Brachytherapy for Radiotherapy-Resistant Head and Neck Cancer: A Review of a Single Center Experience

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1 The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. Brachytherapy for Radiotherapy-Resistant Head and Neck Cancer: A Review of a Single Center Experience Inbal Hazkani, MD; Naomi Rabinovics, MD; Dror Limon, MD; David Silvern, PhD; Sion Koren, PhD; Tuvia Hadar, MD; Gideon Bachar, MD; Thomas Shpitzer, MD; Aron Popovtzer, MD Objectives/Hypothesis: Despite advances in radiotherapy and chemotherapy treatments for head and cancers, the local failure rate is high. In most radiotherapy-resistant cases, surgery is performed; however, some cases are considered unresectable. No standard treatment for these situations has been established. In this study, we review our experience with brachytherapy (BT), which has a different biological mechanism than standard radiotherapy. Methods: All patients received prior radiation to the recurrence area. Median high-dose radiation BT dose was 50 Gy, administered in 5 to 10 Gy fractions twice daily for 5 days. High-dose radiation was given via four to 10 catheters inserted under local anesthesia (3 patients) or general anesthesia with preventive tracheostomy (10 patients). Results: Thirteen patients received BT from 2010 to Male:female ratio was 1.6:1, and median age was 66 years (range 23 89). Of those 13 patients, 10 patients were diagnosed with squamous cell carcinoma (SCC) of the oral cavity, two patients with SCC of the nasal mucosa, and one patient with eccrine duct carcinoma. Prior radiation dose ranged from 60 to 70 Gy. Local control was achieved in 11 of 13 patients; only 15.3% (2 of 13) had in-field recurrence. Five patients developed local out-of-field recurrence, and two developed distant metastases. Five patients are alive with no evidence of disease. No major toxicities were encountered. Two patients had severe mucositis and recovered within several weeks. Conclusion: Brachytherapy for radiotherapy-resistant head and cancers is feasible with minor adverse events, which enables good local control. However, many advanced head and cancers develop regional or distant metastases; therefore, additional treatment should be suggested. Key Words: Brachytherapy, radiotherapy-resistant head and cancer. Level of Evidence: 4. Laryngoscope, 126: , 2016 INTRODUCTION Despite meticulous multidisciplinary treatment protocols, about 30% of patients with head and cancers develop local recurrences, mostly within the first 2 years following primary treatment. 1,2 Patients with head and cancer recurring in a previously irradiated area generally have a poor prognosis 3 and present a clinical challenge. When surgical salvage is impossible due to tumor extent, location, or patient comorbidities, reirradiation can be considered. However, if radiation has previously failed or in areas that are traditionally considered radioresistant (oral cavity), standard radiation has no value From the Department of Otorhinolaryngology Head and Neck Surgery, Meir Medical Center (I.H.), Kfar Saba; the Department of Otorhinolaryngology Head and Neck Surgery (N.R., T.H., G.B., T.S.); and the Department of Oncology (D.L., D.S., S.K., A.P.), Davidoff Center, Rabin Medical Center, Petach Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Editor s Note: This Manuscript was accepted for publication January 29, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Inbal Hazkani MD, Department of Otorhinolaryngology Head and Neck Surgery, Meir Medical Center, 59 Tshernichovsky St, Kfar Saba Israel. hazkani@gmail.com DOI: /lary and brachytherapy (BT) is one of the few available options. Brachytherapy is a form of radiation therapy that delivers a high, localized dose of radiation over a short period and conformal dose distribution with respect to tumor shape. It can be used as an intraoperative adjuvant, combined with external beam radiation (EBRT), or used as a single-treatment modality. 4 6 Brachytherapy has a potentially large advantage in these cases. Due to its different biology, it delivers a high radiation dose over a short period to the tumor while sparing normal tissue; thus preventing damage to critical sites and preserving organ function. 4,6,7 The main disadvantage of BT is that it is useful for localized treatment alone and not acceptable in relatively large fields. Whereas external beam reirradiation is often associated with unacceptable risk of late complications, 2,3,6,8 10 in most reports high-dose radiation brachytherapy (HDR-BT) complications ranged from 5% to 50%. 3,4,9,11 14 The most common early side effects reported are impaired wound healing, flap and soft tissue necrosis and fistulas (when BT is combined with surgery), and mucositis. Common late complications are osteoradionecrosis and intensified fibrosis. 4,9,11 Complications occur more often in the elderly 9 and in HDR-BT compared to low-dose radiation (LDR) BT and pulse-dose radiation (PDR) BT. 4,11,15 However, the data conflict

2 because some studies reported no correlation between local complications and BT dosage. 9,16,17 Nonetheless, only a few studies have investigated the side effects of reirradiation with HDR after initial external beam irradiation. In most articles, local control rates 2 years after salvage BT range between 30% to 80%, and the 2-year overall survival rates vary from 17% to 71%. 4,9 The wide range can be attributed to the heterogeneity of the groups analyzed. There are no randomized data regarding treatment for radiation-resistant head and carcinoma patients. Thus, treatment decisions are based on prospective, nonrandomized trials and retrospective outcome studies. This study reviews our experience with HDR-BT for radiation-resistant head and cancer patients, with a specific focus on feasibility and outcome. MATERIALS AND METHODS Patients From 2010 to 2014, a total of 13 patients received HDR- BT as monotherapy or combined with surgery for recurrent head and cancer after definitive EBRT. The eligibility criteria were histologically proven recurrent tumor, with no evidence of distant metastasis. All patients were treated with curative intent. In all cases, the tumor occurred in an area that was priorly radiated in a curative intent. The study population included eight males and five females at a mean age of 66 years (range years). Squamous cell carcinoma was confirmed in 12 patients and eccrine duct carcinoma in one. All patients had undergone previous definitive EBRT and surgery for the management of their head and disease (median dosage 66 Gy, range Gy). Nine patients had also undergone dissection. Patient characteristics are shown on Table I. The median time from the end of primary treatment with EBRT to relapse was 14 months (range 3 84 months). Method of Implant and Radiation All patients were hospitalized for the entire duration of HDR-BT. Before implantation, the radiation oncologist defined the preliminary target volume according to images and bimanual palpation of the tumor bed performed under general anesthesia. In the sole case of HDR treatment, the target area was defined as the gross tumor volume with a 0.5-cm margin. If treatment was performed after surgery, a 1-cm surrounding volume was defined. Hollow curved implant needles, 1.7 mm in diameter (Varian Medical Systems, Charlottesville VA) were inserted into the target. The tips of the stylets were brought through to the dorsum of the tongue. Usually, stylets were placed approximately 10-mm apart and parallel to each other. Peripheral stylets were placed at the periphery of the target. Next, fixable implant tubes with blind-end postloading catheters (Varian Medical Systems) were introduced through the needle. After removal of the stylets, these catheters were secured with buttons to the catheter blind end. Patients received prophylactic broad-spectrum antibiotics and steroids during and after the implant procedure. All patients underwent computed tomography (CT) simulation for the three-dimensional (3D) BT plan. The target definition and dose calculation were performed using the brachytherapy planning system (BrachyVision, Varian Medical TABLE I. Patient Characteristics. Characteristic N 5 13 Gender Male 8 Female 5 Median age (range), years 66 (23 89) Primary Tumor Site: SCC Oral cavity 10 Nasal cavity 2 Primary Tumor Site: non-scc Adenocarcinoma 1 Primary Treatment Surgery and EBRT 8 Surgery and chemoradiation 5 Secondary Treatment Surgery and BT 8 BT 5 Radiation Dose (EBRT) (Gy) Median 66 Range Time to Relapse (months) Median 14 Range 3 84 BT 5 brachytherapy; EBRT 5 external beam radiation; SCC 5 squamous cell carcinoma. Systems). The planning target volume (PTV) was defined as the circumferential area connecting the peripheral catheters encompassing the target, plus 5-mm margins. In addition, structures at risk, particularly the mandible, were delineated. Modification of the PTV was allowed to exclude critical structures, particularly the mandible. To define the source positions and calculate the dwell times, treatment planning was performed by 3D reconstruction of the target and surrounding structures, such as the mandible, using CT simulation (Fig. 1). The plan was optimized to deliver the prescribed dose (the minimum peripheral dose) to cover at least 95% of the PTV, whereas the dose to the mandible was kept as low as possible to minimize the risks of radio-osteonecrosis. Irradiation was performed by connecting the catheters to an afterloader device (microselectron HDR; Nucletron Corp., Columbia, MD). Treatment and Follow-Up Five patients had BT as definitive treatment (one due to severe comorbidities and four with unresectable tumors). Surgical resection combined with BT was performed in eight patients. All had positive or narrow surgical margins, and three had perineural or lymphatic invasion as well. No gross disease remained in any of the patients after surgery. A total of four to 10 plastic catheters were placed in the operative bed (or through the tumor in the group of BT as definitive treatment), with 10-mm margins. The catheters were inserted under local anesthesia in three patients or under general anesthesia with preventive tracheostomy in 10 patients. All patients received HDR-BT; 12 of 13 received a total of 50 Gy in 5 Gy fractions, given twice daily for 5 days. One patient received a total of 60 Gy twice daily for 6 days due to large tumor burden. All patients achieved the planned BT dose. 2247

3 Fig. 1. (A) Treatment planning, performed by three-dimensional reconstruction of the target and surroundings structures. (B) Dose volume histogram. [Color figure can be viewed in the online issue, which is available at The patients were followed up every 3 to 6 months on an outpatient basis. Evaluation consisted of clinical interview and full head and examination. Computed tomography, magnetic resonance imaging, or positron emission tomography CT was performed routinely after 8 to 12 weeks and according to the physician s discretion thereafter. Median follow-up (surviving patients only) was 15.5 months (range months). progression was 8 months (range months).two patients had recurrent disease in the reirradiated area, and five patients had locoregional disease out of the reirradiation field. Two patients developed distant metastasis within 6 months of HDR-BT. Thus, local control was achieved in 10 of 13 patients, with only 15.3% (2 of 13) in-field recurrence. The disease-free survival at 12 months was 12.5% (Fig. 2). Statistical Analysis Kaplan-Meier curve was used to estimate overall survival (months between the first day of BT to the date of death or last follow-up) and local control (months from first day of BT treatment to the date of local recurrence or regional lymph nodes). RESULTS Local Control Of the 13 patients under study, seven had further disease progression after HDR-BT. The median time to 2248 Overall Survival The overall survival (OS) was 80.8% at 1 year, and 69.3% at 5 years. Of 13 patients, one died shortly after BT due to severe comorbidities, and two others died after 5 and 12 months due to locoregional disease. Five patients are alive and disease-free (Fig. 3). Toxicity Toxicities were documented according to the Radiation Therapy Oncology Group (RTOG) morbidity scoring

4 Fig. 2. Kaplan-Meier curve for disease-free survival. [Color figure can be viewed in the online issue, which is available at criteria. 18 During the first weeks of follow-up after BT, only mild acute toxicities were reported, mostly mucositis grade 1 to 2, which was seen in all patients. Two patients had grade 3 mucositis and recovered within several weeks. None of the patients required hospitalization, and the symptoms resolved with supportive care. None of the patients became gastrostomy- or tracheostomy-dependent, One patient developed hematemesis that resolved with local pressure ( 3 toxicity). There were no grade 4 to 5 toxicities. One elderly patient developed arrhythmia and aspiration pneumonia and died shortly after the completion of BT. None of the patients who had surgery combined with BT developed wound dehiscence or soft tissue necrosis, and no late complications were recorded. Six patients had systemic therapy (chemotherapy and or biologic treatment) adjuvant to BT. DISCUSSION Recurrent head and carcinoma in a previously irradiated area poses a therapeutic challenge. Salvage surgery is the treatment of choice. However, when surgery is not feasible, reirradiation is the only potentially curative option. Traditionally, inoperable patients were treated with palliative chemotherapy, which in this setting is associated with a median survival of 5 to 6 months, with no chance of long-term control. The unique potential of BT, which provides focal high-dose radiation and steep dose dropoff in the surrounding healthy tissue, offers the possibility of reirradiation in a different biology and potential long-term local disease control. In this study, 13 patients were treated for recurrent, radiotherapy-resistant head and cancer with HDR-BT. Although the small number of patients and the retrospective nature of the analysis limit the interpretation of data, HDR-BT treatment was effective and welltolerated by most patients, with local control rate of 76.9% and only minor adverse events; none were hospitalized for a long term and none were gastrostomydependent. The overall recurrence rate was 53.8%, with in-field recurrence in two patients only. A good local control rate was achieved despite the fact that, in this special group of patients, all tumors were radiotherapyresistant because all patients received prior curative radiation in the recurrence area. The 2-year local control rate reported here is comparable with that of other studies, which reported a local control rate of up to 80% with salvage BT without major side effects. However, five patients (38.4%) developed out-offield recurrence (median time to relapse 14 months), and two developed distant metastasis. The OS at 1 and 5 years was 80.8% and 69.3%, respectively. The high number of patients who developed out-of-field recurrence compared to the rare relapse of the disease in the reirradiated field reflects the disadvantage of BT because it provides local control only. Therefore, although offering good local control, additional methods of treatment should be considered, such as external beam radiation or systemic therapy. In this study, six of 13 patients were treated with adjuvant chemotherapy or biologic therapy. Among them, three had out-of-field recurrence within a median of 9 months (range months), and two had in-field recurrence. One patient s symptoms subsided after treatment with Keytruda (pembrolizumab; Merk & Co., Kenilworth, NJ). The pattern of failure after BT reirradiation in our study differs from the reported in other series of reirradiation In a retrospective review of 66 patients who underwent reirradiation for recurrent or persistent SCC of the head and, 77% had a third recurrence, and almost all (96%) occurred within the reirradiated area despite omitting prophylactic reirradiation of lymph nodes at risk. 22 The high rate of out-of-field recurrence in our series may reflect the unique effectiveness of BT because all of the tumors in this study were radiotherapy-resistant. Clinical studies have shown that high dose reirradiation can be administered in most patients without Fig. 3. Kaplan-Meier curve for overall survival. [Color figure can be viewed in the online issue, which is available at

5 TABLE II. Selected Published Data of Salvage HDR and LDR BT for Recurrent Head and Neck Tumors. Primary Site Toxicity Overall Survival Local Control Dose BT Technique References Neck Neck Neck 3 4: 3% Overall complication rate: 35% 3 4: 33% 3: 13% 3 4: 13% 3 4: 16% 3 4: 27% Early RTOG grade 3 4: 13% Late RTOG grade 3 4: 13% 3 4: 35% 5: 7% 3: 3% 3: 23% 1 year: 63% 2 years 47% 1 year: 73% 30Gy HDR Rudzinaskas et al. 2 1 year: 22% 6 months: 20% 12 30Gy HDR Bartochowska et al. 9 1 year: 50% 1 year: 41% 30 60Gy LDR Grimard et al years: 63% 2 years: 71% 34 40Gy HDR Narayana et al year: 42% 2 years:19% 1 year: 56% 2 years: 37% 1 year: 67% 2 years: 67% 10 36Gy HDR Tselis et al year: 69% 18 48Gy HDR Hepel et al years: 43% 6 months: 77% Median dose 53 Gy 1 year: 82% 2 years: 57% 1 year: 33% 2 years: 13% 1 year: 52% 2 years: 31% LDR Puthawala et al years: 67% 20 60Gy LDR Kupferman et al year: 49% 2 years: 31% 69% (median follow-up 19 months) 1 year: 81% 76% (median follow-up 15.5 months) Median dose 35 Gy LDR Bollet et al Gy HDR Kolotas et al Gy HDR Present study BT 5 brachytherapy; HDR 5 high-dose radiation; LDR 5 low-dose radiation; RTOG 5 Radiation Therapy Oncology Group. significant toxicity, 1,2,22 whereas other studies reported high rates of severe complications 12 14,26,27 ranging from 28% to 50%, especially with HDR salvage brachytherapy compared to LDR or PDR. 11,14,26 LDR BT has an advantage over EBRT of delivering high doses to the tumor while sparing the normal adjacent tissue. 27,28 However, HDR-BT offers a significant benefit over LDR- BT in optimizing the dose distribution and protecting the staff from radiation. The HDR BT approach has shown superior outcomes compare to LDR-BT for tumors located outside the head and region. A phase III trial comparing HDR and LDR monotherapy for T1T2N0 carcinoma of the oral tongue lesions revealed slightly better local control in the HDR group 6,28 ; To date, no trial comparing salvage HDR and LDR-BT has been published. In our study, the median HDR dose was 50 Gy, given twice daily in 5 Gy fractions. Although these are high doses compared to other HDR studies, 2,28 30 only 15.3% of patients developed grade 3 mucositis, one patient developed hematemesis that resolved with local pressure, and no grade 4 to 5 toxicities or serious late complications were documented. Although the follow-up was retrospective, it is clear that there were no prolonged hospitalization or gastrostomy dependency. Treatment results of selected published data of salvage HDR and LDR BT for recurrent head and tumors are summarized in Table II. It should be emphasized that of the eight patients who were treated surgically, no adverse events were reported regarding wound healing, as opposed to other reports. 4,9,11,13 It is known that reirradiation complications occur more often in the elderly. 9 Therefore, special consideration should be given to these patients regarding the risks and benefits of treatment. CONCLUSION Although limited by the small number of patients, our study demonstrates the effectiveness and safety of BT as a retreatment alternative for patients with radiotherapy-resistant, recurrent head and cancer. However, many of these patients will develop out-of-field or distant metastases, and additional treatment should be considered. Acknowledgments All authors had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis. All information and materials in the manuscript are original and have not been published previously. 2250

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