Intensity-modulated radiotherapy followed by a brachytherapy boost for oropharyngeal cancer

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1 ORIGINAL ARTICLE Intensity-modulated radiotherapy followed by a brachytherapy boost for oropharyngeal cancer Abrahim Al-Mamgani, MD, PhD, 1 * Peter C. Levendag, MD, PhD, 1 Peter van Rooij, MSc, 2 Cees A. Meeuwis, MD, PhD, 3 Aniel Sewnaik, MD, PhD, 3 David N. Teguh, MD, PhD 1 1 Departments of Radiation Oncology, Erasmus Medical Center Daniel den Hoed Cancer Center, Rotterdam, The Netherlands, 2 Department of Biostatistics, Erasmus Medical Center Daniel den Hoed Cancer Center, Rotterdam, The Netherlands, 3 Department of Otorhinolaryngology, Erasmus Medical Center Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. Accepted 6 December 2012 Published online 9 March 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to reduce the incidence of radiation-induced toxicity in patients with early-stage oropharyngeal cancer, using highly conformal radiation techniques. Methods. Between 2000 and 2011, 167 patients with T1-3N0-3 oropharyngeal cancer were treated with 46-Gy intensity-modulated radiation therapy (IMRT) followed by 22-Gy brachytherapy boost. In patients with node-positive disease, neck dissection was performed. Results. The 5-year Kaplan Meier estimates of local control, regional control, disease-free survival (DFS), and overall survival (OS) were 94%, 97%, 84%, and 72%, respectively. Feeding tubes were required in 26% of the patients. Grade 2 late xerostomia and dysphagia were 11% and 8%, respectively. Chemotherapy, tumor subsite, and bilateral neck irradiation correlate significantly with toxicity. Quality of life (QOL) scores deteriorate during and shortly after treatment but returned in all scales to baseline scores within 6 to 12 months, with the exception of xerostomia. Conclusion. Brachytherapy boost and neck dissection (in node-positive oropharyngeal cancer) after 46-Gy of IMRT resulted in excellent outcomes with low incidence of late toxicity and good QOL scores. VC 2013 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: oropharyngeal cancer, brachytherapy, IMRT, toxicity, quality of life INTRODUCTION Oropharyngeal cancer is a potentially curable disease that is increasingly being reported in relatively young patients. Of 649 patients with oropharyngeal cancer treated at our institution in the last 15 years, 55% had T1 or T2 tumors. Several retrospective series showed that early-stage oropharyngeal cancer can be treated by either definitive radiotherapy 1,2 or surgery and postoperative radiotherapy, when indicated. 3 However, there are no high-quality comparative studies of the 2 treatment modalities within the same population. During the past 30 years, treatments for head and neck cancer have changed dramatically. Different strategies were implemented in order to improve locoregional control and overall survival (OS) such as concomitant chemoradiotherapy, altered fractionation schedules, and the integration of targeted therapy. However, the improvements in oncologic outcomes achieved by these efforts have come at the cost of increased toxicity and deterioration of quality of life (QOL), mostly because of the increasing incidence of dysphagia and xerostomia. Beside the achievement of cure as the primary goal of radical treatment of these patients, the *Corresponding author: A. Al-Mamgani, Department of Radiation Oncology, Erasmus Medical Center Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. a.al-mamgani@erasmusmc.nl prevention or the reduction of the incidence of these troublesome complications have become very important secondary considerations. In order to reduce the incidence and severity of these complications, highly conformal radiation techniques are required. In the Erasmus Medical Center Daniel den Hoed Cancer Center, the treatment philosophy for early-stage oropharyngeal cancer has been to aim for organ preservation. In line with this concept, since 1990, we treat earlystage oropharyngeal cancer with combined-modality treatment consisting of 46 Gy of external-beam radiotherapy followed by a brachytherapy boost. Levendag et al 1 reported earlier on the outcome and toxicity of 104 patients treated in the 1990s by 46 Gy of 2-dimensional (2D) or 3D conformal radiotherapy (3DCRT) followed by a brachytherapy boost. Since 2000, high-conformal intensity-modulated radiotherapy (IMRT) was introduced at our department. The purpose of the present study was to report on the outcome, toxicity, and QOL of 167 patients with early-stage oropharyngeal cancer treated by 46 Gy of IMRT followed by a brachytherapy boost. MATERIALS AND METHODS From April 2000 to June 2011, 167 patients with earlystage oropharyngeal cancers were treated with curative intention at our institution. Pretreatment evaluations consisted of complete medical history and physical examination, including direct HEAD & NECK DOI /HED DECEMBER

2 AL-MAMGANI ET AL. laryngoscopy with the patient under general anesthesia. All patients had a chest X-ray, ultrasound with fine-needle aspiration, and a head and neck MRI or CT scan. In case of any doubt about the tumor and/or nodal staging, a fluorodeoxyglucose-positron emission tomography scan was performed. All patients were presented at our weekly multidisciplinary head and neck conference. Based on the joint recommendations of the multidisciplinary meeting, patients were selected for the Rotterdam organ function preservation protocol. The details of the protocol have been published earlier. 1 In brief, patients with early-stage oropharyngeal cancer (T1, T2, and small T3) with or without pathologically positive cervical lymph nodes are treated with 46 Gy of external-beam radiotherapy to the primary tumor and the unilateral or bilateral neck in 2-Gy fractions daily, 6 fractions/week. Unilateral nodal irradiation was preserved for those primary tumors limited to the tonsillar fossa, soft palate with at least 1 cm from the midline or lateral pharyngeal wall. All other patients were treated bilaterally. After a split period of 7 to 10 days (depending on the availability of the operating room and the head and neck surgeon), the clinical target volume of the primary tumor was implanted while the patient was under general anesthesia using 2 to 6 (mean 3) after-loading catheters, preferably 1 to 1.5 cm apart, to ensure optimal coverage. In case of node-positive disease, neck dissection was performed at the same session as the implantation. Patients not suitable for brachytherapy boost (gross tumor >5 cm, tumors adjacent to the mandible or great vessels, retropharyngeal lymph node involvement, tumors of the posterior pharyngeal wall or those involving the parapharyngeal space) receive a boost by means of CyberKnife stereotactic radiotherapy or IMRT. However, these patients are not the subject of the current study. Radiotherapy For the first series of 46 Gy of IMRT, patients were immobilized in the supine treatment position in a custommade head and neck mask. CT scan simulation was performed on all patients. The planning treatment volume included a margin of 5 mm beyond the clinical target volume of the primary tumor and the neck to account for different targeting uncertainties. The rationale and technical details of the implants of oropharyngeal cancer have been previously published. 1,4,5 In brief, a fractionated pulsed-dose-rate (PDR) regimen was used. With PDR (MicroSelectron PDR, 192 Ir point source; activity 637 GBq), patients received a mean total dose of 22 Gy (EQD Gy for tumor and 26.5 Gy for late responding normal tissue), given in 8 fractions a day, with a minimal of 3-hour intervals between fractions. Only 5 patients received 20 Gy because of logistical problems. The dose was prescribed according to the International Commission on Radiation Units and Measurements guidelines to predefined points of interest marked with metallic seeds during implantation. For dose specification and prescription, the rules were used similar to the Paris system, as described in earlier reports. 1,4,5 The mean dose per pulse (d p ) was 0.56 Gy corresponded to the reference dose (D ref ), which was prescribed at 85% of the mean central dose. The mean values for dose homogeneity index and the uniformity index were 0.8 and 1.76, respectively. The dose calculation was performed by means of the Plato Brachytherapy Planning System (Nucletron, Veenendaal, The Netherlands), using geometrical optimization. When chemotherapy was indicated (T3 or N3), 2 cycles of cisplatin were given (100 mg/m 2 on days 1 and 22 of radiotherapy). Endpoints Endpoints of the study were rates of local control, regional control, disease-free survival (DFS), OS, acute and late toxicity, and QOL. The first time local and/or regional recurrence was reported, this was registered as the date of failure. The ultimate local and regional control rates reflect the proportion of patients primarily cured by radiotherapy added to those who were successfully salvaged after local or regional recurrence. DFS was measured from the date of completion of treatment to the date of first relapse (local, regional, or distant). Acute (90 days after treatment) and late toxicity (>90 days after treatment) was evaluated by the radiation oncologist during each visit of patients to our outpatients clinic. The radiation oncologists at our institution are instructed to describe each radiation-related toxicity in details at each visit (see items scored Table 1). During the data collection, the staff of the Head and Neck Cancer Registry of our hospital re-coded these side effects to the corresponding grade of toxicity using the Common Terminology Criteria for Adverse Events v3.0. QOL assessment was done at the first visit to the radiotherapy department (baseline), at the first and the last day of treatment, at 2, 4, and 6 weeks, and at 3, 6, 12, 18, 24, and 36 months after treatment. QOL assessment was done prospectively using 2 types of questionnaires: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC QLQ C30) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Head and Neck 35-questions (EORTC QLQ C30 H&N35). 6 For the EORTC QLQ C30; the higher the score, the better the QOL. For the EORTC QLQ H&N35; the higher the score, the more problems the patient will have. Follow-up The treatment response was evaluated by clinical examination 6 to 8 weeks after completion of treatment and by MRI or CT scan 12 weeks after treatment. On completion of treatment, patients were followed up every 2 months for the first year, every 3 months for the second and third years, and every 6 months thereafter. At each visit, medical history and clinical examination were performed, including flexible nasoendoscopy. Statistical analysis Survival rates were calculated from the completion of treatment using the Kaplan Meier technique. Possible predictive factors for local control and toxicity were tested using exact logistic regression model. The tested variables were age (<60 vs 60 years), sex, T classification, N classification, American Joint Committee on 1690 HEAD & NECK DOI /HED DECEMBER 2013

3 BRACHYTHERAPY FOR OROPHARYNGEAL CANCER TABLE 1. Acute and late radiation-induced toxicity, according to Common Terminology Criteria for Adverse Events version 3.0 (n 5 167). Cancer (AJCC) stage, tumor subsites (base of tongue vs tonsillar fossa and/or soft palate), nodal irradiation (unilateral vs bilateral), chemotherapy, and neck dissection. The Mann Whitney sign test was used for nonparametric significance tests. All significant tests were 2-sided and p values <.05 were considered statistically significant. RESULTS Patient demographics are illustrated in Table 2. Oncologic outcomes No. of patients (%) Acute toxicity Overall grade 2 acute toxicity 127 (76) Overall grade 3 acute toxicity 65 (39) Dermatitis Grade 2 12 (7) Grade 3 8 (5) Mucositis Grade 2 49 (29) Grade 3 50 (30) Dysphagia Grade 2 67 (40) Grade 3 44 (26) Pain Grade 2 26 (16) Grade 3 27 (16) Late toxicity Overall grade 2 late toxicity 36 (23) Overall grade 3 late toxicity 8 (5) Skin Grade 2 3 (2) Grade 3 0 Subcutaneous Grade 2 3 (2) Grade 3 0 Mucosal Grade 2 13 (8) Grade 3 5 (3) Xerostomia Grade 2 15 (9) Grade 3 3 (2) Dysphagia Grade 2 11 (7) Grade 3 2 (1) Pain Grade 2 11 (7) Grade 3 3 (2) Trismus Grade 2 2 (1) Grade 3 0 Osteoradionecrosis Grade 2 1 (0.6) Grade 3 0 Twenty-eight events were reported in 26 patients: 12 local failures, 7 regional failures, and 9 distant failures. In 2 patients, the distant metastasis was diagnosed simultaneously with local failure, resulting in crude local control, regional control, distant metastasis-free survival, and DFS rates of 93%, 96%, 95%, and 83%, respectively. The median time from treatment completion to local-regional recurrence or distant metastasis was 13 months (range, 3 54 months). After a median follow-up of 56 months (range, months), the 5-year Kaplan Meier estimates of local control, regional control, DFS, and OS were 94%, 97%, 84%, and 72%, respectively (Figure 1). Local disease control The 5-year actuarial incidence of local control was 94%. Twelve local failures were reported; 7 of these were successfully salvaged with surgery resulting in an excellent ultimate local control rate of 96.4%. On univariate analysis, none of the tested parameters correlated significantly with local control. Only T classification showed a trend toward significant correlation. The 5-year actuarial rates of local control by T classification were 96%, 94%, and 88%, for T1, T2, and T3, respectively (p ¼.07). Control of neck disease Only 7 patients developed regional failure (4.2%); 2 of these were contralateral recurrence (1.2%). No regional failure was reported in patients with node-positive disease who underwent neck dissection. All regional failures were TABLE 2. Patient characteristics and treatment data (n 5 167). Variables No. of patients (%) Sex Male 110 (66) Female 57 (34) Age, y Range Median 54 Follow-up, mo Range Median 56 Tumor classification T1 56 (34) T2 86 (51) T3 25 (15) Nodal classification N0 73 (44) N1 34 (21) N2a 19 (11) N2b 32 (19) N2c 4 (2) N3 5 (3) Tumor subsite Tonsillar fossa 99 (59) Soft palate 30 (18) Base of tongue and vallecula 38 (23) Neck dissection Yes 94 (56) No 73 (44) Neck irradiation Unilateral 117 (70) Bilateral 50 (30) Chemotherapy Yes 28 (17) No 139 (83) HEAD & NECK DOI /HED DECEMBER

4 AL-MAMGANI ET AL. cancer-related mortality of 10%. All other patients died because of comorbidity (n ¼ 15) or second primary tumor (n ¼ 11). FIGURE 1. Kaplan Meier curve of regional control (RC), local control (LC), disease-free survival (DFS), and overall survival (OS). successfully salvaged with surgery and postoperative radiotherapy, resulting in an ultimate regional control rate of 100%. All these patients were still alive at the time of the last follow-up without evidence of disease progression. No univariate analysis was done to identify clinical or pathological factors predictive for regional failure, because of the small number of regional failures reported in the present study. In the present study, 94 neck dissections were performed. On average, 22 lymph nodes were removed (range, 9 54), 1 lymph node was involved (range, 1 15), and in 11% of the neck dissection specimens there was extracapsular extension. In 44 patients who underwent neck dissection (47%), downstaging was achieved after 46 Gy of IMRT to the involved neck, in 9 patients from cn2 to pn1, and in 35 patients from cnþ to pn0. In order of decreasing frequency, the levels involved were level II, III, I, IV, and V in 71%, 26%, 18%, 14%, and 5% of positive nodes, respectively. The median duration of hospitalization was 6 days (range, 4 9 days). Wound complications (hematoma, abscess, and dehiscence; 2%) and general complications (airway infection, aspiration, and deep vein thrombosis; 2%) were the most commonly reported acute complications after neck dissection. With regard to late complications, submental or facial edema, shoulder problems, and fibrosis of subcutaneous tissue were reported in only 3% of patients. Distant metastasis Nine patients developed distant metastasis, mainly to the lung, bone, and/or brain. One patient with lung metastasis was treated by means of the CyberKnife stereotactic radiotherapy. All other patients died because of local or distant disease progression. Survival Of the whole group, 43 patients (26%) died; the cause of death was cancer-related in 17 patients, resulting in a Acute toxicity No grade 4 to 5 acute toxicities were reported. The overall incidence of acute grade 3 toxicities was 39%. As shown in Table 1, the most serious acute toxicities were grade 3 mucosal toxicity (confluent mucositis) and dysphagia (feeding-tube dependency) and were reported in 30% and 26% of patients, respectively. On univariate analysis, the overall incidence of grade 3 acute toxicity was significantly higher in patients with tumors of the base of the tongue, in those treated with chemotherapy and in which bilateral nodal irradiation was applied. However, on multivariate analysis, only chemotherapy and bilateral nodal irradiation still showed a significant correlation (Table 3). Of the entire group, 6% of the patients had tube feeding before starting the treatment and 26% at the end of treatment. However, the weaning from the tube feeding over time was very fast with 10%, 6%, 4%, 2%, and 1% of patients still having tube feeding 1, 2, 3, 6, and 12 months after treatment (Figure 2). The median duration of tube feeding was 3 weeks; ranging from 10 days to >3 years, because all patients who had tube feeding at 1 year (n ¼ 2) still needed it at 5 years. These patients were 71 and 73 years old and had tumors at the base of the tongue and received bilateral nodal irradiation and chemotherapy. The incidence of feeding-tube dependency was significantly higher in patients treated with chemoradiation compared to radiotherapy alone in patients with tumors at the base of the tongue compared to those with tumors of tonsillar fossa and/or soft palate in those in which bilateral nodal irradiation or neck dissection was given. On multivariate analysis, only the first 3 factors were predictive for the need of tube feeding (Table 3). Late toxicity The overall incidences of grade 2 and grade 3 late toxicities were 23% and 5%, respectively. As shown in Table 1, mucosal ulceration was a commonly reported late toxicity. The incidence of grade 2 mucosal ulceration was 11%. Three percent of patients had grade 3 ulcers requiring treatment with hyperbaric oxygen. The ulcers in all other patients were small and shallow and showed spontaneous healing after a median period of 6 months. The incidence of grade 2 xerostomia and dysphagia were 11% and 8%, respectively. The figures for grade 3 were 2% and 1%, respectively. No grade 4 toxicity was reported. From the tested variables, tumors of the base of the tongue, use of chemotherapy, and bilateral nodal irradiation were predictive for the development of late grade 2 late toxicity (Table 4). Quality of life The baseline scores of the EORTC QLQ-C30 Global Health and the EORTC QLQ-H&N35 Swallowing and 1692 HEAD & NECK DOI /HED DECEMBER 2013

5 BRACHYTHERAPY FOR OROPHARYNGEAL CANCER TABLE 3. Logistic regression analysis: correlation between different clinical and pathological parameters and overall grade 3 acute toxicity and feeding tube dependence. Overall grade acute 3 toxicity Feeding tube dependence Variables UVA p value MVA OR (95% CI) p value UVA p value MVA OR (95% CI) p value Age Sex T classification N classification AJCC stage Tumor subsites.01 NS ( ), p ¼.001 BNI ( ) p ¼ ( ), p ¼.001 Chemotherapy ( ) p < ( ), p ¼.0001 Neck dissection NS Abbreviations: UVA, univariate analysis; MVA, multivariate analysis; OR, odds ratio; 95% CI, confidence interval; AJCC, American Joint Committee on Cancer; NS, nonsignificant p value; BNI, bilateral nodal irradiation. Significant p values are indicated in boldface. Dry mouth were 76, 14, and 22, respectively, which means that the patient population functioned reasonably within the tested domains at baseline but with slightly impaired scores on Global Health, Swallowing, or Dry mouth scales. QOL scores on all scales deteriorated during treatment, reaching the worst scores around the end of treatment. For the EORTC QLQ-C30, the scores on all scales started to improve within 2 to 4 weeks and returned to baseline levels at 3 to 6 months after treatment, whereas the scores on almost all scales of the EORTC QLQ-H&N35 took longer to improve toward baseline levels. After 3-year follow-up, the scores on all scales of the EORTC QLQ-H&N35 had returned to almost baseline level, with the exception of Dry mouth. The median score on this scale remained worse than baseline levels and was 38 (-16 compared to baseline; Figure 3). With regard to the impact of neck dissection on QOL, there was a mild and transient decline in the EORTC QLQ-C30 Global Health scores at 4 weeks after the end of chemoradiation, around the recovery from the neck dissection. At 6 weeks, the scores were comparable to those observed in patients who did not undergo neck dissection. Moreover, the difference in scores between patients who underwent and those who did not undergo neck dissection was neither statistically significant (p ¼.35) nor clinically relevant (52 vs 58 at 4 weeks; Figure 4). DISCUSSION The excellence of brachytherapy with regard to organ and function preservation has long been demonstrated. Mazeron et al 7 concluded that the combination of external-beam radiotherapy followed by a brachytherapy boost resulted in a significant improvement of local control and OS, compared to either modality alone. In that study, conventional radiation techniques were used. Therefore, it is not totally surprising that the combination of 2 highly FIGURE 2. The incidence and the duration of feeding tube dependency and pattern of weaning from tube feeding. SOT, start of treatment; EOT, end of treatment. HEAD & NECK DOI /HED DECEMBER

6 AL-MAMGANI ET AL. TABLE 4. Logistic regression analysis: correlation between different clinical and pathological parameters and late toxicity. Variables Age.9 Sex.3 T classification.22 N classification.11 AJCC stage.24 UVA p value Grade 2 late toxicity MVA OR (95% CI) p value Tumor subsites ( ), p ¼.001 BNI ( ), p ¼.004 Chemotherapy ( ), p ¼.0001 Neck dissection.06 Abbreviations: UVA, univariate analysis; MVA, multivariate analysis; OR, odds ratio; 95% CI, confidence interval; AJCC, American Joint Committee on Cancer; BNI, bilateral nodal irradiation. Significant p values are indicated in boldface. conformal radiation techniques (IMRT and brachytherapy boost), as in the present study, would result in excellent local control rates with low rates of radiation-induced toxicity. Figure 5 illustrates the high conformality of a brachytherapy boost planning with very rapid radiation dose falloff at the periphery of the tumor and subsequently low radiation dose to the adjacent organs at risk, especially salivary glands and swallowing muscles. Since 1990, organ-preservation protocol was introduced at our institution for oropharyngeal cancer. 1 In the 1990s, according to that protocol, brachytherapy boost was given after 46 Gy of 2D or 3DCRT. Since 2000, IMRT was introduced at our department for head and neck cancer. Levendag et al 1 reported on outcomes of patients treated in the first timeframe of the organ-preservation protocol with 2D or 3DCRT. The 5-year actuarial rates of local control, regional control, DFS, and OS were 88%, 93%, 57%, and 67%, respectively. The incidence of grade 3 to 4 late mucosal ulceration, dysphagia, and xerostomia were 39%, 20%, and 6%, respectively. In the current study, the incidences of grade 3 of these complications were significantly reduced by using IMRT followed by brachytherapy boost (3%, 1%, and 2%, respectively). The oncologic outcomes were also improved over time. The significantly reduced toxicity in the current study, compared to the results published earlier by our group, 1,4 might be attributed to 2 important factors. First, 70% of patients in the current study were treated to the ipsilateral neck only, compared to 29% of patients treated in the first timeframe of the organ preservation protocol. As one might expect, this protocol modification has resulted in decreased acute and late radiation-induced toxicity. Our group has recently investigated the outcome and toxicity of 185 consecutive patients with oropharyngeal cancer to the ipsilateral neck treated at our institution and showed an overall incidences of late grade 2 and grade 3 toxicities were 13% and 2.2%, respectively. Furthermore, in the second timeframe of the organ preservation protocol, IMRT had replaced the standard 3DCRT. Different studies have shown a significant reduction of toxicity by using IMRT. 8,9 The recently published results of the randomized controlled trial (PARSPORT-trial) showed that parotidsparing IMRT significantly reduced grade 2 xerostomia at 24 months, compared to 3DCRT (29% vs 83%, p <.0001). 8 Our group has recently performed a matched-pair analysis to compare outcome and toxicity of IMRT with 3DCRT and demonstrates the superiority of IMRT for oropharyngeal cancer by significantly reducing radiationinduced toxicity without jeopardizing outcomes. At this matched-pair analysis, the incidence of grade 2 late dysphagia for IMRT versus 3DCRT were 10% versus 31%, respectively (p ¼.004). The figures for grade 2 late xerostomia were 13% versus 37%, respectively (p ¼.001). Further reduction of late dysphagia might be achieved by reducing the dose to the swallowing muscles. Levendag et al 10 reported a sharp increase in the risk of late dysphagia of approximately 19% per 10 Gy, beyond a mean dose of 55 Gy in superior and middle constrictor muscles. Since the publication of these data, strategies using the possibilities of IMRT to keep the mean radiation dose to constrictor muscles <50 Gy were implemented in our department. As one might expect, QOL scores deteriorated during treatment on all scales, reaching the worst scores around the end of treatment but recovered gradually thereafter. After 3-year follow-up, the scores on all scales of the EORTC QLQ-C30 and the EORTC QLQ-H&N35 had returned to almost baseline level, with the exception of Dry mouth (Figure 3). The median score on this scale remained worse than baseline levels and was 38. However, the score on the EORTC QLQ-H&N35 Dry mouth scale was significantly improved by using IMRT, compared to the median score of 67 reported Nijdam et al 11 on patients treated by 46 Gy of 3DCRT followed by brachytherapy boost. The addition of neck dissection to this multimodality approach did not result in significant deterioration in QOL scores over time, compared with the scores of patients who did not undergo neck dissection (Figure 4). Several factors might have contributed to the improved oncologic outcomes reported in the present study compared to those reported by Levendag et al 1 from our group on patients treated in the 1990s. In the current study, 3DCRT was replaced by IMRT. Different comparative studies have shown that IMRT compared to 3DCRT improved oncologic outcome. 9,12,13 All patients treated in the present study received an accelerated schedule of radiotherapy and all patients with T3 and/or N3 received concomitant chemoradiation. Both accelerated radiotherapy and concomitant chemoradiotherapy resulted in significant improvement of locoregional control and OS in different randomized trials. 14,15 Furthermore, 85% of our patients had early-stage disease (T1 and T2) or node-negative disease (44%). These figures are not in line with those reported by other investigators 16,17 because patients treated in the current study represent a selected group of patients with relatively good prognostic factors, because 1694 HEAD & NECK DOI /HED DECEMBER 2013

7 BRACHYTHERAPY FOR OROPHARYNGEAL CANCER FIGURE 3. The median scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC QLQ C30) and the EORTC QLQ-Core 30 Head and Neck 35-questions (QLQ C30 H&N35) questionnaires. brachytherapy is only applicable to relatively small tumors. Although we did not collect human papillomavirus (HPV) data on patients in this series, another possible explanation of improved outcome is the fact that, currently, a significant proportion of patients with oropharyngeal cancer have HPV-positive disease than in previous years. Different studies showed superior oncologic outcomes in HPV-positive oropharyngeal cancer, compared to those with HPV-negative tumors. 16,17 Comparison between toxicity and outcomes reported in the present study with those of other investigators is complicated by the scarcity of publications on PDR brachytherapy for oropharyngeal cancer and the major differences with respect to study design, patient s demographics, the used staging system, toxicity scores, endpoints, and therapeutic strategies. However, our results seem to be comparable with those reported by one of the largest studies in which brachytherapy boost was combined with HEAD & NECK DOI /HED DECEMBER

8 AL-MAMGANI ET AL. external beam radiation in 92 patients. In that study, 5- year rates of local control and serious late toxicity were 90% and 9.7%, respectively. 18 The limitations of the current study are well recognized by the authors, including the selection biases inherent to the retrospective nature of the study. The toxicity was scored using chart review only. Accurate assessment of less severe complications from the medical records is not really reliable. Therefore, it is likely that not all mild grade 1 toxicities were captured. On the other hand, the present study is, to the best of our knowledge, the largest series to date reporting on outcome, toxicity, and QOL of patients with oropharyngeal cancer treated by combining 2 highly conformal radiation techniques (IMRT and brachytherapy) and the only study in which QOL was prospectively assessed, including baseline scores. Another major limitation of the present study is the lack of data on HPV status of the current study population. A solid conclusion could, therefore, not be made with regard to the possible contribution of HPV-related disease to the improved oncologic outcomes seen at the current study, compared to outcome of patients treated during the 1990s at our institution. CONCLUSIONS FIGURE 4. The median scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30-questions (EORTC QLQ C30) Global Health Status of patients treated with or without neck dissection (ND). FIGURE 5. Isodose distribution in a transverse section of the planning CT scan of the brachytherapy boost demonstrating the highly conformal dose distribution around the brachytherapy catheters (3 dots surrounded by the small 3 circles of the 150% isodose line). It shows also the rapid radiation dose falloff at the periphery of the implanted tonsillar fossa tumor and subsequently a low radiation dose (less than 30% of the prescribed dose, the outermost dashed line) to the adjacent organs-at-risk, especially salivary glands and swallowing muscles. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The combination of 2 highly conformal radiation techniques (46 Gy of IMRT followed by a brachytherapy boost) in 167 patients with oropharyngeal cancer resulted in excellent local control rates with low toxicity and satisfactory QOL scores. In node-positive disease, neck dissection after a relatively low dose of IMRT to the involved neck had resulted in excellent regional control, because no regional failure was reported in those patients. None of the tested variables correlated significantly with local control, whereas chemotherapy, tumor of the base of the tongue, and bilateral nodal irradiation correlate significantly with radiation-induced toxicity. Despite the lower rates of radiation-induced toxicity reported in the present study, predictive models need to be developed and implemented to identify patients at high risk of developing troublesome late side effects, such as dysphagia or xerostomia. Subsequently, new strategies to reduce these complications (for instance minimizing the radiation dose to the swallowing apparatus or the use of swallowing exercise) need to be further investigated in these patients in prospective, preferably randomized studies. REFERENCES 1. Levendag P, Nijdam W, Noever I, et al. Brachytherapy versus surgery in carcinoma of tonsillar fossa and/or soft palate: late adverse sequelae and performance status: can we be more selective and obtain better tissue sparing? 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9 BRACHYTHERAPY FOR OROPHARYNGEAL CANCER therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol 2007;85: Nijdam WM, Levendag PC, Noever I, Schmitz PI, Uyl de Groot CA. Longitudinal changes in quality of life and costs in long-term survivors of tumors of the oropharynx treated with brachytherapy or surgery. Brachytherapy 2008;7: Rusthoven KE, Raben D, Ballonoff A, Kane M, Song JI, Chen C. Effect of radiation techniques in treatment of oropharynx cancer. Laryngoscope 2008;118: Hodge CW, Bentzen SM, Wong G, et al. Are we influencing outcome in oropharynx cancer with intensity-modulated radiotherapy? An inter-era comparison. Int J Radiat Oncol Biol Phys 2007;69: Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368: Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH- NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92: Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363: O sullivan B, Huang SH, Perez Ordonez B, et al. Outcomes of HPVrelated oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol 2012;103: Strnad V, Melzner W, Geiger M, et al. Role of interstitial PDR brachytherapy in the treatment of oral and oropharyngeal cancer. A single-institute experience of 236 patients. Strahlenther Onkol 2005; 181: HEAD & NECK DOI /HED DECEMBER