, 59.4 Gy) in most cases, resulting in 2-year overall survival and 2-year locoregional control rates of 37% and 42%, respectively. In their report, even a significant survival benefit for use of IMRT compared with other radiation techniques was described. In another study on the use of IMRT (median dose 60 Gy) for reirradiation of patients with head and neck cancer, Biagioli et al 17 described a median overall survival of 18 months, but no information about locoregional-control was reported. Chua et al 24 focused on the retreatment of nasopharyngeal cancer by IMRT (median dose 54 Gy) and reached a median overall survival of 13 months with 1-year overall survival and 1-year locoregional control rates of 63% and 56%, respectively. Although based on retrospective, inhomogeneous, single-center studies, these and our data show encouraging results compared with chemotherapy alone or retreatment with conventional or 3D conformal radiation techniques. Nevertheless, even in the studies using IMRT, a wide range of survival and locoregional control rates have been reported. Therefore, patient selection could be a major issue Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December 2011

7 Interestingly, according to histologic study, percentage of patients with surgery before reirradiation, and the use of concurrent systemic treatment, our patient cohort did not vary distinctly from the cohorts reported by Sulman et al 15 and Lee et al. 16 Squamous or undifferentiated histologic conditions were present in most cases (76% in our cohort compared with 77% and 86%, respectively), surgery before reirradiation was possible only in a minority of patients (34% vs. 27% and 42%), and concurrent systemic therapy was given in about half of the patients (50% vs 39% and 43%). Therefore, variations in these factors can hardly explain the different outcomes of the mentioned studies. Aside from these parameters, volume issues could be of further interest. Usually patients with small tumor volumes are chosen for reirradiation. For example, Sulman et al 15 reported a median tumor volume of 65 ccm in their cohort. In contrast, most patients in our study had more advanced lesions (mean tumor volume 102 ccm). Although we observed only a statistically nonsignificant trend toward improved local control in smaller lesions (p ¼.1), which is probably related to the low number of patients in total, several other investigators have described that kind of association. For example, Chua et al 22 found a significant difference in locoregional control according to rt classification (1-year local control rate was 100% for patients with rt1-3 vs 35% for those with rt4), although they treated patients with very small tumor volumes (mean gross tumor volume, 28 ccm). De Crevoisier et al 28 even found a survival benefit depending on the size of the reirradiated volume, although their series is not easily comparable because of the use of conventional treatment techniques and therefore generally much higher irradiated volumes compared with the IMRT series. Therefore, in summary, the variations in outcome reported in the literature including our series could be at least in part attributable to the selection of more or less favorable lesions in terms of tumor volume. Another issue, especially comparing survival rates, is distant failure. In most of the mentioned series with stringent selection criteria, only few patients developed distant failures. For example, Sulman et al 15 reported a crude distant failure rate of 9%, Biagioli et al 17 found distant metastases in 20%, and Lee et al 16 in 22% of their patients. In contrast, in our cohort of patients with advanced recurrences in most patients, a 34% distant failure rate was observed. Whether this difference, especially in comparison to the results reported by Sulman et al, 15 is attributable to the lower median dose and inferior locoregional control in our study remains an open question. These disadvantages within our study could have resulted in increased distant spread caused by uncontrolled local residual tumors or are associated with a higher risk of distant spread in more advanced recurrent lesions per se. To conclude, reirradiation with IMRT results in encouraging rates of locoregional control and survival, which seem to be superior compared with chemotherapy alone. Patient selection remains a major issue, but our results demonstrate that acceptable local control and survival rates can also be achieved in more advanced lesions, which are amenable to the application of doses in the range of 50 Gy only. Despite the dosimetric advantages of IMRT in comparison to other external beam radiation techniques, the high cumulative doses necessary for definitive reirradiation endanger adjacent organs significantly by causing treatment-related morbidity. 15 In our series, severe acute toxicity (grade 4/5) was scored only in 2 patients. No grade 4 hematologic toxicity occurred. Considering late toxicity, a total of 8 patients (20%) had severe radiation-related side effects, but no cases of osteonecrosis, brain necrosis, or brainstem/spinal cord injury were observed. In contrast, most series with conventional or 3D conformal radiation techniques described much higher rates of severe acute and late treatment-related toxicity. De Crevoisier et al 8 observed mucosal necrosis in 21%, osteonecrosis in 8%, and trismus in 30% of their patients. In the mentioned RTOG trials with 3D conformal split-course treatment in most cases, grade 4/5 toxicity occurred in 28% to 31% of the patients, leading to 7% to 8% treatment-related deaths. 11,12 These high rates of severe side effects are probably related to several factors. First, the radiation technique used did not allow optimal sparing of organs at risk with acceptable tumor coverage. Second, the percentage of concurrent chemotherapy was higher in the mentioned trials, which could explain parts of the acute toxicity. Third, the absolute median dose was about 10 Gy higher than in our series, although split course regimens were used. Considering the published IMRT series, 15,16 which are comparable to our cohort, except for differences in median dose and tumor volume, the use of sophisticated radiation treatment techniques seems to result in a distinct reduction of side effects. Sulman et al 15 found a 20% rate of severe reirradiation-related toxicity with 1 retreatment-related death. As stated above, the median reirradiation dose in their report was 60 Gy (49 Gy in our series), but treatment volumes were smaller, and the median cumulative dose was only 5 Gy higher than in our series (116 Gy vs 111 Gy). When comparing the toxicity in our study to the study by Sulman et al, 15 it should be mentioned that in 14% of the patients in Sulman s study the gross tumor volume included uninvolved lymph nodes. Lee et al 16 also described a very favorable late toxicity rate of only 12% after a median cumulative dose of 121 Gy with IMRT in most cases. Besides the known limitations in scoring acute and late toxicity in a retrospective manner, it has to be noted that no cases of brainstem or spinal cord injury have been observed in the IMRT series, and treatment-related Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December

8 deaths were rare compared with reports by use of conventional or 3D conformal techniques. Furthermore, special attention was paid to radiation induced xerostomia in our series. Because many of our patients have been treated with IMRT in their first course of radiation therapy, the rate of severe xerostomia before reirradiation was comparably low. With IMRT used for reirradiation, it was possible to spare dose to parotid glands also during the second treatment course. With this approach, only 31% of all patients had development of an increase in their grade of xerostomia after reirradiation compared with their status after primary treatment. For detailed evaluation, we defined the cumulative mean dose of both parotid glands for each patient assuming an equal volume of both parotid glands. Using this parameter, we found a significant difference in xerostomia rates after reirradiation if the cumulative mean dose of both parotid glands exceeded 45 Gy (75% vs 26%). Thus it even seems possible to spare toxicity in organs with comparably low radiation tolerance by use of IMRT for reirradiation, especially in patients treated by IMRT in their first course of radiotherapy already. Despite some limitations, because of the small cohort of patients (not allowing subgroup analyses) and the retrospective nature of our study, we believe that our work adds some essential information to the important field of reirradiation in head and neck cancer. \In summary, reirradiation of patients with head and neck cancer by use of IMRT is feasible and yields acceptable rates of local control and overall survival rates, even in patients with more advanced recurrent lesions. The patients outcome seems to be superior compared with the results reported with chemotherapy alone. Furthermore, the dosimetric advantages of IMRT over conventional or 3D conformal radiation techniques seem to transfer into clinically measurable benefits in terms of acute and late toxicity. However, special attention has to be paid to patient selection for this aggressive treatment approach, considering the risk of fatal acute and late toxicity. Reirradiation treatment itself and the intended dose prescription should be evaluated carefully in accordance with the treatment volume, prior dose distribution and the possibilities to spare vital organs at risk. This way, a favorable balance between possible gains and risks in an individualized manner can be achieved for each patient. REFERENCES 1. Perez CA, Devineni VR, Marcial-Vega V, et al. Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 1992;23: Bailet JW, Mark RJ, Abemayor E, et al. Nasopharyngeal carcinoma: treatment and results with primary radiation therapy. Laryngoscope 1992;102: Studer G, Graetz KW, Glanzmann C, et al. Outcome in recurrent head and neck cancer treated with salvage IMRT. 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Radiother Oncol 2005;77: Reirradiation with IMRT for Recurrent Head and Neck Cancer HEAD & NECK DOI /hed December 2011