Reirradiation in head and neck recurrent or second primary tumor: efficacy, safety, and prognostic factors


Aims and background

We investigated efficacy, safety, and prognostic factors of reirradiation in patients with recurrent or second primary head and neck cancer.


Records of 75 consecutive patients treated with reirradiation between August 2005 and December 2013 were reviewed.


Median overall survival (OS) and cancer-specific survival (CSS) were 29.5 and 33.6 months. Median local control (LC) and progression-free survival (PFS) were 21.7 and 16.2 months. Univariate analysis showed that patients younger than 70 years, with a Karnofsky Performance Status (KPS) >90 or with 2 or less comorbidities at time of reirradiation, have a better OS; KPS >90 and biological equivalent dose (BED) >72 Gy positively influenced the PFS. At multivariate analysis, KPS at reirradiation was an independent predictive factor for OS, while BED was an independent predictive factor for CSS and OS. At univariate analysis, patients with planning target volume (PTV) >221 mL had worse LC and PFS rates, with results confirmed at multivariate analysis. The rate of fatal treatment-related adverse events was 6.7% (3 carotid blowout, 1 soft tissue necrosis, and 1 thromboembolic event).


This study confirms the role and outcomes of reirradiation. A careful selection of patients could minimize acute and late side effects and influence survival: elderly patients, with significant medical comorbidities or poor KPS, are worse candidate for reirradiation. Total dose delivered with reirradiation and PTV appear to be other potential prognostic factors. Further studies of dose escalation are needed to establish the total dose that could achieve better LC rates with a safer toxicity profile.

Tumori 2015; 101(5): 585 - 592




Michela Buglione, Marta Maddalo, Ercole Mazzeo, Pierluigi Bonomo, Luigi Spiazzi, Alessio Bruni, Fabiola Paiar, Luca Triggiani, Daniela Greto, Laura Rubino, Lorenzo Livi, Filippo Bertoni, Stefano Maria Magrini

Article History


Financial support: None.
Conflict of interest: None.

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The treatment of head and neck cancer (HNC) is mostly based on a multidisciplinary approach including surgery and radiochemotherapy (1, 2). Despite an increase in survival rates during the last few decades, due to advances in therapeutic procedures and treatment intensification, more than half of patients with locally advanced disease experience locoregional recurrence (3, 4).

Patients with early-stage HNC achieve high rates of long-term disease control, but could experience a second primary tumor arising within or in close proximity to previously irradiated tissues.

Evidence mostly based on retrospective series had established surgery as the standard of care for patients with recurrent disease (5-6-7-8-9); however, many patients are medically unfit for surgery, refuse surgery, or have unresectable disease. In these cases, 3 options can be discussed: supportive care only, palliative chemotherapy, or radiotherapy. As shown by several randomized trials, response rates after chemotherapy alone are poor, with median survivals not exceeding 6-8 months (10, 11). Therefore, radiation oncologists increasingly face the challenge of retreating patients who already experienced a high-dose radiotherapy course. Long-term survival rates have been reported after reirradiation of recurrent and second primary HNC in both prospective (12-13-14-15-16-17-18) and large retrospective series (19-20-21).

This retrospective study reports data in terms of efficacy and safety of a large population of patients with HNC treated with reirradiation. Endpoints of the analysis were overall survival (OS), cancer-specific survival (CSS), local control (LC), progression-free survival (PFS), and acute and late toxicities rates.

Materials and methods


We retrospectively reviewed medical records of patients with evidence of recurrence or second primary HNC, reirradiated at 3 Italian radiation oncology departments between August 2005 and December 2013.

Statistical analysis

Statistics were performed by SPSS software (SPSS Statistics 17.0; SPSS, Chicago, IL, USA).

A descriptive statistic of population characteristics and acute and late toxicity rates was carried out.

Toxicities were graded using the National Cancer Institute–Common Toxicity Criteria scale v 4.0 (22).

Kaplan-Meier survival analyses were used to estimate survival and local control rates.

The OS and CSS were calculated from the end of reirradiation up to the date of death or to the date of the last follow-up.

Local control was calculated from the end of reirradiation until the date of local recurrence (at the reirradiated site) or the date of the last follow-up.

The PFS was calculated from the end of reirradiation until the date of first evidence of disease or until the date of the last follow-up in case of disease-free patients.

Univariate analyses were performed using the log-rank test for all variables of interest: age at first diagnosis and at reirradiation (≤70 years versus >70 years), Karnofsky Performance Status (KPS) (23) at first diagnosis and at reirradiation (≥90 versus ≤80), Charlson Comorbidity Index (24, 25) (≤2 versus >2), disease presentation at reirradiation (recurrence versus second primary tumor), external beam radiotherapy (EBRT) technique, median biological equivalent dose (BED) delivered with reirradiation (<72 Gy versus ≥72 Gy), planning target volume (PTV) in quartiles and with a cutoff of 221 mL, concomitant chemotherapy, and LC (as a predictive variable for OS, CSS, and PFS).

Multivariate analyses were done using the Cox stepwise regression test. Variables used for these tests were the significant ones at the univariate analyses. All variables have been used as categorical. The BED was considered to possibly influence LC because it has shown a trend toward significance for this outcome at the univariate analysis. For this reason, it has been used for the respective multivariate analysis.

A p value <0.05 was considered statistically significant.


We identified a total of 75 adult patients, 61 male and 14 female. Fifty-nine patients had recurrent disease, while 16 patients presented a second primary tumor. Table I summarizes patients and tumor characteristics.

Patient and tumor characteristics

Characteristics Values
KPS = Karnofsky Performance Status; RT = radiotherapy.
M/F, n (%) 61 (81.3)/14 (18.7)
Median (range) age, y
 1st RT 58 (18-83)
 Re-RT 64 (25-87)
KPS 1st RT, n (%)
 90-100 66 (88)
 70-80 9 (12)
KPS re-RT, n (%)
 90-100 47 (62.7)
 70-80 27 (36)
 60 1 (1.3)
Charlson Comorbidity Index at re-RT, n (%)
 0 15 (20)
 1-2 40 (53.3)
 3-4 14 (18.7)
 ≥5 6 (8)
1st RT disease site, n (%)
 Nasopharynx 19 (25.3)
 Oropharynx 17 (22.7)
 Hypopharynx 1 (1.3)
 Larynx 20 (26.7)
 Oral cavity 6 (8)
 Nasal cavity and paranasal sinuses 11 (14.7)
 Salivary glands 1 (1.3)
Re-RT disease site, n (%)
 Nasopharynx 15 (20)
 Oropharynx 15 (20)
 Hypopharynx 5 (6.7)
 Larynx 6 (8)
 Oral cavity 2 (2.7)
 Nasal cavity and paranasal sinuses 11 (14.7)
 Salivary glands 1 (1.3)
 Exclusive neck nodal 19 (25.3)
 Subcutaneous tissues 1 (1.3)

Disease presentation and first radiotherapy course

Median age at first diagnosis was 58 years (range 18-83). All patients had excellent (90-100) or good (70-80) KPS and were treated between January 1971 and April 2013 with ­radical purpose. A total of 30.7% of patients received exclusive EBRT, 25.3% of patients were treated with concurrent chemoradiation, while 44% of patients had postoperative radiotherapy (29 with EBRT alone, 4 with concurrent chemotherapy). In all radiotherapy courses, the fractionation schedule was standard. The median dose was 66 Gy (range 40-70) in the curative setting and 60 Gy (range 50-70) in the postoperative one. The patient who received a curative dose of 40 Gy was treated at the beginning for a non-Hodgkin lymphoma, and then developed an oral cavity second primary tumor. The delivery of EBRT changed over the treatment period, ranging from a 2D or 3D conformal technique to intensity-modulated radiation therapy or tomotherapy. Concomitant chemotherapy was cisplatin in all 15 patients except 2 who received cetuximab.

Preretreatment clinical evaluation and reirradiation

Patients were treated with reirradiation between August 2005 and December 2013. Median time between the first radiotherapy course and reirradiation was 28 months (range 3-173) for recurrences and 144 months (range 35-446) for second primary tumors, respectively (p<0.001).

Median age at reirradiation was 64 years (range 25-87). The KPS was excellent in 47 patients, good in 27 patients, and poor in 1 patient.

At the time of preretreatment clinical evaluation, no severe (G3-G4) late dysphagia or dry mouth due to previous radiotherapy course was detected; only 2 patients had a G3 soft tissue fibrosis.

Table II shows T and N stage at the time of reirradiation; the patient with T0N0 stage was treated for a metastatic subcutaneous preauricular recurrence of sinonasal carcinoma.

T and N stage at reirradiation

N0 N1 N2a N2b N2c
Second primary tumor
 T0 - - - - -
 T1 2 - - 1 1
 T2 2 1 - - 1
 T3 4 - - - -
 T4 3 - - 1 -
 T0 1 5 5 7 2
 T1 4 - - - 1
 T2 4 - - - -
 T3 5 - - - -
 T4 20 4 - - 1

Fifty-two patients received EBRT, 12 patients were treated with concurrent chemoradiation (5 cisplatin and 7 cetuximab), and 11 patients had a postoperative radiotherapy (9 with EBRT alone, 2 with concurrent cetuximab). The adjuvant treatment was due to macroscopic persistence after surgery or to high-risk features at the anatomo-pathologic evaluation such as positive margins or massive lymph node involvement with extracapsular extension.

Twenty-six patients were treated with standard fractionated schedule, 30 patients underwent altered fractionation (24 with hyperfractionation once or twice a day and 6 with moderate once-a-day hypofractionation), and the remaining 19 patients received hypofractionated stereotactic body ­radiotherapy (SBRT) with CyberKnife. Patients who underwent SBRT were all treated in the same institution.

Radiotherapy technique in non-SBRT patients was 3D conformal radiotherapy in 9 patients, intensity-modulated radiotherapy in 9 patients, volumetric modulated arc therapy in 2 patients, and tomotherapy in 34 patients. In 2 patients with superficial soft tissue and nodal neck metastases, the technique used was an appositional direct electron field. In all patients, the target volume was represented by the gross tumor volume both for the primary tumor and the lymph nodes involved. Only 9 patients also received a prophylactic neck nodal irradiation.

In order to compare a heterogeneous set of fractionation schedules, a conversion of the total effective dose delivered to each patient to the BED was performed, using a α/β value of 10. The patient sample was split in 2 using the median BED as a cutoff (<72 Gy versus ≥72 Gy), in order to test its potential role in influencing outcomes. The BED in non-SBRT patients ranged from 29 to 84 Gy. In the SBRT group, the fractionation schedule was 25 Gy in 5 fractions in 5 patients (BED of 37.50 Gy), 30 Gy in 6 fractions in 11 patients (BED of 48 Gy), and 35 Gy in 7 fractions in 3 patients (BED of 59.50 Gy). All SBRT doses were prescribed at isodose 80%.

The median follow-up after reirradiation was 12 months (range 1-81).

Clinical results: OS and CSS

Median OS was 29.5 months; median CSS was 33.6 months. One- and 2- year OS rates were 64.4% and 58.2%, respectively. One- and 2- year CSS rates were 71.7% and 67.2%, respectively.

Twenty-six patients died of disease progression, 5 patients died of reirradiation adverse events, and 9 patients died of causes related neither to the treatment nor to the HNC.

Tables III and IV show the results of the univariate and multivariate analysis.

Clinical outcomes with results of univariate analysis

1 year OS 1 year CSS 1 year LC 1 year PFS
BED = biological equivalent dose; CSS = cancer-specific survival; EBRT = external beam radiotherapy; LC = local control; NS = not significant; OS = overall survival; PFS = progression-free survival; PTV = planning target volume; SBRT = stereotactic body radiotherapy.
Overall population 64.4 71.7 68.6 54.9
Age at first diagnosis, y
 ≤70 (n = 60) 73.5 75.7 71.8 57.1
 >70 (n = 15) 26.7 46.7 53.3 44.5
 p 0.002 NS NS NS
Age at reirradiation
 ≤70 years (n = 48) 75.4 78.2 71.6 59.2
 >70 years (n = 27) 45.4 58.9 64 47
 p 0.002 NS NS NS
Karnofsky Performance Status at first diagnosis
 ≥90 (n = 65) 69.1 78 70.3 53.2
 ≤80 (n = 10) 38.1 72.6 44.4 65.5
Karnofsky Performance Status at reirradiation
 ≥90 (n = 47) 78.2 81 68.3 59
 ≤80 (n = 28) 41.9 53.6 67 44.7
 p 0.002 0.059 NS NS
Charlson Comorbidity Index
 ≤2 (n = 54) 69.9 75.2 63.2 56.1
 >2 (n = 21) 48.4 58.6 84 49.6
 p 0.039 NS NS NS
Disease presentation at reirradiation
 Recurrence (n = 59) 60.6 69.6 67 50.1
 Second primary tumor (n = 16) 80 80 75 75
EBRT technique
 Non-SBRT (n = 56) 68.6 73.4 63.7 59.5
 SBRT (n = 19) 52.6 66.1 81.8 42.9
 <72 Gy (n = 38) 56.3 63.2 60.7 48.5
 ≥72 Gy (n = 37) 73.6 81.6 71.1 62.8
 p NS 0.043 NS NS
 0-25th percentile (n = 13) 74.6 90.9 74.1 64.8
 25th-50th percentile (n = 13) 39.5 47.9 82.1 28.8
 50th-75th percentile (n = 13) 57.1 57.1 76.4 58.2
 75th-100 percentile (n = 13) 41.1 44.9 0 0
 p NS NS 0.002 0.047
 <221 mL (n = 39) 57.4 66.1 76.8 51.3
 ≥221 mL (n = 13) 41.1 44.9 0 0
 p NS NS <0.0001 0.018
Concomitant chemotherapy during reirradiation
 Yes (n = 15) 57.8 67.4 42.9 39.6
 No (n = 60) 65.9 72.6 74.2 58.5
Local control
 Yes (n = 42) 60.2 70.2 69.8
 No (n = 33) 70.2 73.7 37.5
 p NS NS <0.0001

Results of multivariate analyses

Endpoint Significant variables Relative risk (confidence interval) p Value
BED = biological equivalent dose; CSS = cancer-specific survival; KPS = Karnofsky Performance Status; LC = local control; OS = overall survival; PFS = progression-free survival; PTV = planning target volume.
OS Age at diagnosis (≤70 years vs >70 years) 3.5 (1.6-7.7) 0.002
KPS at reirradiation (≥90 vs <80) 2.2 (1.1-4.4) 0.018
BED (≥72 Gy vs <72 Gy) 2.2 (1.1-4.7) 0.031
CSS BED (≥72 Gy vs <72 Gy) 2.2 (1.0-4.9) 0.048
LC PTV (<221 cm3 vs ≥221 cm3) 7.4 (2.3-23.5) 0.001
PFS PTV (<221 cm3 vs ≥221 cm3) 3.1 (1.0-9.6) 0.045
Local control (yes vs no) 4.0 (1.8-9.2) 0.001

Elderly patients (both at the time of first diagnosis and at the time of reirradiation) had a lower 1- and 2-year OS compared to those younger than 70 years (p = 0.002).

Patients with excellent KPS (≥90) at time of reirradiation had higher OS compared to those with a KPS ≤80 (p = 0.002).

At univariate analysis, having 2 or fewer major comorbidities (Charlson Comorbidity Index ≤2) before reirradiation is a prognostic factor for both a better 1-year OS (69.9% vs 48.4%, p = 0.039) and a better CSS (75.2% vs 58.6%, p = NS).

A trend for improved OS and CSS was seen with increasing radiation dose. Using a BED cutoff of 72 Gy (median BED), the 1-year OS and 1-year CSS were 56.3% and 63.2%, respectively, for patients who received less than 72 Gy (38 patients) and 73.6% and 81.6%, respectively, for those who received more than 72 Gy (37 patients), reaching statistical significance only for CSS (p = 0.043).

At multivariate analyses, KPS at reirradiation appears to be an independent variable that influences OS, while BED was an independent variable that influences both OS and CSS.

Patterns of failure: LC and PFS

Median LC was 21.7 months, while median PFS was 16.2 months. One- and 2-year LC rates were 68.6% and 46.4%, ­respectively. One- and 2-year PFS rates were 54.9% and 38.5%, respectively.

Among patients who died of disease progression (n = 26), 2 patients had progression at the site of reirradiation, 6 patients had systemic progression, and 18 patients had both local and systemic recurrence.

At the first clinical examination 3 months after the end of the treatment, 12, 20, and 27 patients had a response scored as <25%, between 25% and 75%, and ≥75%, respectively, while 11 patients had evidence of disease progression. In 5 patients, the clinical response cannot be assessed because they died before the first scheduled follow-up visit.

The PTV appears to be a critical aspect for both LC and PFS. A double univariate analysis was performed on this ­issue. The analysis per quartiles demonstrated that patients included in the upper quartile had worse LC and PFS outcomes compared to those included in all the other lower quartiles (p = 0.002 and 0.047, respectively). Based on this finding, we decided to carry on the same analysis using the 75th percentile (221 mL) as a cutoff for both the univariate and the multivariate analyses.

At multivariate analyses, the PTV (<221 mL vs ≥221 mL) is confirmed as an independent variable that influences both PFS and LC. The PFS was also influenced by LC.

Clinical results: toxicity

Table V reports data about acute and late toxicity.

Acute and late toxicity (NCI-CTC scale v 4.0)

Toxicity G0 G1-G2 G3-G4 G5
NCI-CTC = National Cancer Institute–Common Toxicity Criteria.
Acute Salivary duct inflammation 43 32 / /
Mucositis oral 29 42 4 /
Dermatitis radiation 38 36 1 /
Dysphagia 31 41 3 /
Dry mouth 37 24 / /
Superficial soft tissue fibrosis 36 23 2 /
Late Trismus 54 7 / /
Dysphagia 45 14 2 /
Myelitis 61 / / /
Injury to carotid artery 57 / 1 3
Thromboembolic event 60 / / 1
Head and/or neck soft tissue necrosis 60 / / 1
Osteonecrosis of jaw 60 1 / /

Eight patients (11%) complained of Grade 3 acute toxicities. These toxicities included dermatitis (1), dysphagia (3), and mucositis (4).

For 14 patients, data on late toxicity are not available: 8 patients died within 6 months from the end of reirradiation, 3 patients had an early disease progression and were submitted to palliative chemotherapy, and 3 patients were alive at the time of the analysis but were followed by other physicians.

Three patients died of a blowout of the carotid artery. One patient with a carotid hemorrhage underwent surgery both before reirradiation and before the first course of radiotherapy (lifetime dose of radiation 120 Gy). One patient was treated at presentation with postoperative radiotherapy and with concurrent radiochemotherapy at time of recurrence (lifetime dose of radiation 126 Gy). One patient aged 80 years at time of reirradiation received exclusive radiotherapy for both the first radiotherapy course and reirradiation (lifetime dose of radiation 120 Gy).

One patient died 7 months after the end of reirradiation with concurrent chemotherapy for a soft tissue necrosis in the oropharynx that probably brought on a carotid hemorrhage (lifetime dose of radiation 140 Gy).

One patient had a carotid stent after a transitory ischemic attack (classified as grade 3 injury to carotid artery) 4 months after SBRT treatment for a oropharynx recurrence; at the beginning, he was treated with postoperative concurrent chemoradiation.

One patient died 5 months after the end of palliative hypofractionated (30 Gy in 10 fractions) reirradiation for a second primary tumor of the oropharynx staged T2N3; the death was probably due to a thrombosis of the left jugular venous system, although the response after treatment was not assessable.


Patients with recurrent and second primary HNC have limited salvage options. For resectable disease, surgery has represented the standard of care; however, no randomized trials have been performed to compare surgery and reirradiation in this subset of patients.

Currently, there are no randomized trials that define the optimal approach and evidence concerning the role of reirradiation as a valuable option in these patients comes mainly from retrospective and phase II trials (12-13-14-15-16-17-18-19-20-21). Our study reports data of a large retrospective series with 1-year and 2-year survival rates comparable to or higher than those described in the literature. In 2007, long-term outcomes of RTOG 99-11 were reported by Langer et al (16). This was a prospective phase 2 trial on reirradiation with twice-daily radiotherapy plus chemotherapy with cisplatin and paclitaxel; 99 patients were enrolled, and the 1-year OS and PFS rates were 50.2% and 35%, respectively. In 2008, Spencer et al (18) reported a 1-year OS rate of 41.7% in another large phase 2 trial in which 81 patients were treated with twice-daily radiotherapy plus chemotherapy with hydroxyurea and 5-fluorouracil. Other prospective studies among smaller cohorts of patients evaluated the role of normo-fractionated radiotherapy (13, 14, 17) and SBRT (12, 15), with similar survival outcomes. None of these prospective and retrospective studies analyzes at the same time all the variables used for univariate and multivariate analyses in our series. A critical review of the published data shows that the selection of patients represents a crucial aspect in reirradiation; patients with significant medical comorbidities, poor performance status, or severe sequelae from prior radiation have typically been demonstrated to be poor candidates for reirradiation. The retrospective nature of this analysis did not allow us to report the features of patients who were excluded from reirradiation: the decision to treat or not to treat a patient was made by a multidisciplinary team at each institution and patients who did not undergo radiotherapy were treated with other single modality (surgery or chemotherapy) or addressed to supportive care. However, an analysis of our patients’ characteristics at the time of preretreatment clinical evaluation shows that no severe late dysphagia or dry mouth due to previous radiotherapy course was detected, and just 2 patients had a G3 soft tissue fibrosis: a selection of patients, based on late sequelae of the first radiotherapy treatment, has surely been done. In our analysis, KPS at time of reirradiation was an independent predictive variable for both OS and CSS. Tanvetyanon et al (26) published a paper that demonstrated the role of comorbidity and preexisting organ dysfunction as important prognostic factors for patients undergoing reirradiation. Looking at our results, we can draw similar conclusions, with poor OS and CSS rates in patients with a Charlson Index higher than 2 (2 or more major comorbidities). However, these findings have not been confirmed at multivariate analysis.

The optimum dose and fractionation schedule for recurrent HNC is currently under investigation.

In 2009, Heron et al (27) performed a dose-escalation phase I trial on 25 patients treated with SBRT in 5 dose tiers up to 44 Gy in 5 fractions. However, the goal of the study was to evaluate the safety and acute tolerability, and no conclusions were drawn on the efficacy of the higher dose regimen among the others. The same authors reported a retrospective analysis (28) on 96 patients showing that patients receiving more than 40 Gy in 5 fractions (BED equal to 72 Gy) had significantly higher LC compared with those receiving 36 Gy or lower. To our knowledge, no other studies of dose escalation have been published on patients reirradiated for a recurrence or a second primary head and neck tumor (and particularly on those treated with conventional techniques). In our series, with all the limitations due to the conversion of a SBRT high dose per fraction into a BED, an increasing BED seems to positively influence survival outcomes. In fact, even if the log-rank test on BED <72 Gy versus ≥72 Gy reached significance only for CSS, better rates with a BED ≥72 Gy were seen also for LC, PFS, and OS, and a larger sample of patients could possibly enhance these findings.

Ozyigit et al (29) reported a series of 51 patients treated for nasopharyngeal cancer with either SBRT or conventional radiotherapy. Our findings are similar to ones reported by these authors, with no benefit in terms of survival outcomes between patients treated with conventional and stereotactic techniques. To our knowledge, there are no other data in the literature that compare high dose per fraction SBRT with other EBRT techniques. It is important to note that in our non-SBRT population, we collected data of different techniques, including both less and more sophisticated ones: however, the patient sample for each single technique did not allow us to make a direct comparison between SBRT and standard fractionation therapy delivered with highly conformed techniques, such as tomotherapy, and further investigations are needed.

Treatment volume at time of reirradiation has been reported in few articles in the literature as a predictive variable of survival. Still, as shown in 2 recent reviews by Chen et al (30) and Cacicedo et al (31), the best volume cutoff has not yet been established. In fact, while De Crevoisier et al (21) used a treatment volume cutoff of 650 cm3, other authors (14, 30, 32) reported a cutoff of 25-27 cm3. For this reason, we decided to start our analysis without using a cutoff volume and we stratified patients in quartiles. This analysis allowed us to find a threshold at the 75th percentile (221 cm3), which correlates with LC and PFS outcomes.

Only 20% of our patients have been treated with concomitant chemotherapy and no conclusive statements can be done on the influence of concurrent chemotherapy on survival.

Our results on acute and late toxicities are similar to those reported in previous published experiences. As reported in the literature, the adverse event most feared in patients treated with reirradiation is the carotid blowout (33-34-35). In our experience, 3 patients (4%) died of a fatal hemorrhage and the overall rate of treatment-related death, which ranged in previous published series between 2.9% and 15.6% (16, 18, 19-20-21), was 6.7%. McDonald et al (33) report both surgery and chemotherapy as factors that may contribute to a carotid blowout: 4/6 patients who died of toxicity in our series had been treated with a more intensified multidisciplinary approach, including surgery and chemoradiation.

This study confirms the role and the outcomes of reirradiation in patients with a recurrence or a second primary HNC. A careful selection of patients could minimize acute and late side effects and probably influence survival: KPS, comorbidities, and type and number of previous interventions are major criteria that need to be taken into account. Fatal events seem to correlate more with treatments received before reirradiation than with dose fractionation or technology adopted: patients should be informed in detail of increased potential of side effects. Further studies are needed to establish the role of concurrent chemotherapy and the fractionation schedule and total dose delivered with reirradiation that could achieve better local control and safer toxicity profile. The PTV (and therefore, probably, recurrent/second primary tumor volume) is confirmed as an important variable that could predict LC and PFS.


Financial support: None.
Conflict of interest: None.
  • 1. Pignon JP.,Bourhis J.,Domenge C.,Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355: 949-955 Google Scholar
  • 2. Eskander A.,Merdad M.,Irish JC. Volume-outcome associations in head and neck cancer treatment: a systematic review and meta-analysis. Head Neck 2014; 36: 1820-1834 Google Scholar
  • 3. Garden AS.,Kies MS.,Morrison WH. Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century. Radiat Oncol 2013; 8: 21- Google Scholar
  • 4. Bernier J.,Domenge C.,Ozsahin M. European Organization for Research and Treatment of Cancer Trial 22931. N Engl J Med 2004; 350: 1945-1952 Google Scholar
  • 5. Jones AS.,Bin Hanafi Z.,Nadapalan V.,Roland NJ.,Kinsella A.,Helliwell TR. Do positive resection margins after ablative surgery for head and neck cancer adversely affect prognosis? A study of 352 patients with recurrent carcinoma following radiotherapy treated by salvage surgery. Br J Cancer 1996; 74: 128-132 Google Scholar
  • 6. Ridge JA. Squamous cancer of the head and neck: surgical treatment of local and regional recurrence. Semin Oncol 1993; 20: 419-429 Google Scholar
  • 7. Goodwin WJ. 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 Google Scholar
  • 8. Wong LY.,Wei WI.,Lam LK.,Yuen AP. Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 2003; 25: 953-959 Google Scholar
  • 9. Agra IM.,Carvalho AL.,Ulbrich FS. Prognostic factors in salvage surgery for recurrent oral and oropharyngeal cancer. Head Neck 2006; 28: 107-113 Google Scholar
  • 10. Forastiere AA.,Metch B.,Schuller DE. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245-1251 Google Scholar
  • 11. Gibson MK.,Li Y.,Murphy B. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005; 23: 3562-3567 Google Scholar
  • 12. Lartigau EF.,Tresch E.,Thariat J. Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer. Radiother Oncol 2013; 109: 281-285 Google Scholar
  • 13. Balermpas P.,Keller C.,Hambek M. Reirradiation with cetuximab in locoregional recurrent and inoperable squamous cell carcinoma of the head and neck: feasibility and first efficacy results. Int J Radiat Oncol Biol Phys 2012; 83: - Google Scholar
  • 14. Chen AM.,Farwell DG.,Luu Q.,Cheng S.,Donald PJ.,Purdy JA. Prospective trial of high-dose reirradiation using daily image guidance with intensity-modulated radiotherapy for recurrent and second primary head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011; 80: 669-676 Google Scholar
  • 15. Comet B.,Kramar A.,Faivre-Pierret M. Salvage stereotactic reirradiation with or without cetuximab for locally recurrent head-and-neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2012; 84: 203-209 Google Scholar
  • 16. Langer CJ.,Harris J.,Horwitz EM. 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; 25: 4800-4805 Google Scholar
  • 17. Langendijk JA.,Kasperts N.,Leemans CR.,Doornaert P.,Slotman BJ. A phase II study of primary reirradiation in squamous cell carcinoma of head and neck. Radiother Oncol 2006; 78: 306-312 Google Scholar
  • 18. Spencer SA.,Harris J.,Wheeler RH. Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck 2008; 30: 281-288 Google Scholar
  • 19. Duprez F.,Madani I.,Bonte K. Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory. Radiother Oncol 2009; 93: 563-569 Google Scholar
  • 20. Salama JK.,Vokes EE.,Chmura SJ. 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: 382-391 Google Scholar
  • 21. De Crevoisier R.,Bourhis J.,Domenge C. Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 1998; 16: 3556-3562 Google Scholar
  • 22. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 2009 May. ; : - Google Scholar
  • 23. Karnofsky Performance Status Scale definitions rating (%) criteria. ; : - Google Scholar
  • 24. Charlson ME.,Pompei P.,Ales KL.,MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-383 Google Scholar
  • 25. Singh B.,Bhaya M.,Stern J. Validation of the Charlson Comorbidity Index in patients with head and neck cancer: a multi-institutional study. Laryngoscope 1997; 107: 1469-1475 Google Scholar
  • 26. Tanvetyanon T.,Padhya T.,McCaffrey J. Prognostic factors for survival after salvage reirradiation of head and neck cancer. J Clin Oncol 2009; 27: 1983-1991 Google Scholar
  • 27. Heron DE.,Ferris RL.,Karamouzis M. Stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: results of a phase I dose-escalation trial. Int J Radiat Oncol Biol Phys 2009; 75: 1493-1500 Google Scholar
  • 28. Rwigema JC.,Heron DE.,Ferris RL. The impact of tumor volume and radiotherapy dose on outcome in previously irradiated recurrent squamous cell carcinoma of the head and neck treated with stereotactic body radiation therapy. Am J Clin Oncol 2011; 34: 372-379 Google Scholar
  • 29. Ozyigit G.,Cengiz M.,Yazici G. A retrospective comparison of robotic stereotactic body radiotherapy and three-dimensional conformal radiotherapy for the reirradiation of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011; 81: - Google Scholar
  • 30. Chen AM.,Phillips TL.,Lee NY. Practical considerations in the re-irradiation of recurrent and second primary head-and-neck cancer: who, why, how, and how much? Int J Radiat Oncol Biol Phys 2011; 81: 1211-1219 Google Scholar
  • 31. Cacicedo J.,Navarro A.,Alongi F. The role of re-irradiation of secondary and recurrent head and neck carcinomas. Cancer Treat Rev 2014; 40: 178-189 Google Scholar
  • 32. Vargo JA.,Heron DE.,Ferris RL. Examining tumor control and toxicity after stereotactic body radiotherapy in locally recurrent previously irradiated head and neck cancers: implications of treatment duration and tumor volume. Head Neck 2014; 36: 1349-1355 Google Scholar
  • 33. McDonald MW.,Moore MG.,Johnstone PA. Risk of carotid blowout after reirradiation of the head and neck: a systematic review. Int J Radiat Oncol Biol Phys 2012; 82: 1083-1089 Google Scholar
  • 34. Yamazaki H.,Ogita M.,Kodani N. Frequency, outcome and prognostic factors of carotid blowout syndrome after hypofractionated re-irradiation of head and neck cancer using CyberKnife: a multi-institutional study. Radiother Oncol 2013; 107: 305-309 Google Scholar
  • 35. Yazici G.,Sanlı TY.,Cengiz M. A simple strategy to decrease fatal carotid blowout syndrome after stereotactic body reirradiaton for recurrent head and neck cancers. Radiat Oncol 2013; 8: 242- Google Scholar



  • Radiation Oncology Department, University and Spedali Civili, Brescia - Italy
  • Radiation Oncology Department, Azienda Ospedaliero-Universitaria di Modena Policlinico, Modena - Italy
  • Radiation Oncology Department, Azienda Ospedaliero-Universitaria Careggi, Firenze - Italy
  • Medical Physics Department, Spedali Civili di Brescia, Brescia - Italy

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