Reirradiation for Recurrent Head and Neck Cancer
Recurrence of head and neck cancer in a previously irradiated volume presents a challenging problem and has poor prognosis. A minority of patients are eligible for the preferred therapy, surgical resection. Systemic therapy is offered to patients with unresectable disease but offers little, if any, chance of cure. Repeat irradiation with systemic therapy is a potentially curative option. One randomized trial and several cooperative group and institutional studies support its use. Long-term disease-free survival has been observed, albeit with the risk of significant, possibly life threatening, late complications. Intensity-modulated radiotherapy has been shown to reduce toxicity and improve disease control. Novel systemic therapies and radiotherapy techniques, including stereotactic body radiotherapy, are under active study.
Radiation therapy plays a central role in the treatment of head and neck cancer (HNC) patients. Within a treatment paradigm of functional organ preservation, evidence-based guidelines recommend radiotherapy for three quarters of all patients with HNC.  Both organ-preserving definitive chemoradiotherapy (CRT) and selective postoperative CRT improve locoregional recurrence (LRR) and prolong overall survival (OS). [2,3] Nevertheless, despite improvements, LRR after CRT continues to be a vexing problem for 20–35% of patients. [4–8] Even patients with favorable prognosis human papillomavirus-related HNC  have a LRR rate of nearly 15%.  Locoregional recurrence is related to a number of different factors. Some tumors are inherently radioresistant. Additionally, as radiation is delivered more precisely with smaller margins, the potential for recurrences related to ‘marginal misses’ has increased. Ongoing exposure to carcinogens, such as cigarette smoke, leads to a 3–5% yearly risk of a second malignancy. [4,10]
Recurrent or second primary HNC in a previously irradiated field has a poor prognosis with a median survival of approximately 6 months with best supportive care.  Uncontrolled disease at the primary site or regional lymph nodes can cause complications including pain, disfigurement, significant difficulties with speech and swallowing, as well as the development of metastatic disease.  Treatment options are often limited. A small proportion of patients have resectable disease recurrence and are sufficiently fit to undergo salvage resection. However, adverse pathologic features, such as extra-capsular extension (ECE) or positive surgical margins are often seen, raising concern for postoperative disease recurrence. For unresectable disease, systemic therapy alone, the historical standard of care, results in 10–15% 1-year OS and virtually no long-term survivors. [11,13] Previously irradiated patients fare even worse. 
For patients with recurrent or second primary HNC within a previously irradiated area, the only potentially curative option is a second course of radiation, with or without chemotherapy, termed reirradiation (RRT). Early experiences with RRT in selected patients demonstrated OS rates (30–50%) that compared favorably to chemotherapy.  More recently, concomitant chemotherapy and RRT has been adopted by some as a treatment strategy of choice. Unfortunately, given the heterogeneous patient population, very limited level I evidence is available to inform decision making of physicians and patients. This manuscript will review the evidence base supporting RRT and concurrent chemotherapy with RRT (CRRT) for both resectable and unresectable, recurrent and previously irradiated HNC.
Workup & staging
The care of patients with recurrent HNC is challenging from beginning to end. Even establishing the diagnosis can be problematic given the possibility of false-positive  or -negative  biopsy results. As discussed herein, treatment options should be tailored for each patient. The significant potential for lasting and debilitating harm from treatment-induced injury to normal structures must be carefully considered. Without exception, the care of these patients should be coordinated by an interdisciplinary team,  consisting of representatives from radiology, pathology, otolaryngology, medical oncology, radiation oncology, dentistry, speech pathology and nutrition.
Following pathologically confirmed tumor recurrence, re-staging is of paramount importance as up to 25% of patients will have metastatic disease. [19,20] Currently, there is no standard imaging protocol, and therefore, this should be tailored for each patient. However, when recurrent HNC is suspected, the sensitivity and specificity of PET-computed tomography (CT) for detecting distant metastasis is reported to be 86–91 and 84–93%, respectively. [19,20] The use of whole-body MRI is not routinely recommended as it did not improve upon the accuracy of PET-CT for the diagnosis of primary, regional or distant recurrence in patients with nasopharyngeal carcinoma.  Dedicated head and neck MRI demonstrated a trend towards improved sensitivity (96.4 vs 82%) for detecting local recurrence of nasopharyngeal carcinoma when compared with PET-CT,  and therefore should be considered for patients with recurrent tumors in this region.
Adjuvant Therapy Following Salvage Surgical Resection
Surgical salvage is the preferred curative treatment for LRR following prior radiotherapy. Unfortunately, resection is attempted in a small proportion of patients due to tumor extension, medical comorbidity and patient preference. [23–26] More than a quarter of the patients experience major postoperative complications  and operative mortality is approximately 5%. [23,27] Even for the selected patients who undergo resection, rates of second recurrence remain suboptimal (50–65%). [11,27,28] A detailed discussion regarding the many factors that influence surgical outcomes is beyond the scope of this review. Readers who desire more detail are encouraged to review a meta-analysis on this topic. 
Following surgical salvage, multiple single-institution series [29–32] and one multicenter, randomized trial have shown improved disease-free survival (DFS) following postoperative CRRT. The specifics of these studies are summarized in and the following paragraphs concisely present the relevant information.
Single Institution Studies (Level II Evidence)
Several single institution series have evaluated CRRT following surgical resection of recurrent HNC. Summarized in , a total of 129 patients have been followed for a median of 32–67.4 months from four institutions. [29–32] The Institut Gustave–Roussy,  reported a series of 25 patients who underwent postoperative CRRT with the FHX regimen (5 day cycles of 2 Gy every day [q.d.] radiotherapy [RT] with concurrent hydroxyurea [1.5 g/day] and continuous infusion 5-fluorouracil [800 mg/m 2] were given every other week for a total of 6 cycles). [33,34] Conventional radiotherapy planning was used and cobalt-60 photons were given to a median dose of 60 Gy. CRRT was given a median of 40 days following surgery and no patients experienced acute wound breakdown. A vast majority of patients received all planned treatment. Encouraging locoregional control (64% at 6 months) and OS (43% at 4 years) led to the aforementioned randomized trial. Acute grade 3 and 4 mucositis was observed in 40 and 12% of patients, respectively. Of the six disease-free surviving patients, five had grade 2–3 cervical fibrosis, three had moderate dysphagia, two had trismus, two had moderate facial pain and one had osteoradionecrosis (ORN). As part of a series of University of Chicago (IL, USA) Phase I studies testing novel agents in combination with the FHX regimen,  postoperative CRRT was given to 49 patients using 4–6 MV linear accelerators and 3D conformal RT (3DCRT) planning to a median dose of 64.8 Gy. Three year locoregional control (LRC) and OS was 68 and 39%, respectively. Of the 22 patients suffering treatment failure, 13 had evidence of distant metastasis. On multivariate analysis, triple-agent chemotherapy (hazard ratio [HR]: 0.33; 95% CI: 0.15–0.83; p = 0.006) and radiation dose (HR: 0.73; 95% CI: 0.60–0.90; p = 0.003) were associated with improved OS. Likewise, when compared with patients with unresectable disease, salvage surgery was associated with superior survival (HR: 0.50; 95% CI: 0.32–0.77; p = 0.002).
Randomized Trials (Level I Evidence)
The Group d’Etude des Tumeurs de la Tete et du Cou (GETTEC) and Group d’Oncologie Radiotherapie Tete Et Cou (GORTEC) accrued 130 patients to a Phase III, multicenter, randomized trial comparing CRRT with observation following R0 or R1 surgical resection of previously irradiated, recurrent HNC.  Patients were required to have ‘rapid and complete’ wound healing by postoperative week 8 and no severe sequelae from prior RT. High-risk pathologic features of ECE and positive surgical margins were observed in 26 and 29% of patients, respectively, and well balanced between groups. Patients were randomized to either observation or CRRT with the FHX regimen. Adjuvant CRRT improved both LRR (HR: 2.73; 95% CI: 1.66–4.51; p < 0.0001) and DFS (HR: 1.68; 95% CI: 1.13–2.50; p = 0.01), but not OS (p = 0.50). Acute toxicity was increased following CRRT and was observed in 28% of patients in the CRRT arm, and three patients died during CRRT. At 1 and 2 years, the actuarial rates of grade 3 or 4 toxicity were 26 and 39%, respectively, in the CRRT arm compared with 9 and 10% in the observation arm. Death related to treatment (5 vs 0), distant metastasis (6 vs 3) and second primary malignancy (4 vs 1) were higher in the CRRT arm.
Level III Evidence
The American College of Radiology (ACR) Expert Panel on HNC authored Appropriateness Criteria for the treatment of recurrent, previously irradiated HNC.  In the setting of positive margins following salvage resection of recurrent HNC, the panel favored CRRT over RRT alone. Chemotherapy alone was not recommended for fit candidates who were thought to be RRT candidates. External beam RT, brachytherapy, alone or in combination was deemed appropriate. Following resection of an isolated nodal recurrence with ECE, the panel again favored CRRT over RRT. Chemotherapy alone was not recommended. In addition to the RT techniques listed above, intraoperative RT was also considered appropriate in this setting.
RRT for Unresectable Disease
Nonsurgical salvage therapies are generally offered to patients with a greater burden of disease and to those unfit for surgery. Two randomized trials were prematurely closed due to poor accrual. Several single institution and two multi-institutional trials have evaluated a variety of CRRT regimens. [32,33,37–43] Significant caveats notwithstanding, modern trials have shown incremental improvements in clinical outcomes when compared with historical controls. They are summarized in and selected studies are detailed below.
Randomized Trials (Level I Evidence)
No randomized controlled trials examining curative intent CRRT have completed planned accrual to date. In the USA, RTOG 04-21, a multicenter, Phase III, randomized trial was opened to compare salvage CRRT (RTOG 99-11 regimen, below) with doublet chemotherapy alone. Unfortunately, this trial was closed due to poor accrual.
Palliative intent CRRT (FHX regimen) and indefinite single agent methotrexate (40 mg/m 2) were compared in a randomized, Phase III trial (GORTEC 98-03) that accrued 57 out of a planned 160 patients.  Patients ineligible for salvage surgery or ‘curative intent’ CRRT were enrolled. Patients in the CRRT arm had more extensive disease (83% T3–4 and 80% with tumor extension to multiple sites) and only 43% of patients completed protocol-directed CRRT. More late toxicity was observed in the CRRT arm with 11 out of 23 patients developing RTOG/EORTC grade 3+ toxicity compared with five out of 20 in the methotrexate arm. With limited statistical power, no difference was detected in 1-year OS, the primary end point, between groups (23 and 22%; p = 0.6). No patients survived beyond 5 years and 77% died due to locoregional disease progression. Four patients died of toxicity – three received CRRT and one methotrexate.
Multi-institutional Trials (Level II Evidence)
RTOG 96-10 was a multi-institutional, Phase II trial that evaluated the FHX regimen for unresectable, recurrent, previously irradiated HNC in 79 patients. [42,43] Radiotherapy was delivered 1.5 Gy twice per day (b.i.d.), with hydroxurea (1.5 g/day) and 5-fluorouracil (300 mg/m 2 bolus) for 5 consecutive days followed by 9 days rest for four cycles. 3DCRT and CT simulations were encouraged but not mandated; no patients received intensity-modulated RT (IMRT). The median RT dose delivered was 60 Gy and 73% of patients completed all planned therapy. The 2-year OS was 15.2% (95% CI: 7.3–23.1) and three patients survived beyond 5 years. Patients with a disease-free interval of greater than 1 year showed improved median survival (5.8 vs 9.8 months; p = 0.036). Six patients (7.6%) died during treatment – two from bleeding in an area of compromised vasculature and four due to neutropenia. Grade 3 and 4 late toxicity was observed in 19.4 and 3.0% of patients, respectively. No new late effects were noted beyond 2 years.
Subsequently, RTOG 99-11, a similar multi-institutional, Phase II trial, tested the combination of paclitaxel (20 mg/m 2/day) and cisplatin (15 mg/m 2/day) in place of FHX.  Radiotherapy treatment planning with CT or conventional simulation was mandated. In addition, both 3DCRT and IMRT were allowed. Ninety nine patients were enrolled and 82% completed protocol-directed therapy with minor deviations. The 2-year OS rate of 25.9% (95% CI not given) compared favorably to RTOG 96-10. Disease-free interval did not correlate with clinical outcomes. Eight patients (8%) died as a result of treatment – two from neutropenic sepsis, one from pneumonitis, one from dehydration, one from cerebrovascular accident, two from carotid hemorrhage and one from oral-cutaneous fistula. In the first 2 years, RTOG/EORTC grade 3–5 toxicity was reported in 85% of patients; 48% had grade 3–4 gastrointestinal toxicity.
Single Institution Studies (Level II Evidence)
One of the largest experiences comes from the Institut Gustave–Roussy.  Three institutional regimens were used throughout the study period: 65 Gy RT alone (2 Gy q.d.), 60 Gy RT (2 Gy daily every other week) with FHX, 60 Gy split course RT (1.5 Gy b.i.d.) with mitomycin (5 mg/m 2 day 1), 5-fluorouracil (150–450 mg/m 2/day) and cisplatin (60 mg/m 2/week, continuous infusion). A total of 139 patients (27, 106 and 36, respectively) were treated with cobalt photons between 1980 and 1996. Unbalanced clinical factors and small numbers made comparisons between groups infeasible. Overall, DFS and OS at 2 years was 11% (95% CI: 7–17) and 21% (95% CI: 15–29), respectively. Multivariate analysis identified RT target volume as the only significant factor associated with survival (relative risk: 1.8; 95% CI: 1.13–5.7; p = 0.01). As expected, grade 3 and 4 mucositis were worse when chemotherapy was given. The crude rates of late toxicity were significant but acceptable with 11 patients developing ORN (three requiring hemimandibulectomy) and five dying of carotid hemorrhage. Thirteen long-term survivors were disease free a median of 42 months after CRRT.
Investigators at the University of Chicago reported on 85 patients undergoing CRRT for unresectable, recurrent HNC following prior RT from 1986 to 2006.  A vast majority of patients were treated with the FHX regimen (described above) with a variety of third chemotherapy agents on several institutional protocols. The median RT dose was 64.8 Gy and median cumulative dose was 131 Gy. The 5-year rate of DFS and OS was 13.4% (95% CI: 8.4–19.8) and 14.3% (95% CI: 9.1–20.7), respectively. Increasing radiation dose was associated with improved progression-free survival (HR: 0.82; 95% CI: 0.71–0.95; p = 0.008).  Multivariate analysis identified radiation dose greater than 60 Gy (HR: 0.35; 95% CI: 0.23–0.53; p < 0.0001) and disease free interval greater than 36 months (HR: 0.64; 95% CI: 0.42–0.95; p = 0.026) as significant predictors of improved OS. Prior CRT, on the other hand, was associated with worse OS (HR: 1.83; 95% CI: 1.21–2.70; p = 0.0043). Triple-agent chemotherapy was not associated with OS. Eighteen patients died during CRRT and an additional 15 died of treatment-related complications. Carotid hemorrhage occurred in 15 patients. Eighteen patients required surgery for ORN of the mandible.
Between 1996 and 2005, 105 patients with recurrent, previously irradiated HNC underwent CRRT at the Memorial Sloan–Kettering Cancer Center (NY, USA).  Chemotherapy was not standardized, and 68% of patients were treated with CRRT with or without induction and/or adjuvant chemotherapy. All patients underwent CT-based RT planning and 70% were treated with IMRT. The median RT dose was 59.4 Gy with cumulative dose 121.4 Gy. At 2 years, LRC and OS were 42 and 37%, respectively. On multivariate analysis, IMRT was associated with improved LRC (HR: 0.37; 95% CI: 0.19–0.76; p = 0.006) and RT dose ≥50 Gy with improved OS (HR: 0.44; 95% CI: 0.20–0.98; p = 0.043). There were no treatment-related deaths. Grade 3–4 late toxicity occurred in 11% of patients with no cases of carotid hemorrhage and one case of grade 2 osteitis.
Level III Evidence
The ACR Expert Panel on HNC offered appropriateness criteria for unresectable, recurrent, previously irradiated HNC.  For patients with unresectable recurrence who are fit for a second course of CRT, the panel recommends CRRT. A limited RT target volume encompassing known disease with a safety margin was favored over elective nodal RRT. RRT with less than 50 Gy was considered inappropriate, and 60 Gy or higher was recommended. Continuous course once (2 Gy per fraction) or twice daily RT (1.2 Gy per fraction) was considered appropriate. Twice daily RT using 1.5 Gy fractions with planned split course was considered appropriate but split course once daily RT was not recommended.
CRRT with or without salvage surgery offers a small, but real, chance of long-term survival, which may come at the price of significant treatment-related morbidity and mortality. However, the grave prognosis of these patients left untreated may indeed sanction high risk, high reward therapy. That said, the exact toxicity associated with RRT and CRRT is very difficult to elucidate, as toxicity may be ascribed to one of multiple therapies (initial RT, chemotherapy, surgery and CRRT). It is likely that the reported rates of adverse effects may be underestimates.  Moreover, heterogeneity in toxicity scoring obfuscates meaningful comparisons between studies.
Acute toxicity, occurring during and within 60–90 days after CRRT, is comparable with that seen with primary CRT. Early Phase I/II trials that established the FHX regimen showed no difference in acute mucositis between patients irradiated de novo or for a second time.  In fact, when paclitaxel was added to the FHX platform, the rate of grade 3–4 mucositis was lower for previously irradiated patients.  More contemporary trials have demonstrated similar results. Primary CRT is associated with higher rates of grade 3–4 mucositis (71–77%) [48,49] when compared with CRRT (14–26%). This is probably due to the smaller RT target volumes that are commonly used for a course of salvage RRT. Hematologic toxicity appears to correlate with the intensity of the systemic therapy regimen and is also not influenced by prior therapy. Rates of grade 3 or worse febrile neutropenia, anemia and thrombocytopenia were 15, 21 and 6%, respectively, in RTOG 99-11 versus 11, 14, 3%,respectively, in a Phase II trial evaluated concomitant docetaxel and cisplatin given every 3 weeks with standard daily RT.  Unfortunately, rates of treatment-related death are higher during CRRT (5–19.9%). This may be related to the fact that functional reserve is compromised in heavily pretreated patients and similar rates of acute toxicity have more dire consequences, as well as the cumulative impact of high radiation doses on normal tissues.
Second courses of radiation to the same treatment area, particularly the head and neck, have long aroused fear of significant late toxicity. While CRRT is associated with significant late toxicity, grade 4–5 late toxic events are relatively rare. In the GETTEC–GORTEC randomized trial, the actuarial rate of grade 3–4 toxicity at 2 years was 39%.  The crude rates of grade 4 or higher toxicity in RTOG 96-10 and RTOG 99-11 were 3 and 31.8%, respectively. [40,43]
One of the most feared consequences of repeat irradiation is delayed neurologic toxicity. Reports of central or peripheral CNS toxicity associated with CRRT are rare. This may be due in part to mandated cumulative dose limits of 50 Gy to the spinal cord in many studies. Following delivery of a median cumulative RT dose of 130.9 Gy, investigators at the University of Chicago identified only one patient with myelopathy and none with either brachial plexopathy or brain necrosis.  Out of 139 patients undergoing CRRT at the Institut Gustave–Roussy to a median cumulative dose of 115 Gy, one patient developed brachial plexopathy after receiving 130 Gy.  For patients with base of skull recurrences, temporal lobe necrosis is a small but real possibility even following treatment with IMRT. 
Carotid artery rupture (CAR) is a devastating complication for patients treated with salvage therapies for recurrent, previously irradiated HNC. Risk factors for CAR include tumor recurrence, chronic infection, surgery (pharyngocutaneous fistula and neck dissection), poor nutrition and chronic inflammation (long-term tracheostomy and nasogastric tubes).  A meta-analysis of CRRT trials reporting CAR showed a crude incidence rate of 2.6% at a median of 7.5 months following CRRT.  Surgical salvage or concurrent chemotherapy did not significantly affect incidence. CAR was often fatal (76%). Optimal treatment is therefore prophylactic when there is high risk of CAR.  Reconstructive  or deconstructive endovascular management [53,55] of the carotid artery is often employed in lieu of open surgery.  However, rates of rebleeding, restenosis, cerebral ischemia and thromboembolism remain suboptimal.
ORN of the mandible is a concerning late toxicity following radiotherapy. The rate of mandibular ORN is likely associated with the cumulative radiation dose delivered to a specific volume of tissue. Conventional radiotherapy technique with opposed lateral treatment portals leads to a 10–15% overdose approximately 0.5–1.5 cm below the skin surface precisely over the mandible. Increasing photon energies, 3DCRT and IMRT ameliorate this phenomenon. However, ORN is relatively uncommon (8 and 11% of patients, respectively) in large single institution series. [32,33] In one of these series, cases of ORN only occurred in patients receiving a cumulative RT dose of greater than 120 Gy. It is possible that the rates of ORN are less in patients treated with more modern radiotherapy techniques for CRRT. In a cohort of 105 patients treated between 1996 and 2005, 70% of whom received IMRT, only one case of grade 2 osteitis was reported.  In another cohort of 74 patients all treated with IMRT between 1999 and 2004, only 5% developed ORN. 
Treatment Planning & Delivery
Accurate and precise delivery of RT is vital in previously irradiated HNC. As newer technologies, such as IMRT, allow more conformal targeting and avoidance, reproducible patient positioning takes on greater importance. Thoughtful selection of immobilization devices reduce patient discomfort, which is especially important in this patient population who often have significant difficulties with swallowing and breathing, and simultaneously optimize exposure of the target. Commonly used devices include body molds, thermoplastic face masks and bite blocks (to minimize irradiation of the oral cavity).
Contrast-enhanced computed tomography (CT) images of the target volume are acquired with generous superior and inferior margins for treatment planning. Additional diagnostic studies including preoperative imaging (when surgery is performed), PET and MRI may be fused with the planning CT when indicated. Using all available information (e.g., surgical reports, physical exam findings, diagnostic imaging and so on), at-risk target volumes and critical organs at risk (OARs) should be delineated. When possible, the prior RT treatment plan should be recreated in the treatment planning software to estimate doses to OARs. When unavailable, it should be assumed that all OARs received the smaller of the full prescription dose or specific organ tolerance.
Conventional and 3DCRT forward planning requires manual selection of RT field shapes and angles assuming static photon fluence through the aperture. Using a computer algorithm, IMRT allows dynamically modulated photon fluence at each gantry angle to optimally attain physician-entered dosimetric priorities. Overall, compared with 3DCRT, IMRT treatment plans generally offer more conformal coverage of targets and avoidance of critical OARs. The downsides of IMRT include increased daily treatment time and greater low-dose irradiation of non-target structures.
IMRT is a potentially useful tool for a second course of radiation as a means of reducing the volume of high radiotherapy doses as well as minimizing doses to critical normal structures, primarily the spinal cord, brain and brainstem. A randomized trial comparing conventional RT and IMRT for primary HNC showed improved avoidance of the parotid, resulting in less chronic xerostomia without compromised disease control.  Several institutional reports of IMRT for RRT have demonstrated favorable disease control and toxicity when compared with historical standards (). [41,56,58–61] Sixty seven patients underwent RRT with IMRT with curative intent for recurrent, previously irradiated HNC at the MD Anderson Cancer Center (TX, USA).  The median IMRT dose was 63 Gy and median cumulative dose was 116 Gy. LRC and OS at 4 years was 52 and 46%, respectively. Five patients developed ORN, four developed dysphagia requiring hospitalization, and one developed temporal lobe necrosis. A comparison of 3DCRT and IMRT in 38 patients undergoing CRRT with weekly carboplatin (area under the curve 2) and paclitaxel (50 mg/m 2) showed significantly greater late toxicity with 3DCRT compared with IMRT (44 vs 7%; p < 0.05). 
Treatment volumes for RRT are in general more limited than for initial courses of radiotherapy. This is due to the fact that the primary pattern of progression is within known disease as well as to minimize the risk of toxicity. In general, margins of 0.5–2.5 cm are often added to the detectable gross tumor volume to envelop microscopic disease and to account for patient setup uncertainty and organ motion. [39,41,56,60,62–64] To minimize toxicity to nearby critical OARs, the smallest possible target volume is used. Elective nodal irradiation is generally not recommended, as the risk of failure in these sites is low (0–6%). [30,60,63] However, patients who were treated to small target volumes in their initial course of radiotherapy, such as those used for early-stage laryngeal cancer, may benefit from and better tolerate more comprehensive elective nodal irradiation.
The effect of RRT fraction size is difficult to estimate. Rapidly evolving RT delivery systems, from 3DCRT to IMRT to stereotactic body radiotherapy (SBRT), have called into question the previously undisputed radiobiological advantages of fractionation. 2D and 3D treatment planning was utilized in every study listed in & . Many of these reports, including the two RTOG Phase II trials for unresectable disease, utilized hyperfractionated RT schedules to offset the toxicity expected with large irradiation targets. With more conformal treatment planning, studies utilizing IMRT () all used standard fractionation with no obvious exacerbation of late toxicity. The ongoing study of SBRT in this patient population detailed below and in , utilizes further hypofractionated treatment schedules. It remains unclear, however, if sophisticated nontarget avoidance can compensate for less sublethal and potentially lethal damage repair, as RT schedules become less fractionated. Regardless, hyperfractionated RT will continue to play a role in RRT and CRRT, particularly in patients with disease recurrence in close proximity to critical normal tissues or those with significant chronic sequelae from prior irradiation.
Patients undergoing RRT for HNC are commonly afflicted with chronic toxicities from prior therapy that may make supine positioning uncomfortable. IMRT may be disadvantageous in this setting due to increased treatment delivery times. Ongoing study of volumetric modulated arc radiotherapy reportedly offers up to 35% reductions in treatment time without compromising conformality when compared with IMRT. 
SBRT consists of the image-guided delivery of a few (three to ten) relatively large, highly conformal RT doses, which are thought to exploit fundamentally different biologic mechanisms for tumor control. [66,67] Following the development and application of radiotherapy planning and delivery advances, including improved image-guidance and respiratory motion management, a substantial body of literature supporting the use of SBRT for medically inoperable lung cancer  and isolated sites of extra-cranial metastasis  has emerged. The utility of SBRT to control tumors resistant to conventionally fractionated radiotherapy has led investigators to explore the utility of SBRT for RRT of HNC. Several reports of SBRT for RRT of recurrent HNC have recently been published (). [70–79] Researchers at the University of Pittsburgh (PA, USA) published a series of 96 patients with recurrent HNC treated with salvage SBRT.  From 2003 to 2008, patients were treated with one to five fractions in four SBRT dose groups, 15–28 Gy, 30–36 Gy, 40 Gy and 44–50 Gy. Thirty nine patients (41%) received concurrent cetuximab. Higher SBRT dose (40–50 Gy) was associated with improved LRC (HR: 0.7; 95% CI: 0.3–0.9; p = 0.02). At 2 years, OS was 28.4% and LRC for patients treated with 40–50 Gy was 57.8%. No late grade 4–5 toxicities were observed. Three late grade 3 toxicities (two for dysphagia, one for fibrosis) were reported. The same group compared 35 patients treated with salvage SBRT and concurrent cetuximab (400 mg/m 2 loading dose, then 250 mg/m 2 weekly) versus 63 patients treated with SBRT alone.  Patients treated with cetuximab showed improved LRC (HR: 0.37; 95% CI: 0.14–0.79; p = 0.009) and OS on multivariate analysis (HR: 0.48; 95% CI: 0.11–0.89; p = 0.008). Reporting of late toxicity such as soft tissue necrosis following SBRT has been variable but at least one group identified an unacceptable rate of CAR (17%) following SBRT to a median dose of 30 Gy.  Further study is required before SBRT is recommended for routine use in this clinical setting. While SBRT may have clinical utility for RRT or CRRT for HNC patients, studies performed to date have been careful to select patients who have the potential to benefit from the therapy. Certainly, patients with large tumors, those enveloping critical normal structures and those with ill-defined borders, may have difficulties with technologies developed to pinpoint small, well-circumscribed targets.
Patients with tumor recurrences in close proximity to critical normal structures develop significant late toxicity even after conformal IMRT RRT.  For patients in these unique circumstances, charged particle therapy may offer uncompromised disease control without the untoward effects of photon irradiation. A sharp dose gradient at the end range of charged particles, called the Bragg peak, theoretically allows high-dose delivery at depth without exit dose. Two reports of patients with recurrent nasopharyngeal cancer, one from Loma Linda University Medical Center (CA, USA)  and one from The Lawrence Berkeley Laboratory (CA, USA),  treated with charged particle re-irradiation showed a 2-year OS of 50% and 3-year OS of 59%, respectively, with no significant late complications. In addition, 15 German patients tolerated RRT with carbon ions or protons predominantly for recurrent skull base tumors without significant acute toxicity. 
Systemic Therapy Considerations
Patterns of failure analyses suggest LRR remains the predominant mode of salvage treatment failure for recurrent HNC. The rationale then for concurrent chemotherapy is primarily as a radiosensitizer and secondarily for systemic disease control. No direct comparisons of RRT and CRRT have been completed, and the benefit of systemic therapy is not clearly established. Indeed, recently reported institutional series from The Netherlands evaluated modern RRT without chemotherapy and showed promising DFS and OS when compared with contemporary CRRT trials. [30,39]
A promising use of systemic therapy that has garnered considerable research interest is as a selection criterion when given as induction therapy prior to planned surgery or RRT. In the primary treatment of HNC, complete response to induction chemotherapy (IC) is associated with superior clinical outcomes.  Investigators at the University of Chicago studied IC as a selection metric to more accurately identify patients with previously irradiated recurrent HNC for surgical salvage.  IC consisted of gemcitabine (1500 mg/m 2) and pemetrexed (500 mg/m 2) every other week for 4 cycles. Surgery was then attempted if feasible. Subsequent CRRT consisted of 70 Gy (1.8–2.0 Gy q.d., 3DCRT or IMRT) with concurrent pemetrexed (500 mg/m 2) and carboplatin (area under the curve: 5–6) every 3 weeks. Eighteen out of 35 enrolled patients completed all protocol-directed therapy. Twenty of the 30 patients deemed resectable prior to IC underwent surgery. The 1 year rate of OS was 64% (95% CI: 30–85) for patients responding to IC and 35% (95% CI: 16–55) for those who did not (p = 0.019).
The classic radiobiological tenant that tumor hypoxia confers radioresistance has been confirmed clinically in HNC.  Prior radiotherapy, surgery and/or systemic therapy may worsen tumor hypoxia in recurrent HNC. A multi-institutional Phase II trial tested tirapazamine (TPZ), a selective hypoxic cell sensitizer, in combination with cisplatin concurrent with RRT. Twenty five patients received cisplatin (50 mg/m 2) and TPZ (260 mg/m 2) on weeks 1, 3 and 5 during daily RRT to a total dose of 72 Gy. Additional TPZ (160 mg/m 2) was given on days 1, 3 and 5 of week 2, and possibly week 4, based on randomization. Locoregional control was 56% overall and the 1- and 2-year rates of OS were 56 and 27%, respectively. Treatment-related toxicity was comparable with other CRRT trials. Given these promising results, study of additional hypoxia-directed therapies is warranted.
A variety of targeted agents have been studied as a component of CRRT. Bevacizumab was added to the FHX platform with median survival 10.3 months and high rates of fistula formation (11.6%) and soft tissue necrosis (9.3%).  EGF-receptor inhibitors have shown promise for primary HNC  and have also been studied in recurrent HNC. Both cetuximab, [72,87,88] a monoclonal antibody, and erlotinib, [89,90] a small molecule inhibitor, have been studied. A group at the NIH (MD, USA) evaluated bortezomib, a proteasome inhibitor, concurrently with RRT for recurrent HNC.  These and other novel agents require further study prior to more widespread adoption.
Expert Commentary & Five-year View
In the next 5 years, locally recurrent, previously irradiated HNC is likely to remain a significant challenge. Over the past 20 years, improvements in treatment outcomes have been limited. It is reasonable to expect continued incremental gains in clinical outcomes due to improved patient stratification and treatment advances. The treatment of primary HNC may schism due to the vastly different prognoses of human papillomavirus-positive and -negative HNC. It is unknown, however, how such a divide would affect the treatment of recurrent HNC within 5 years.
Radiotherapy techniques have evolved and will continue to do so over the next 5 years. While IMRT has already largely supplanted more conventional RT techniques, the next 5 years will likely provide additional evidence of improved disease control and lowered toxicity. Early experiences with SBRT will probably mature eventually, allowing meaningful comparisons of both treatment efficacy and late effects to fractionated treatment programs. Likewise, targeted systemic agents that improve the therapeutic ratio of CRRT may be identified. While outside the scope of this manuscript, the most significant advancement may come from surgeons as they continue to gain experience with robotic surgery for both primary and recurrent HNC.  Similarly, treatment advances are likely to improve primary HNC outcomes and potentially reduce the need for retreatment.
Strategies to better personalize therapy for patients with recurrent HNC are under study. It is quite likely that induction chemotherapy will be further studied in this setting as a possible selective screen. Novel functional imaging agents, such as 3′-deoxy-3′-[ 18F]-fluorothymidine or 18fluoro-misonidazole, may lend insight into tumor biology and allow tailored therapies. While gene signatures are now widely used in the treatment of breast cancer, it is unlikely that genetic or molecular profiling will affect treatment decisions for recurrent HNC within the next 5 years.
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