- Email: [email protected]
Reirradiation after salvage surgery and microvascular free flap reconstruction for recurrent head and neck carcinoma
Otolaryngology–Head and Neck Surgery (2008) 139, 781-786
ORIGINAL RESEARCH—FACIAL PLASTIC AND RECONSTRUCTIVE SURGERY
Reirradiation after salvage surgery and microvascular free flap reconstruction for recurrent head and neck carcinoma Jeffrey D. Suh, MD, Brian P. Kim, MD, Elliot Abemayor, MD, PhD, Joel A. Sercarz, MD, Vishad Nabili, MD, Jerome H. Liu, MD, MSHS, Guy J. Juillard, MD, and Keith E. Blackwell, MD, Los Angeles, CA OBJECTIVE: To evaluate the outcome and complications of reirradiation of recurrent head and neck cancer after salvage surgery and microvascular reconstruction. STUDY DESIGN: Retrospective. SUBJECTS AND METHODS: Twelve patients underwent salvage surgery with microvascular reconstruction for recurrent or second primary head and neck cancer in a previously irradiated field. Median prior radiation therapy dose was 63.0 Gy. Patients then underwent postoperative reirradiation, and received a median total cumulative radiation dose of 115.0 Gy. RESULTS: Three (25%) patients experienced acute complications (⬍3 months) during reirradiation. Four (33%) patients developed grade 3 or 4 late reirradiation complications (⬎3 months). There were no incidences of free flap failure, brain necrosis, spinal cord injury, or carotid rupture. The incidence of soft tissue necrosis and osteoradionecrosis was 8%. Six (50%) patients are alive without evidence of recurrent disease a median of 40 months after reirradiation. CONCLUSION: Microvascular free flaps allow for maximal resection and reliable reconstruction of previously irradiated cancers before high dose reirradiation and may reduce the incidence of severe late complications and treatment related mortality. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
Even after salvage surgery, many patients can be at a high risk of recurrence. There is increasing evidence that postoperative reirradiation with or without chemotherapy can improve locoregional control and overall survival.3-6 However, there is an understandable reluctance to deliver reirradiation because of well-documented severe complications that include osteoradionecrosis, fistula formation, soft tissue necrosis, brain necrosis, spinal cord injury, and carotid artery hemorrhage.7,8 We hypothesized that the use of well-vascularized tissue and bone at the time of salvage surgery could reduce the incidence of severe late reirradiation complications. This would allow patients at a high-risk for recurrence after salvage surgery to more safely receive a second course of radiation therapy. We report our results of full-dose external beam reirradiation after salvage surgery with curative intent for recurrent head and neck SCC. We examined the incidence of acute (⬍3 months) and late reirradiation complications (⬎3 months) after salvage surgery with microvascular free flap reconstruction as well as the outcomes of these patients. To our knowledge, this is the first report of the effects of microvascular free flap reconstruction on complications and outcomes of patients who underwent salvage surgery and external beam reirradiation.
T
reatment options for recurrent head and neck squamous cell carcinoma (SCC) include salvage surgery, radiation, and chemotherapy. When possible, salvage surgery offers the best rates of overall survival, locoregional control, and quality of life when compared with chemotherapy or reirradiation alone.1 Fortunately, advances in microvascular reconstruction have greatly expanded the potential population of patients who might be considered for salvage surgery. Our group has demonstrated that microvascular free flaps are a reliable method of reconstructing extensive defects after salvage surgery, although prognosis remains guarded in patients treated for advanced stage recurrent cancer.2
METHODS Patients for this study were identified from a database of 941 consecutive patients who received microvascular free flap reconstruction by a single surgeon (K.E.B.) in an 11year period between 1996 and 2007. This study was approved by the UCLA Institutional Review Board. All patients included in this study were treated with salvage surgery, microvascular free flap reconstruction, and reirradiation. All patients had undergone prior attempted defini-
Received August 2, 2008; revised August 4, 2008; accepted September 2, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.09.002
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tive therapy with radiation, sometimes combined with prior surgery and/or chemotherapy. Contraindications for salvage surgery included evidence of distant metastasis, carotid artery encasement, regional cancer recurrence within the field of a prior modified radical or radical neck dissection, dermal lymphatic metastases, prevertebral fascia invasion, and unresectable skull base invasion. The free flap database, operative reports, results from surgical pathology, radiation treatment information, and office follow-up notes were reviewed. Patient outcomes were assessed. The disease-free survival and overall survival were calculated using the Kaplan-Meier method. Adverse events were defined as acute (occurring ⬍3 months after reirradiation) or late (occurring ⬎3 months after reirradiation). Statistical analysis was performed with Intercooled Stata 7.0 (Stata Corporation, College Station, TX).
RESULTS Twelve patients met eligibility requirements for this study. Baseline patient demographics are shown in Table 1. There were 9 males and 3 females, with a mean age of 59 years (median, 64 years). Nine patients were treated for local recurrent squamous cell carcinoma, and three patients were treated for second primary squamous carcinomas within the field of previous radiation. Free flap donor sites included radial forearm (n ⫽ 5), fibula (n ⫽ 4), latissimus dorsi (n ⫽ 1), rectus abdominus (n ⫽ 1), and anterolateral thigh flaps (n ⫽ 1). The predominant site of recurrence was oral cavity (42%); the oropharynx (25%) was the second most common. One patient had microscopically positive margins at the skull base (patient 4), and another had macroscopic residual disease involving the dura (patient 7) at the time of salvage surgery. Patient 8 had extracapsular invasion of cervical metastases. Pathologic examination for patients 3, 8, and 10 demonstrated perineural invasion by tumor. All patients received some form of external beam radiation during their initial and repeat treatments. Table 2 summarizes the radiation data. One patient (patient 8) also received supplemental brachytherapy prior to free flap surgery. All patients received full courses of primary radiotherapy (RT) for treatment of their primary tumors, with the exception of one patient (patient 2) because of intolerable mucositis. Initial radiation treatment information for one patient (patient 8) was unavailable for this study. This patient had a history of rhabdomyosarcoma treated with surgery and radiation at five years of age. Median time from prior radiation therapy to second course of radiation therapy was 16 months (range, 8 to 140); 7 (58%) of 12 patients received reirradiation over 3 years after the first course. Median prior RT dose was 63.0 Gy (range, 30.0 to 72.8). Four (33%) patients received prior chemotherapy. Reirradiation doses were lower for most patients, with a median of 50.5 Gy. The median total cumulative radiation dose was 115.0 Gy. In all cases, the reirradiation fields coincided with
Table 1 Distribution of patient and tumor characteristics (n ⴝ 12) Characteristic Age, years Median Range Sex Male Female Recurrence type Locoregional Recurrence Second primary Primary site at study entry Oral cavity Oropharynx Larynx Other Tumor histology Squamous cell Carcinoma Recurrent tumor stage at study entry rT4 rT3 rT2 rT1 Months from prior RT Mean Median Range ⬍36 ⬎36 Prior RT dose, Gy Median Range
Number of patients
%
64 30-79 9 3
75% 25%
9 3
75% 25%
5 3 1 3
42% 25% 8% 25%
12
100%
6 1 3 2
50% 8% 25% 17%
76.9 15.5 8-516 5 7
42% 58%
63 30-72.8
RT, Radiation therapy.
or overlapped previous radiation fields and included the free flap site. There were no perioperative mortalities. All free flaps were inset directly into the field of previous radiation and were exposed to reirradiation. There were no cases of free flap failure. Table 3 summarizes the complications that occurred in this series. Excluding near-universal mild mucositis during reirradiation, 3 (25%) of 12 patients had acute reirradiation complications (⬍3 months) during therapy. Patient 2 developed an infection at the site of the neck incision that required local wound care and antibiotics. Patient 4 developed severe mucositis that caused a oneweek treatment break. Patient 6 developed an intraoral ulceration with minimal bone exposure in the treatment field during reirradiation that was initially managed conservatively. Four (33%) patients developed severe, grade 3 or 4, late radiation complications as defined by Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer.9 There were no fatalities attributed to complications of reirradiation. Patient 4 has been diagnosed
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Reirradiation after salvage surgery and . . .
783
Table 2 Radiation data Primary XRT Number dose (Gy) 1 2 3 4 5 6 7 8 9 10 11† 12
61.2 30* 66 72.8 60 63 60 70 63 55 Unk 72
Previous XRT Ext beam Ext beam Ext beam Hyperfractioned Ext beam Proton Ext beam Ext beam, BT Ext beam Ext beam Unk IMRT
Reirradiation Interval Cumulative XRT dose between XRT dose Chemo (Gy) Reirradiation XRT Chemo XRT (months) (Gy) ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹
50.4 45 70 50.6 60 48.6 57.6 25 30 60 41.4 52.2
Hyperfractioned IMRT Ext beam Ext beam Ext beam Proton Ext beam Ext beam Ext beam Proton Proton Ext beam
⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫹
9 12 11 19 140 64 60 12 60 12 516 8
111.6 75 136 123.4 120 111.6 117.6 95 93 115 ⬎41.4 124.2
Extb beam, external beam; MRT, intensity modulated radiation therapy. *Patient 2 could not complete primary XRT due to severe mucositis. †Patient 11 had surgery and XRT for rhabdomyosarcoma at age 5 (records not available).
with severe glaucoma (grade 3) over three years after reirradiation. Patient 5 developed worsening dysphagia (grade 3) and was found to have a scar band in his reconstructed hypopharynx and proximal esophagus. This scar was treated by laser excision. Patient 11 developed mandible osteoradionecrosis (grade 4) and was treated with hardware removal, local debridement, long term antibiotics, and two courses of hyperbaric oxygen therapy with resolution of his osteoradionecrosis. Patient 6 had soft tissue necrosis that resulted in an oral ulcer and orocutaneous fistula (grade 4) that was treated by surgical reconstruction. There were no
incidences of carotid artery rupture, spinal cord injury, or brain necrosis. Table 4 summarizes the survival data for this study. For all patients in this study, the median survival was 17 months. Four (33%) patients died from disease-related causes. The median survival of these patients was 10 months (range, 4 to 20). Patient 2 died of intra-abdominal sepsis that was unrelated to the head and neck cancer treatment. Patient 8 committed suicide one month after reirradiation. At the time of study completion, 6 (50%) of 12 patients were alive with no evidence of recurrent disease a
Table 3 Reirradiation complications Number
Complication
Time (months)
1 2
None Wound infection Hardware infection None Severe mucositis Glaucoma Severe dysphagia Intraoral ulcer Fistula None None None Hardware extrusion Mandible ORN Hardware infection None
⫺ 3 30 ⫺ ⴱ 39 9 ⴱ 17 ⫺ ⫺ ⫺ 7 5 14 ⫺
3 4 5 6 7 8 9 10 11 12
ORN, Osteoradionecrosis. Time, Number of months after reirradiation the complication occurred. *Complication occurred during radiation treatments.
Treatment
Treated conservatively Treated conservatively Caused radiation treatment break of 1 week None Required laser surgery of a hypopharyngeal scar Treated conservatively Surgical closure
Surgical removal Debridement, antibiotics, and hyperbaric oxygen Surgical removal
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Table 4 Survival data Number
Site
Stage
Survival after reirradiation (months)
1 2 3 4 5 6 7 8 9 10 11 12
Scalp Oral cavity Oral cavity Oral cavity 2nd primary oropharynx 2nd primary oropharynx Scalp Oral cavity Scalp Oral cavity 2nd primary oropharynx Larynx
T4N0 T4N2a T2N0 T4N1 T1N0 T2N0 T4N1 T4N2b T4N0 T2N0 T1N0 T3N0
6 51 14 36 54 20 64 1 4 7 44 4
Status DOD * DOD Alive, NED Alive, NED DOD Alive, NED † DOD Alive, NED Alive, NED Alive, NED
Stage, Stage at time of salvage surgery; DOD, dead of disease; NED, no evidence of disease. *Patient died of sepsis related to a bowel infection. †Patient committed suicide.
median of 40 months after reirradiation (range, 4 to 64 months). There were no fatalities attributed to complications of reirradiation. Figure 1 shows the Kaplan-Meier survival estimate for our study population.
DISCUSSION Despite the use of aggressive therapy of primary disease, locoregional recurrence remains the primary cause of mortality for patients with head and neck squamous cell carcinoma.3,10,11 Moreover, in the face of locoregional recurrences, the average salvage rate is only 16%.12 For patients with inoperable recurrent SCC who have been previously irradiated, treatment options include chemotherapy with or without reirradiation or supportive care. Currently, single agent platinum-based chemotherapy is the standard of care.11 However, response rates to chemotherapy alone are poor, with an average survival between 6 to 9 months.13
Figure 1
Overall Survival. (Y axis, % survival; X axis, months.)
Multi-agent chemotherapy in this group of patients has not been shown to improve survival.14 Radiation oncologists have been understandably reluctant to reirradiate due to fear of unacceptable and severe treatment toxicity. The overall incidence of complications is markedly increased with reirradiation compared with primary radiation.8 The late tissue effects more commonly seen after reirradiation include soft tissue necrosis, trismus, cervical fibrosis, fistulas, osteoradionecrosis, and carotid artery rupture. In a study by De Crevoisier et al8 of 169 patients with unresectable head and neck cancer who receive reirradiation, five patients died of carotid hemorrhage. Their rate of osteoradionecrosis was 18% after conventional reirradiation. In a study of 35 patients, Langlois et al15 reported a 37% incidence of delayed necrosis or bleeding in patients who had been reirradiated with total doses greater than 80 Gy. Recently, several multi-institutional trials have challenged the principle that reirradiation is contraindicated and have suggested that reirradiation may provide improved locoregional control and superior survival rates compared with chemotherapy alone. The Radiation Therapy Oncology Group (RTOG) 9610 evaluated the toxicities of reirradiation and chemotherapy for previously irradiated patients with unresectable disease.6 Encouraging results from this trial led to another multi-institutional study that evaluated reirradiation, the RTOG 9911.3 The results from the RTOG 9911 showed an estimated 1-year overall survival (OS) of 50.2% and a 2-year OS of 25.9%. These 1- and 2-year survival rates were shown to exceed those of the two trials from the Eastern Cooperative Oncology Group, the ECOG 1393 and 1395, which evaluated chemotherapy alone. However, the toxicity in the RTOG 9911 was substantial, with a relatively high incidence of treatment-related deaths. In the first two years, 84.9% of patients experienced grade 3 to 5 toxicity,
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Reirradiation after salvage surgery and . . .
with an estimated 31.8% experiencing grade 4 or 5 nonhematologic toxicity. Five (6%) patients died from treatmentrelated causes. Another study that seeks to establish the benefits of concurrent reirradiation and chemotherapy, the RTOG 0421, has recently closed enrollment. When possible, surgical treatment of recurrent SCC offers the best chance of locoregional control and possibility of cure when compared with chemotherapy or reirradiation.2 In a large meta-analysis, Goodwin12 found that salvage surgery offers a median survival of 10 to 20 months and 5-year survival rates as high as 39.4% for patients with advanced local and regional recurrences. Survival rates were generally better for recurrent cancer of the larynx and oral cavity compared with the pharynx. In addition, in this study, a majority of patients had improved quality of life scores compared with presurgery. However, surgical complications were reported in 20% to 39% of patients who undergo salvage surgery with as high as a 5.2% operative mortality. There has been increasing interest in combining surgical salvage with postoperative reirradiation. Data from the University of Chicago demonstrated that surgery before reirradiation and chemotherapy for recurrent SCC was an independent prognostic factor that predicted improved locoregional control and progression free survival.16 De Crevoisier et al17 examined the tolerance and efficacy of full dose reirradiation and chemotherapy for 25 patients at a high risk of recurrence after salvage surgery. The overall 4-year survival rate in their study was 43%, which is superior to either chemotherapy or reirradiation alone. Their most frequent late toxicities (⬎6 months) included a 16% incidence of osteoradionecrosis, 20% incidence of mucosal necrosis, and a 44% incidence of cervical fibrosis. In an effort to reduce the complications associated with combined surgery and reirradiation, several studies investigate the use of regional tissue flaps. Stafford et al18 investigated Ir-192 afterloading after surgical debulking of recurrent, previously irradiated neck disease. In this series, all patients who underwent primary closure had postoperative wound necrosis when compared with the absence of complications in the group who underwent locoregional flap resurfacing. A similar study with Ir-192 brachytherapy for partially resected, irradiated neck disease found a late toxicity rate of 46% for patients who underwent primary closure, and a late tissue complication rate of 12% for patients who underwent locoregional flap coverage.19 These data suggest that bringing in tissue from outside of the irradiated field (in the form of rotational or other flap closure) could diminish late radiation complications. Microvascular free flaps have proven to be reliable in the reconstruction of defects after salvage surgery.2 There are some studies that suggest that free flaps can reduce complications associated with reirradiation compared with regional flaps in the setting of brachytherapy. Moscoso et al20 investigated both locoregional and free flap reconstruction performed in conjunction with surgery and reirradiation by
785 Ir-192 or I-125. Ten patients who underwent locoregional flap repair had an acute complication rate of 40% versus a rate of 20% in the 5 patients of the free flap group. There were no late complications during the follow-up period, which led the authors to suggest that reconstruction with nonirradiated, vascularized free flaps could prevent wound complications. Unlike previous reirradiation literature with locoregional and free flaps in the setting of brachytherapy or intraoperative radiation, our patients exclusively received external beam reirradiation. With external beam radiation, a larger volume of tissue can receive more radiation compared with brachytherapy, even if intensity modulated radiation therapy (IMRT) is used. Four (33%) patients in our series had grade 3 or 4 late reirradiation complications. The late complications in our study included one patient each with severe glaucoma, severe dysphagia, osteoradionecrosis, and soft tissue necrosis that caused a salivary fistula. There were no incidences of carotid rupture in our series. The incidence of carotid rupture after reirradiation is reported to be 3% to 5% in the literature.3,8,16 The 8% incidence of soft tissue necrosis reported in our series compares favorably with the incidence of delayed tissue necrosis reported in literature, which has been reported to be as high as 37% after high cumulative dose reirradiation.15 Only one (8%) patient in our study developed osteoradionecrosis, which has previously been reported to occur in 16% to 18% of patients who underwent reirradiation.8,17 In our series, there was no mortality attributed to treatment-related complications compared with a 6% mortality reported in the literature.3 Although our study is too small to allow for statistical analysis, a possible explanation for the reduced incidence of reirradiation complications is that the presence of well-vascularized, nonradiated tissue and bone from the free flap might be better able to tolerate reirradiation. Six (50%) patients in our series are still alive and free of disease with a median follow-up of 40 months. Of these patients, half have undergone treatment for advanced stage recurrent cancer. Two patients with residual cancer at the margins of their salvage surgery resection are alive and disease-free after treatment intervals of 36 and 64 months after they underwent reirradiation. This result is encouraging when compared with our larger clinical experience with 106 cases of salvage surgery with free flap reconstruction for head and neck squamous cell carcinoma, in which the 2-year disease free survival was 26% among all patients and 16% among patients treated for advanced stage recurrent cancer.2 Larger studies will be necessary to perform a statistical analysis in order to determine the significance of these observations. Some might argue that after a full course of primary radiotherapy, a recurrence represents a proliferation of tumor cells that are relatively resistant to radiation and would therefore be unlikely to benefit from a second course of radiotherapy. There are a number of potential options to overcome this problem of radiation resistance, including use
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of hyperfractionated regimens, and by the addition of radiation-sensitizing agents such as chemotherapy or molecular targeting therapies.5,12 In addition, side effects from reirradiation might be minimized with the use of cytoprotective agents such as Amifostine, or the use of more precise radiotherapy techniques such as IMRT to spare the brain, eye, and spinal cord from unnecessary radiation.
CONCLUSION The treatment of previously irradiated recurrent head and neck cancer with additional radiation remains controversial. However, there is increasing data from recent multi-institutional studies that demonstrate survival benefit and improved locoregional control with reirradiation, especially when following salvage surgery. This additional treatment comes at the cost of increased acute and late toxicity. Although this study is too small to allow for a statistical analysis of the reported outcomes, our results suggest that microvascular free flaps are reliable in the setting of reirradiation and can reduce the incidence of severe and potentially fatal late complications such as soft tissue necrosis and carotid artery rupture.
AUTHOR INFORMATION From the Divisions of Head and Neck Surgery (Drs Suh, Abemayor, Sercarz, Nabili, and Blackwell) and Plastic and Reconstructive Surgery (Dr Kim), and the Department of Radiation Oncology (Dr Juillard), University of California, Los Angeles, and the Department of Head and Neck Surgery (Dr Kim), Kaiser Permanente, Orange County. Corresponding author: Jeffrey D. Suh, 62-132 CHS, UCLA Medical Center, Los Angeles, CA 90095-1624. E-mail: [email protected].
AUTHOR CONTRIBUTION Jeffrey D. Suh, study design, data collection, writer, statistical analysis; Brian P. Kim, study design, writer, data collection; Elliot Abemayor, writer, data collection; Joel A. Sercarz, writer, data collection; Vishad Nabili, writer, data collection; Jerome H. Liu, statistical analysis; Guy J. Juillard, study design, data collection; Keith E. Blackwell, study design, data collection, writer.
FINANCIAL DISCLOSURE None.
REFERENCES 1. Schwartz GJ, Mehta RH, Wenig BL, et al. Salvage treatment for recurrent squamous cell carcinoma of the oral cavity. Head Neck 2000;22:34 – 41.
2. Kim AJ, Suh JD, Sercarz JA, et al. Salvage surgery with free flap reconstruction: factors affecting outcome after treatment of recurrent head and neck squamous carcinoma. Laryngoscope 2007;117(6): 1019 –1023. 3. Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol 2007 Oct 20;25(30):4800 – 4805. 4. Kasperts N, Slotman B, Leemans CR, et al. A review on re-irradiation for recurrent and second primary head and neck cancer. Oral Oncol 2005;41(3):225–243. 5. Langendijk JA, Bourhis J. Reirradiation in squamous cell head and neck cancer: recent developments and future directions. Curr Opin Oncol 2007;19(3):202–209. 6. Spencer SA, Harris J, Wheeler RH, et al. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5- fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 2001;51:1299 –1304. 7. Lee N, Chan K, Bekelman JE, et al. Salvage re-irradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007;68(3):731– 740. 8. De Crevoisier R, Bourhis J, Domenge C, et al. Full-dose reirradiation for unresectable head and neck carcinoma: experience at the GustaveRoussy Institute in a series of 169 patients. J Clin Oncol 1998;16(11): 3556 –3562. 9. 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 1995;31(5):1341–1346. 10. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;154(4):439 – 442. 11. Jassem J, Bartelink H. Chemotherapy in locally advanced head and neck cancer: a critical reappraisal. Cancer Treat Rev 1995;21(5):447– 462. 12. Goodwin WJ Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? Laryngoscope 2000;110:1–18. 13. Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? J Clin Oncol 2006;24(17):2653–2658. 14. Vokes EE, Weichselbaum RR, Lippman SM, et al. Head and neck cancer. N Engl J Med 1993;328(3):184 –194. 15. 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 1985;3(1):27–33. 16. Salama JK, Vokes EE, Chmura SJ, et al. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006;64(2):382–391. 17. De Crevoisier R, Domenge C, Wibault P, et al. Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer 2001;91(11):2071–2076. 18. Stafford N, Dearnaley D. Treatment of inoperable neck nodes using surgical clearance and postoperative interstitial irradiation. Br J Surg 1988;75:62– 64. 19. Cornes PGS, Cox HJ, Rhys-Evans PR, et al. Salvage treatment for inoperable neck nodes in head and neck cancer using combined iridium-192 brachytherapy and surgical reconstruction. Br J Surg 1996; 83:1620 –1622. 20. Moscoso JF, Urken ML, Dalton J, et al. Simultaneous interstitial radiotherapy with regional or free-flap reconstruction, following salvage surgery of recurrent head and neck carcinoma. Arch Otolaryngol Head Neck Surg 1994;120(9):965–972.
ORIGINAL RESEARCH—FACIAL PLASTIC AND RECONSTRUCTIVE SURGERY
Reirradiation after salvage surgery and microvascular free flap reconstruction for recurrent head and neck carcinoma Jeffrey D. Suh, MD, Brian P. Kim, MD, Elliot Abemayor, MD, PhD, Joel A. Sercarz, MD, Vishad Nabili, MD, Jerome H. Liu, MD, MSHS, Guy J. Juillard, MD, and Keith E. Blackwell, MD, Los Angeles, CA OBJECTIVE: To evaluate the outcome and complications of reirradiation of recurrent head and neck cancer after salvage surgery and microvascular reconstruction. STUDY DESIGN: Retrospective. SUBJECTS AND METHODS: Twelve patients underwent salvage surgery with microvascular reconstruction for recurrent or second primary head and neck cancer in a previously irradiated field. Median prior radiation therapy dose was 63.0 Gy. Patients then underwent postoperative reirradiation, and received a median total cumulative radiation dose of 115.0 Gy. RESULTS: Three (25%) patients experienced acute complications (⬍3 months) during reirradiation. Four (33%) patients developed grade 3 or 4 late reirradiation complications (⬎3 months). There were no incidences of free flap failure, brain necrosis, spinal cord injury, or carotid rupture. The incidence of soft tissue necrosis and osteoradionecrosis was 8%. Six (50%) patients are alive without evidence of recurrent disease a median of 40 months after reirradiation. CONCLUSION: Microvascular free flaps allow for maximal resection and reliable reconstruction of previously irradiated cancers before high dose reirradiation and may reduce the incidence of severe late complications and treatment related mortality. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
Even after salvage surgery, many patients can be at a high risk of recurrence. There is increasing evidence that postoperative reirradiation with or without chemotherapy can improve locoregional control and overall survival.3-6 However, there is an understandable reluctance to deliver reirradiation because of well-documented severe complications that include osteoradionecrosis, fistula formation, soft tissue necrosis, brain necrosis, spinal cord injury, and carotid artery hemorrhage.7,8 We hypothesized that the use of well-vascularized tissue and bone at the time of salvage surgery could reduce the incidence of severe late reirradiation complications. This would allow patients at a high-risk for recurrence after salvage surgery to more safely receive a second course of radiation therapy. We report our results of full-dose external beam reirradiation after salvage surgery with curative intent for recurrent head and neck SCC. We examined the incidence of acute (⬍3 months) and late reirradiation complications (⬎3 months) after salvage surgery with microvascular free flap reconstruction as well as the outcomes of these patients. To our knowledge, this is the first report of the effects of microvascular free flap reconstruction on complications and outcomes of patients who underwent salvage surgery and external beam reirradiation.
T
reatment options for recurrent head and neck squamous cell carcinoma (SCC) include salvage surgery, radiation, and chemotherapy. When possible, salvage surgery offers the best rates of overall survival, locoregional control, and quality of life when compared with chemotherapy or reirradiation alone.1 Fortunately, advances in microvascular reconstruction have greatly expanded the potential population of patients who might be considered for salvage surgery. Our group has demonstrated that microvascular free flaps are a reliable method of reconstructing extensive defects after salvage surgery, although prognosis remains guarded in patients treated for advanced stage recurrent cancer.2
METHODS Patients for this study were identified from a database of 941 consecutive patients who received microvascular free flap reconstruction by a single surgeon (K.E.B.) in an 11year period between 1996 and 2007. This study was approved by the UCLA Institutional Review Board. All patients included in this study were treated with salvage surgery, microvascular free flap reconstruction, and reirradiation. All patients had undergone prior attempted defini-
Received August 2, 2008; revised August 4, 2008; accepted September 2, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.09.002
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tive therapy with radiation, sometimes combined with prior surgery and/or chemotherapy. Contraindications for salvage surgery included evidence of distant metastasis, carotid artery encasement, regional cancer recurrence within the field of a prior modified radical or radical neck dissection, dermal lymphatic metastases, prevertebral fascia invasion, and unresectable skull base invasion. The free flap database, operative reports, results from surgical pathology, radiation treatment information, and office follow-up notes were reviewed. Patient outcomes were assessed. The disease-free survival and overall survival were calculated using the Kaplan-Meier method. Adverse events were defined as acute (occurring ⬍3 months after reirradiation) or late (occurring ⬎3 months after reirradiation). Statistical analysis was performed with Intercooled Stata 7.0 (Stata Corporation, College Station, TX).
RESULTS Twelve patients met eligibility requirements for this study. Baseline patient demographics are shown in Table 1. There were 9 males and 3 females, with a mean age of 59 years (median, 64 years). Nine patients were treated for local recurrent squamous cell carcinoma, and three patients were treated for second primary squamous carcinomas within the field of previous radiation. Free flap donor sites included radial forearm (n ⫽ 5), fibula (n ⫽ 4), latissimus dorsi (n ⫽ 1), rectus abdominus (n ⫽ 1), and anterolateral thigh flaps (n ⫽ 1). The predominant site of recurrence was oral cavity (42%); the oropharynx (25%) was the second most common. One patient had microscopically positive margins at the skull base (patient 4), and another had macroscopic residual disease involving the dura (patient 7) at the time of salvage surgery. Patient 8 had extracapsular invasion of cervical metastases. Pathologic examination for patients 3, 8, and 10 demonstrated perineural invasion by tumor. All patients received some form of external beam radiation during their initial and repeat treatments. Table 2 summarizes the radiation data. One patient (patient 8) also received supplemental brachytherapy prior to free flap surgery. All patients received full courses of primary radiotherapy (RT) for treatment of their primary tumors, with the exception of one patient (patient 2) because of intolerable mucositis. Initial radiation treatment information for one patient (patient 8) was unavailable for this study. This patient had a history of rhabdomyosarcoma treated with surgery and radiation at five years of age. Median time from prior radiation therapy to second course of radiation therapy was 16 months (range, 8 to 140); 7 (58%) of 12 patients received reirradiation over 3 years after the first course. Median prior RT dose was 63.0 Gy (range, 30.0 to 72.8). Four (33%) patients received prior chemotherapy. Reirradiation doses were lower for most patients, with a median of 50.5 Gy. The median total cumulative radiation dose was 115.0 Gy. In all cases, the reirradiation fields coincided with
Table 1 Distribution of patient and tumor characteristics (n ⴝ 12) Characteristic Age, years Median Range Sex Male Female Recurrence type Locoregional Recurrence Second primary Primary site at study entry Oral cavity Oropharynx Larynx Other Tumor histology Squamous cell Carcinoma Recurrent tumor stage at study entry rT4 rT3 rT2 rT1 Months from prior RT Mean Median Range ⬍36 ⬎36 Prior RT dose, Gy Median Range
Number of patients
%
64 30-79 9 3
75% 25%
9 3
75% 25%
5 3 1 3
42% 25% 8% 25%
12
100%
6 1 3 2
50% 8% 25% 17%
76.9 15.5 8-516 5 7
42% 58%
63 30-72.8
RT, Radiation therapy.
or overlapped previous radiation fields and included the free flap site. There were no perioperative mortalities. All free flaps were inset directly into the field of previous radiation and were exposed to reirradiation. There were no cases of free flap failure. Table 3 summarizes the complications that occurred in this series. Excluding near-universal mild mucositis during reirradiation, 3 (25%) of 12 patients had acute reirradiation complications (⬍3 months) during therapy. Patient 2 developed an infection at the site of the neck incision that required local wound care and antibiotics. Patient 4 developed severe mucositis that caused a oneweek treatment break. Patient 6 developed an intraoral ulceration with minimal bone exposure in the treatment field during reirradiation that was initially managed conservatively. Four (33%) patients developed severe, grade 3 or 4, late radiation complications as defined by Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer.9 There were no fatalities attributed to complications of reirradiation. Patient 4 has been diagnosed
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Table 2 Radiation data Primary XRT Number dose (Gy) 1 2 3 4 5 6 7 8 9 10 11† 12
61.2 30* 66 72.8 60 63 60 70 63 55 Unk 72
Previous XRT Ext beam Ext beam Ext beam Hyperfractioned Ext beam Proton Ext beam Ext beam, BT Ext beam Ext beam Unk IMRT
Reirradiation Interval Cumulative XRT dose between XRT dose Chemo (Gy) Reirradiation XRT Chemo XRT (months) (Gy) ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹
50.4 45 70 50.6 60 48.6 57.6 25 30 60 41.4 52.2
Hyperfractioned IMRT Ext beam Ext beam Ext beam Proton Ext beam Ext beam Ext beam Proton Proton Ext beam
⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫹
9 12 11 19 140 64 60 12 60 12 516 8
111.6 75 136 123.4 120 111.6 117.6 95 93 115 ⬎41.4 124.2
Extb beam, external beam; MRT, intensity modulated radiation therapy. *Patient 2 could not complete primary XRT due to severe mucositis. †Patient 11 had surgery and XRT for rhabdomyosarcoma at age 5 (records not available).
with severe glaucoma (grade 3) over three years after reirradiation. Patient 5 developed worsening dysphagia (grade 3) and was found to have a scar band in his reconstructed hypopharynx and proximal esophagus. This scar was treated by laser excision. Patient 11 developed mandible osteoradionecrosis (grade 4) and was treated with hardware removal, local debridement, long term antibiotics, and two courses of hyperbaric oxygen therapy with resolution of his osteoradionecrosis. Patient 6 had soft tissue necrosis that resulted in an oral ulcer and orocutaneous fistula (grade 4) that was treated by surgical reconstruction. There were no
incidences of carotid artery rupture, spinal cord injury, or brain necrosis. Table 4 summarizes the survival data for this study. For all patients in this study, the median survival was 17 months. Four (33%) patients died from disease-related causes. The median survival of these patients was 10 months (range, 4 to 20). Patient 2 died of intra-abdominal sepsis that was unrelated to the head and neck cancer treatment. Patient 8 committed suicide one month after reirradiation. At the time of study completion, 6 (50%) of 12 patients were alive with no evidence of recurrent disease a
Table 3 Reirradiation complications Number
Complication
Time (months)
1 2
None Wound infection Hardware infection None Severe mucositis Glaucoma Severe dysphagia Intraoral ulcer Fistula None None None Hardware extrusion Mandible ORN Hardware infection None
⫺ 3 30 ⫺ ⴱ 39 9 ⴱ 17 ⫺ ⫺ ⫺ 7 5 14 ⫺
3 4 5 6 7 8 9 10 11 12
ORN, Osteoradionecrosis. Time, Number of months after reirradiation the complication occurred. *Complication occurred during radiation treatments.
Treatment
Treated conservatively Treated conservatively Caused radiation treatment break of 1 week None Required laser surgery of a hypopharyngeal scar Treated conservatively Surgical closure
Surgical removal Debridement, antibiotics, and hyperbaric oxygen Surgical removal
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Table 4 Survival data Number
Site
Stage
Survival after reirradiation (months)
1 2 3 4 5 6 7 8 9 10 11 12
Scalp Oral cavity Oral cavity Oral cavity 2nd primary oropharynx 2nd primary oropharynx Scalp Oral cavity Scalp Oral cavity 2nd primary oropharynx Larynx
T4N0 T4N2a T2N0 T4N1 T1N0 T2N0 T4N1 T4N2b T4N0 T2N0 T1N0 T3N0
6 51 14 36 54 20 64 1 4 7 44 4
Status DOD * DOD Alive, NED Alive, NED DOD Alive, NED † DOD Alive, NED Alive, NED Alive, NED
Stage, Stage at time of salvage surgery; DOD, dead of disease; NED, no evidence of disease. *Patient died of sepsis related to a bowel infection. †Patient committed suicide.
median of 40 months after reirradiation (range, 4 to 64 months). There were no fatalities attributed to complications of reirradiation. Figure 1 shows the Kaplan-Meier survival estimate for our study population.
DISCUSSION Despite the use of aggressive therapy of primary disease, locoregional recurrence remains the primary cause of mortality for patients with head and neck squamous cell carcinoma.3,10,11 Moreover, in the face of locoregional recurrences, the average salvage rate is only 16%.12 For patients with inoperable recurrent SCC who have been previously irradiated, treatment options include chemotherapy with or without reirradiation or supportive care. Currently, single agent platinum-based chemotherapy is the standard of care.11 However, response rates to chemotherapy alone are poor, with an average survival between 6 to 9 months.13
Figure 1
Overall Survival. (Y axis, % survival; X axis, months.)
Multi-agent chemotherapy in this group of patients has not been shown to improve survival.14 Radiation oncologists have been understandably reluctant to reirradiate due to fear of unacceptable and severe treatment toxicity. The overall incidence of complications is markedly increased with reirradiation compared with primary radiation.8 The late tissue effects more commonly seen after reirradiation include soft tissue necrosis, trismus, cervical fibrosis, fistulas, osteoradionecrosis, and carotid artery rupture. In a study by De Crevoisier et al8 of 169 patients with unresectable head and neck cancer who receive reirradiation, five patients died of carotid hemorrhage. Their rate of osteoradionecrosis was 18% after conventional reirradiation. In a study of 35 patients, Langlois et al15 reported a 37% incidence of delayed necrosis or bleeding in patients who had been reirradiated with total doses greater than 80 Gy. Recently, several multi-institutional trials have challenged the principle that reirradiation is contraindicated and have suggested that reirradiation may provide improved locoregional control and superior survival rates compared with chemotherapy alone. The Radiation Therapy Oncology Group (RTOG) 9610 evaluated the toxicities of reirradiation and chemotherapy for previously irradiated patients with unresectable disease.6 Encouraging results from this trial led to another multi-institutional study that evaluated reirradiation, the RTOG 9911.3 The results from the RTOG 9911 showed an estimated 1-year overall survival (OS) of 50.2% and a 2-year OS of 25.9%. These 1- and 2-year survival rates were shown to exceed those of the two trials from the Eastern Cooperative Oncology Group, the ECOG 1393 and 1395, which evaluated chemotherapy alone. However, the toxicity in the RTOG 9911 was substantial, with a relatively high incidence of treatment-related deaths. In the first two years, 84.9% of patients experienced grade 3 to 5 toxicity,
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with an estimated 31.8% experiencing grade 4 or 5 nonhematologic toxicity. Five (6%) patients died from treatmentrelated causes. Another study that seeks to establish the benefits of concurrent reirradiation and chemotherapy, the RTOG 0421, has recently closed enrollment. When possible, surgical treatment of recurrent SCC offers the best chance of locoregional control and possibility of cure when compared with chemotherapy or reirradiation.2 In a large meta-analysis, Goodwin12 found that salvage surgery offers a median survival of 10 to 20 months and 5-year survival rates as high as 39.4% for patients with advanced local and regional recurrences. Survival rates were generally better for recurrent cancer of the larynx and oral cavity compared with the pharynx. In addition, in this study, a majority of patients had improved quality of life scores compared with presurgery. However, surgical complications were reported in 20% to 39% of patients who undergo salvage surgery with as high as a 5.2% operative mortality. There has been increasing interest in combining surgical salvage with postoperative reirradiation. Data from the University of Chicago demonstrated that surgery before reirradiation and chemotherapy for recurrent SCC was an independent prognostic factor that predicted improved locoregional control and progression free survival.16 De Crevoisier et al17 examined the tolerance and efficacy of full dose reirradiation and chemotherapy for 25 patients at a high risk of recurrence after salvage surgery. The overall 4-year survival rate in their study was 43%, which is superior to either chemotherapy or reirradiation alone. Their most frequent late toxicities (⬎6 months) included a 16% incidence of osteoradionecrosis, 20% incidence of mucosal necrosis, and a 44% incidence of cervical fibrosis. In an effort to reduce the complications associated with combined surgery and reirradiation, several studies investigate the use of regional tissue flaps. Stafford et al18 investigated Ir-192 afterloading after surgical debulking of recurrent, previously irradiated neck disease. In this series, all patients who underwent primary closure had postoperative wound necrosis when compared with the absence of complications in the group who underwent locoregional flap resurfacing. A similar study with Ir-192 brachytherapy for partially resected, irradiated neck disease found a late toxicity rate of 46% for patients who underwent primary closure, and a late tissue complication rate of 12% for patients who underwent locoregional flap coverage.19 These data suggest that bringing in tissue from outside of the irradiated field (in the form of rotational or other flap closure) could diminish late radiation complications. Microvascular free flaps have proven to be reliable in the reconstruction of defects after salvage surgery.2 There are some studies that suggest that free flaps can reduce complications associated with reirradiation compared with regional flaps in the setting of brachytherapy. Moscoso et al20 investigated both locoregional and free flap reconstruction performed in conjunction with surgery and reirradiation by
785 Ir-192 or I-125. Ten patients who underwent locoregional flap repair had an acute complication rate of 40% versus a rate of 20% in the 5 patients of the free flap group. There were no late complications during the follow-up period, which led the authors to suggest that reconstruction with nonirradiated, vascularized free flaps could prevent wound complications. Unlike previous reirradiation literature with locoregional and free flaps in the setting of brachytherapy or intraoperative radiation, our patients exclusively received external beam reirradiation. With external beam radiation, a larger volume of tissue can receive more radiation compared with brachytherapy, even if intensity modulated radiation therapy (IMRT) is used. Four (33%) patients in our series had grade 3 or 4 late reirradiation complications. The late complications in our study included one patient each with severe glaucoma, severe dysphagia, osteoradionecrosis, and soft tissue necrosis that caused a salivary fistula. There were no incidences of carotid rupture in our series. The incidence of carotid rupture after reirradiation is reported to be 3% to 5% in the literature.3,8,16 The 8% incidence of soft tissue necrosis reported in our series compares favorably with the incidence of delayed tissue necrosis reported in literature, which has been reported to be as high as 37% after high cumulative dose reirradiation.15 Only one (8%) patient in our study developed osteoradionecrosis, which has previously been reported to occur in 16% to 18% of patients who underwent reirradiation.8,17 In our series, there was no mortality attributed to treatment-related complications compared with a 6% mortality reported in the literature.3 Although our study is too small to allow for statistical analysis, a possible explanation for the reduced incidence of reirradiation complications is that the presence of well-vascularized, nonradiated tissue and bone from the free flap might be better able to tolerate reirradiation. Six (50%) patients in our series are still alive and free of disease with a median follow-up of 40 months. Of these patients, half have undergone treatment for advanced stage recurrent cancer. Two patients with residual cancer at the margins of their salvage surgery resection are alive and disease-free after treatment intervals of 36 and 64 months after they underwent reirradiation. This result is encouraging when compared with our larger clinical experience with 106 cases of salvage surgery with free flap reconstruction for head and neck squamous cell carcinoma, in which the 2-year disease free survival was 26% among all patients and 16% among patients treated for advanced stage recurrent cancer.2 Larger studies will be necessary to perform a statistical analysis in order to determine the significance of these observations. Some might argue that after a full course of primary radiotherapy, a recurrence represents a proliferation of tumor cells that are relatively resistant to radiation and would therefore be unlikely to benefit from a second course of radiotherapy. There are a number of potential options to overcome this problem of radiation resistance, including use
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of hyperfractionated regimens, and by the addition of radiation-sensitizing agents such as chemotherapy or molecular targeting therapies.5,12 In addition, side effects from reirradiation might be minimized with the use of cytoprotective agents such as Amifostine, or the use of more precise radiotherapy techniques such as IMRT to spare the brain, eye, and spinal cord from unnecessary radiation.
CONCLUSION The treatment of previously irradiated recurrent head and neck cancer with additional radiation remains controversial. However, there is increasing data from recent multi-institutional studies that demonstrate survival benefit and improved locoregional control with reirradiation, especially when following salvage surgery. This additional treatment comes at the cost of increased acute and late toxicity. Although this study is too small to allow for a statistical analysis of the reported outcomes, our results suggest that microvascular free flaps are reliable in the setting of reirradiation and can reduce the incidence of severe and potentially fatal late complications such as soft tissue necrosis and carotid artery rupture.
AUTHOR INFORMATION From the Divisions of Head and Neck Surgery (Drs Suh, Abemayor, Sercarz, Nabili, and Blackwell) and Plastic and Reconstructive Surgery (Dr Kim), and the Department of Radiation Oncology (Dr Juillard), University of California, Los Angeles, and the Department of Head and Neck Surgery (Dr Kim), Kaiser Permanente, Orange County. Corresponding author: Jeffrey D. Suh, 62-132 CHS, UCLA Medical Center, Los Angeles, CA 90095-1624. E-mail: [email protected].
AUTHOR CONTRIBUTION Jeffrey D. Suh, study design, data collection, writer, statistical analysis; Brian P. Kim, study design, writer, data collection; Elliot Abemayor, writer, data collection; Joel A. Sercarz, writer, data collection; Vishad Nabili, writer, data collection; Jerome H. Liu, statistical analysis; Guy J. Juillard, study design, data collection; Keith E. Blackwell, study design, data collection, writer.
FINANCIAL DISCLOSURE None.
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2. Kim AJ, Suh JD, Sercarz JA, et al. Salvage surgery with free flap reconstruction: factors affecting outcome after treatment of recurrent head and neck squamous carcinoma. Laryngoscope 2007;117(6): 1019 –1023. 3. Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol 2007 Oct 20;25(30):4800 – 4805. 4. Kasperts N, Slotman B, Leemans CR, et al. A review on re-irradiation for recurrent and second primary head and neck cancer. Oral Oncol 2005;41(3):225–243. 5. Langendijk JA, Bourhis J. Reirradiation in squamous cell head and neck cancer: recent developments and future directions. Curr Opin Oncol 2007;19(3):202–209. 6. Spencer SA, Harris J, Wheeler RH, et al. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5- fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 2001;51:1299 –1304. 7. Lee N, Chan K, Bekelman JE, et al. Salvage re-irradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007;68(3):731– 740. 8. De Crevoisier R, Bourhis J, Domenge C, et al. Full-dose reirradiation for unresectable head and neck carcinoma: experience at the GustaveRoussy Institute in a series of 169 patients. J Clin Oncol 1998;16(11): 3556 –3562. 9. 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 1995;31(5):1341–1346. 10. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;154(4):439 – 442. 11. Jassem J, Bartelink H. Chemotherapy in locally advanced head and neck cancer: a critical reappraisal. Cancer Treat Rev 1995;21(5):447– 462. 12. Goodwin WJ Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? Laryngoscope 2000;110:1–18. 13. Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? J Clin Oncol 2006;24(17):2653–2658. 14. Vokes EE, Weichselbaum RR, Lippman SM, et al. Head and neck cancer. N Engl J Med 1993;328(3):184 –194. 15. 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 1985;3(1):27–33. 16. Salama JK, Vokes EE, Chmura SJ, et al. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006;64(2):382–391. 17. De Crevoisier R, Domenge C, Wibault P, et al. Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer 2001;91(11):2071–2076. 18. Stafford N, Dearnaley D. Treatment of inoperable neck nodes using surgical clearance and postoperative interstitial irradiation. Br J Surg 1988;75:62– 64. 19. Cornes PGS, Cox HJ, Rhys-Evans PR, et al. Salvage treatment for inoperable neck nodes in head and neck cancer using combined iridium-192 brachytherapy and surgical reconstruction. Br J Surg 1996; 83:1620 –1622. 20. Moscoso JF, Urken ML, Dalton J, et al. Simultaneous interstitial radiotherapy with regional or free-flap reconstruction, following salvage surgery of recurrent head and neck carcinoma. Arch Otolaryngol Head Neck Surg 1994;120(9):965–972.