ORIGINAL ARTICLE

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

John A. Vargo, MD,1 Dwight E. Heron, MD,1,2* Robert L. Ferris, MD, PhD,1,2 Jean-Claude M. Rwigema, MD,1 Ronny Kalash, BS,1
Rodeny E. Wegner, MD,1 James Ohr, DO,3 Steven Burton, MD1

1
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, 2Division of Head and Neck Surgery, Department of Otolaryngology, Univer-
sity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, 3Division of Medical Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania.

Accepted 13 August 2013

Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23462

ABSTRACT: Background. Stereotactic body radiotherapy (SBRT) has
been studied in locally recurrent previously-irradiated head and neck
cancers; however, the optimum fractionation and patient selection con-
tinues to be defined.
Methods. Patients (n 5 132) with locally recurrent head and neck cancer
salvaged via SBRT 6 cetuximab (median, 44 Gy/5 fractions) from
November 2004 to May 2011 were retrospectively reviewed. Disease
outcomes and toxicity were analyzed by predictive factors including
(p 5 .029). Tumor volume >25 cc remained a significant predictor
of inferior survival and tumor control, and was associated with
significantly more acute toxicity (p 5 .017) but no difference in late
toxicity.
Conclusion. SBRT 6 cetuximab achieves promising tumor control and
survival with low rates of acute/late toxicity even for recurrences >25
cc. Prolongations in treatment time may decrease late toxicity at the
expense of disease control. VC 2013 Wiley Periodicals, Inc. Head Neck

treatment duration and tumor volume. 00: 000–000, 2014

Results. At a median 6-month follow-up (range, 0–55 months),
KEY WORDS: stereotactic body radiation therapy (SBRT), reirradia-
treatment duration <14 days was associated with significantly improved
tion head and neck, cetuximab, treatment time, tumor volume
recurrence-free survival (RFS) at the expense of increased late toxicity

INTRODUCTION remains unknown (single fraction vs daily vs alternating

In 2012, an estimated 11,500 deaths were attributed to
head and neck cancer in the United States, with locore-
gional recurrence representing the primary mode of fail-
ure in head and neck cancers (locoregional recurrence
rates approaching 20% to 50%) placing increasing impor-
tance on salvage therapy for recurrent head and neck can-
cer.1,2 Salvage surgery remains the standard, however,
many patients present with unresectable recurrences, and
reirradiation 6 chemotherapy represents the only curative
salvage option.3 We, as well as others, have studied ste-
reotactic body radiotherapy (SBRT) 6 cetuximab as a
promising reirradiation strategy for unresectable, locally
recurrent head and neck cancers.4–10
Although multiple clinical studies have documented the
tumor control, survival, and toxicity benefits for SBRT 6
cetuximab, the optimum duration for SBRT fractionation
*Corresponding author: D. E. Heron, University of Pittsburgh Medical Center
Cancer Pavilion, 5150 Centre Ave, Pittsburgh, PA 15232.
E-mail: herond2@umpc.edu
This work was presented in abstract form at the 54th Annual Meeting of
American Society for Radiation Oncology, Boston, Massachusetts, October
27–31, 2012.
days). Our phase I dose-escalation trial suggested the
safety of fractionated regiments administered in alternat-
ing days over 1 to 2 weeks without meeting the maxi-
mum tolerated dose in excess of 44 Gy in 5 fractions.11
The importance of treatment time on disease outcomes in
conventional radiotherapy for head and neck cancers is
well documented based on established radiobiologic tene-
ments, in which prolongation in treatment duration nega-
tively impacts disease control secondary to concepts of
accelerated repopulation.12,13 The high-dose per-fraction
technique of SBRT affords the delivery of high biological
doses to increasingly conformal tumor volumes, which
may improve outcomes for locally recurrent head and
neck cancer; however, shorter treatment duration may not
allow for maximal normal tissue repair of sublethal dam-
age, thus increasing toxicity and accounting for discrepan-
cies in the SBRT literature for incidences of toxicity.
Furthermore, tumor volume >25 cc has been estab-
lished in prior series from the University of Pittsburgh as
a strong predictor of locoregional recurrence and overall
response after SBRT.14,15 The impact of tumor volume on
toxicity after SBRT remains undocumented; theoretically,
larger tumors increase the volume of tissue at risk for
radiation-related toxicity. Additionally, larger treatment

HEAD & NECK—DOI 10.1002/HED MONTH 2014 1

VARGO ET AL.

TABLE 1. Baseline patient characteristics stratified by treatment duration (14 days) and tumor volume (25 cc).

All patients TD <14 days TD 14 days TV 25 cc TV >25 cc

Baseline characteristics (n 5 132) (n 5 110) (n 5 22) TD p value (n 5 58) (n 5 67) TV p value

Concurrent cetuximab .306 .135

SBRT 1 cetuximab 72 (55%) 62 (57%) 10 (45%) 27 (47%) 39 (53%)
SBRT alone 58 (45%) 46 (43%) 12 (54%) 31 (53%) 26 (47%)
Age, y, median (range) 66 (32–90) 65 (32–90) 69 (54–90) 1.0 68 (32–90) 65 (34–90) .173
Sex .276 .710
Male 91 (69%) 78 (71%) 13 (59%) 38 (65%) 46 (71%)
Female 41 (31%) 32 (29%) 9 (41%) 20 (34%) 21 (29%)
Primary site .931 .345
Larynx 34 (26%) 28 (26%) 6 (27%) 13 (22%) 18 (29%)
Nasopharynx 9 (7%) 8 (7%) 1 (5%) 3 (5%) 6 (8%)
Oropharynx 27 (21%) 21 (19%) 6 (27%) 15 (26%) 10 (17%)
Oral cavity 34 (26%) 30 (27%) 4 (18%) 10 (17%) 22 (31%)
Salivary gland/paranasal sinus 21 (16%) 17 (15%) 4 (18%) 13 (22%) 8 (11%)
Other/unknown 7 (5%) 6 (5%) 1 (5%) 4 (7%) 3 (4%)
TV, cm3, median (range) 30.9 (4.4–192.4) 28.8 (4.4–170.7) 30 (9.7–192.4) .685 – – –
TD, d, median (range) 9 (7–38) – – – 9 (8–38) 9 (7–20) .685
Baseline KPS 80 (50–100) 80 (50–100) 80 (60–100) .652 90 (50–100) 80 (70–100) .872
Site of recurrence .410 .259
Recurrent/primary tumor 105 (80%) 88 (81%) 17 (77%) 49 (86%) 53 (79%)
Lymph node 21 (16%) 18 (16%) 3 (14%) 8 (14%) 13 (19%)
Nodal 1 primary 5 (4%) 3 (3%) 2 (9%) 0 1 (2%)
HPV positive (n 5 9) 6 4 2 .285 4 1 .217
DM before SBRT (palliative) 27 (23%) 21 (21%) 6 (31%) .315 10 (19%) 15 (24%) .492
Reirradiation interval (2 y) 75 (58%) 63 (57%) 13 (59%) .875 37 (64%) 36 (54%) .257
Prior radiotherapy dose (60 Gy) 104 (79%) 88 (80%) 16 (72%) .480 45 (78%) 55 (82%) .263

Abbreviations: TD, treatment duration; TV, tumor volume; SBRT, stereotactic body radiation therapy; KPS, Karnofsky Performance Scale; HPV, human papillomavirus; DM, distant metastases.

volume may correlate with increased toxicity, especially
for shorter treatment durations that potentially reduce
maximum vascular reperfusion/repair. Thus, herein we
attempt to examine the impact of treatment duration and
tumor volume on toxicity and treatment outcomes after
SBRT for locally recurrent head and neck cancer. To our
knowledge, this represents the first study in the SBRT
locally recurrent head and neck cancer literature to
address treatment time and tumor volume as a function of
toxicity and treatment outcome.
MATERIALS AND METHODS
With approval from our institutional review board (IRB
0406113), all patients completing SBRT for locally recur-
rent head and neck cancer from November 2004 to May
2011 at the University of Pittsburgh Cancer Institute were
retrospectively reviewed. All of our study patients had
locally recurrent or second primary tumors in a previ-
ously-irradiated field, had disease that was deemed unre-
sectable or medically-inoperable by a multidisciplinary
head and neck tumor board, had Karnofsky performance
status (KPS) >50, and signed written informed consent.
SBRT consisted primarily of 44 to 50 Gy in 5 fractions
(median, 44 Gy in 5 fractions; range, 35–50 Gy), for a
median biologic effective dose (BED) of 173.1 Gy for
normal tissue/late toxicity (assumed a/b of 3 Gy) and
82.7 Gy for tumor/acute toxicity (assumed a/b of 10 Gy).
Patients receiving <35 Gy early in our dose-escalation
experience were excluded. SBRT was delivered via either
Trilogy Intensity-Modulated Radiosurgery (Varian Medi-
cal Systems, Palo Alto, CA) or CyberKnife Precision
Radiation Delivery System (Accuracy, Sunnyvale, CA) on
an outpatient basis in 30-minute to 120-minute time slots
on alternating days (excluding weekends and holidays)
over 1 to 2 weeks (thus completing 5 fraction regiment in
7–14 days without interruptions). SBRT techniques for
target delineation, patient setup, and treatment/delivery
were previously described.4,11
Building on promising single-institution data, SBRT
was combined with concurrent cetuximab administered at
400 mg/m2 on day -7 then 250 mg/m2 on day 0 and 18
in select patients (n 5 72).5,16 Beginning in 2003, patients
were considered for concurrent cetuximab based on a
combination of prior therapy, histology, and physician
preferences. More recently, enrollment in ongoing pro-
spective phase II study SBRT 1 concurrent cetuximab
(University of Pittsburgh Cancer Institute 06-093, results
not yet reported) has been encouraged to better define
potential benefits, if any, of cetuximab 1 SBRT.
Although concurrent cetuximab included a loading dose,
induction chemotherapy was not administered before
SBRT, and no changes in treatment volumes were made
based on cetuximab loading. Acute (<90 days) and late
(>90 days) treatment-related toxicities were recorded
above baseline with the National Cancer Institute Com-
mon Toxicity Criteria Events Scale version 3.0.
Local recurrence was defined as progression of disease
in any extracranial head and neck site or regional lymph
nodes in accord with the modified Response Evaluation
Criteria in Solid Tumors criteria. Overall survival (OS),
recurrence-free survival (RFS), locoregional control, and
distant control were estimated using the Kaplan–Meier
method with comparisons between groups dichotomized

2 HEAD & NECK—DOI 10.1002/HED MONTH 2014

 TREATMENT DURATION IN REIRRADIATION HEAD AND NECK CANCERS

FIGURE 1. Kaplan–Meier actuarial overall survival (A), recurrence-free survival (B), locoregional control (C), and distant control (D) for all patients.

by tumor volume (25 cc), treatment duration (14
days), sex, Karnofsky performance status (KPS 70), age
(60), human papillomavirus (HPV) status (where avail-
able), primary site, intent (definitive vs palliative) treat-
ment site, reirradiation interval (2 years), and prior
radiotherapy dose (60 Gy) completed using the log-rank
t test. Tumor volume 25 cc and reirradiation interval
(2 years) represent previously defined predictors of clin-
ical outcomes after SBRT; whereas treatment duration
14 days was chosen as a cutoff as, ideally, without
treatment delays SBRT should be completed within 14
days.8,14,15 Factors significant on univariate analysis were
subsequently included in a multivariate model using step-
wise Cox multivariate analysis. Comparison between
groups for toxicity outcomes were completed using
linear-by-linear chi-square test. All statistical analysis was
carried out using SPSS version 19.0 (SPSS, Chicago, IL)
with a p < .05 considered statistically significant.
RESULTS
Baseline patient characteristics and clinical outcomes
for included patients (n 5 132) are summarized in Table

TABLE 2. Univariate analysis for predictive factors for survival and tumor control.

Univariate analysis 1-y OS 1-y RFS 1-y Locoregional control 1-y Distant control

TV, 25 cc 57% vs 20% 42% vs 22% 51% vs 34% 67% vs 49%
p < .0001 p 5 .045 p 5 .054 p 5 .153
TD, 14 d 32% vs 39% 8% vs 37% 16% vs 47% 47% vs 62%
p 5 .047 p 5 .041 p 5 .169 p 5 .235
Sex, male vs female 35% vs 45% 30% vs 31% 37% vs 50% 54% vs 64%
p 5 .299 p 5 .944 p 5 .390 p 5 .950
Age, 60 y 32% vs 37% 18% vs 36% 25% vs 56% 49% vs 62%
p 5 .986 p 5 .121 p 5 .139 p 5 .575
KPS, 70 39% vs 51% 38% vs 34% 54% vs 50% 55% vs 69%
p 5 .395 p 5 .432 p 5 .308 p 5 .884
HPV positive 53% vs 67% 0% vs 33% 0% vs 33% 40% vs 100%
p 5 .532 p 5 .431 p 5 .611 p 5 .184
Primary site p 5 .028 p 5 .465 p 5 .435 p 5 .881
Larynx 20% 46% 64% 63%
Nasopharynx 17% 0% 0% 32%
Oropharynx 34% 12% 21% 49%
Oral cavity 38% 43% 46% 63%
Nasal cavity/paranasal sinus 60% 21% 46% 60%
Salivary gland 75% 33% 38% 73%
Other 23% 57% 86% 38%
Treatment site p 5 .946 p 5 .980 p 5 .741 p 5 .879
Primary 38% 35% 48% 56%
Nodal 32% 10% 13% 64%
Primary 1 nodal 40% 0% 0% 67%
Intent, definitive vs palliative 43% vs 27% 35% vs 9% 49% vs 11% 66% vs 30%
p 5 .209 p 5 .003 p 5 .016 p < .001
Reirradiation interval, 2 y 38% vs 33% 45% vs 15% 66% vs 22% 66% vs 48%
p 5 .060 p 5 .002 p 5 .002 p 5 .028
Prior radiation dose, 60 Gy 32% vs 58% 33% vs 38% 45% vs 50% 61% vs 46%
p 5 .151 p 5 .338 p 5 .565 p 5 .944

Abbreviations: OS, overall survival; RFS, recurrence-free survival; TV, total volume; TD, treatment duration; KPS, Karnofsky Performance Scale; HPV, human papillomavirus.

HEAD & NECK—DOI 10.1002/HED MONTH 2014 3

VARGO ET AL.

TABLE 3. Multivariate analysis for predictive factors for survival and TABLE 4. Cumulative acute and late toxicity after stereotactic body
tumor control. radiation therapy.

Variables HR (95% CI) p value Acute <90 d Late >90 d

Adverse event (n 5 132) (n 5 90)
OS
TV 25 cc 2.37 (1.51–3.71) <.0001 Patients with no toxicity 39 (30%) 50 (56%)
Primary site 0.84 (0.74–0.95) .004 Patients with grade 3 toxicity 16 (12%) 6 (7%)
RFS Incidence of grade 3 toxicity events 19 (14%) 6 (7%)
TD <14 d 2.19 (1.91–4.03) .012 Xerostomia
Reirradiation interval <2 y 0.43 (0.26–0.71) .001 Grade 1 15 (11%) 7 (8%)
Definitive intent 2.13 (1.23–3.68) .007 Grade 2 2 (2%) 3 (3%)
Distant control Grade 3 3 (2%) –
Reirradiation interval <2 y 0.45 (0.22–0.93) .032 Dysgeusia
Definitive intent 3.64 (1.78–7.42) <.0001 Grade 1 8 (6%) 3 (3%)
Locoregional control Grade 2 5 (4%) 3 (3%)
Reirradiation interval <2 y 0.38 (0.21–0.70) .002 Grade 3 2 (2%) –
Mucositis
Abbreviations: HR, hazard ratio; CI, confidence interval; OS, overall survival; TV, tumor vol-
Grade 1 18 (14%) 3 (3%)
ume; RFS, recurrence-free survival; TD, treatment duration. Grade 2 18 (14%) 3 (3%)
Grade 3 3 (2%) –
Grade 4 1 (1%) –
Edema
1. Briefly, the median treatment duration was 9 days Grade 1 4 (3%) –
(range, 7–38 days) and tumor volume was 30.9 cc (range, Grade 2 1 (1%) 1 (1%)
4.4–192.4 cc). Of patients with treatment duration 14 Dysphagia
days (n 5 22), 86% had prolongation <1 week, with Grade 1 10 (8%) 3 (3%)
14% (n 5 3) representing outliers with treatment times Grade 2 6 (5%) 4 (4%)
ranging from 24 to 38 elapsed days. The median patient Grade 3 1 (1%) 2 (2%)
age at the time of reirradiation was 66 years, with 31% of Grade 4 2 (2%) –
Pain
them women. The median prior dose of conventional
Grade 1 4 (3%) 4 (4%)
radiotherapy was 68 Gy (range, 20.4–140 Gy) at a reirra- Grade 2 4 (3%) 3 (3%)
diation interval of 23 months (range, 2–423 months); with Grade 3 1 (1%) 1 (1%)
59% receiving prior chemotherapy and 70% with prior Fatigue
surgery. Also, included were 27 patients (20%) with Grade 1 5 (4%) 3 (3%)
tumors of the salivary glands, sinuses, or thyroid, which Grade 2 – 2 (2%)
were mostly of nonsquamous histology; however, our pre- Grade 3 2 (2%) –
vious report documented similar clinical outcomes for Skin
nonsquamous recurrences after SBRT.15 SBRT was Grade 1 15 (11%) 5 (6%)
directed to recurrent/primary tumor sites in 80% (n 5 Grade 2 8 (6%) 3 (3%)
Grade 3 3 (2%) 2 (2%)
105), nodal recurrence in 16% (n 5 21), and synchronous
Grade 4 1 (1%) –
nodal/primary recurrence in 4% (n 5 5). Osteonecrosis
At a median follow-up of 6 months (range, 0–55 Grade 3 – 1 (1%)
months), the median OS or time to last follow-up was 7
months (range, 1–60 months) with crude rates of locore-
gional control and distant control of 56% and 62%,
respectively. The 6-month/1-year actuarial OS, RFS, of significance. Similarly tumor volume 25 cc and treat-
locoregional control, and distant control for the entire ment duration <14 days predicted for improved RFS on
cohort were 70% and 38%, 54% and 31%, 68% and 48%, univariate analysis; however, on multivariate analysis,
and 72% and 59%, respectively (Figure 1). Twenty-seven only treatment duration <14 days (p 5 .012; HR, 2.19;
patients had distant failure before SBRT and were thus 95% CI, 1.91–34.03), reirradiation interval, and definitive
treated with palliative versus definitive intent. Defini- intent remained significant. Other than improved locore-
tively treated patients showed superior locoregional con- gional control with tumor volume 25 cc (p 5 .05), reir-
trol (1-year locoregional control, 49% vs 11%; p 5 .016), radiation interval 2 years, and superior locoregional
distant control (66 vs 30%; p < .001), and RFS (35 vs control and distant control with definitive versus pallia-
9%, p 5 0.003); with no significant difference in OS tive intent, there were no other significant predictors for
observed comparing palliative vs definitive intent (1-year locoregional control or distant control on univariate anal-
OS, 43% vs 27%; p 5 .209). Results for univariate and ysis. On multivariate analysis only, reirradiation interval
multivariate analysis are highlighted in Tables 2 and 3. <2 years remained a significant predictor for inferior
Predictors on univariate analysis for improved OS were locoregional control and distant control.
primary site, tumor volume 25 cc, and treatment dura- Overall, toxicity rates were low with only 12% and 7%
tion <14 days; on multivariate analysis, tumor volume of patients experiencing severe (grade 3), acute, and
25 cc (p < .001; hazard ratio [HR] 5 2.37; 95% confi- late toxicity, with the majority of toxicity relating to
dence interval [CI], 1.51–3.71) and primary site remained mucosal and skin reactions (Table 4). No significant dif-
significant with treatment duration <14 days falling out ferences in toxicity were observed by sex, age, HPV

4 HEAD & NECK—DOI 10.1002/HED MONTH 2014


FIGURE 2. The impact of tumor volume (TV) >25 cc on acute (<90 days) and late (>90 days) toxicity after stereotactic body radiation therapy
(SBRT). G, grade.
status, primary site, site of recurrence, KPS, reirradiation
interval (2 years), or prior radiotherapy dose (60 Gy).
Similar to our prior experience, tumor volume >25 cc
was associated with significantly more acute toxicity
(crude rates of any toxicity, 75% vs 66%; grade 3 toxic-
ity, 16% vs 7%; p 5 .017), with no difference in late tox-
icity by tumor volume (Figure 2). Conversely, whereas
the majority of patients experienced little to no toxicity
irrespective of treatment duration, treatment duration <14
days was associated with significantly more toxicity
(crude rates of any toxicity, 48% vs 27%, grade 3 late
toxicity, 8% vs 0%; p 5 .029), with no difference in
acute toxicity by treatment duration (Figure 3). Rates of
acute toxicity were significantly increased with addition
of cetuximab (grade 3 toxicity, 13% vs 10%; p 5 .008),
however, there were no differences in late toxicity by
cetuximab. Of the 2 patients (2%) who experienced
severe grade 3 late dysphagia, both had recurrences
involving the larynx and received maximum point doses
to pharyngeal constrictors/esophagus of 50.3/48 Gy and
47.9/1.3 Gy during SBRT, respectively.
FIGURE 3. The impact of treatment duration (TD) 14 days on acute (<90 days) and late (>90 days) toxicity after stereotactic body radiation ther-
apy (SBRT). G, grade.
TREATMENT DURATION IN REIRRADIATION HEAD AND NECK CANCERS
DISCUSSION
A growing body of literature has suggested a role for
SBRT 6 cetuximab for unresectable locally recurrent pre-
viously irradiated head and neck cancer.4–11 However, the
optimum fractionation schema has yet to be defined; with
daily fractionated regiments delivered over 5 elapsed days
versus alternating day fractionation typically delivered
over 7 to 14 days. In the SBRT literature, there exists a
wide variation of reported severe toxicity ranging from
0% to 20% with the majority of institutions reporting
higher rates of toxicity incorporating shorter daily versus
every other day fractionation (Table 5). As seen in Table
5, the 2 series by Kodani et al8 and Roh et al9 in the
SBRT literature using daily fractionation in doses over 5
Gy per fraction report significant soft tissue complications
with late toxicities grade 41 10% to 18%, which is in
stark contrast to those using every other day fractionation
with late grade 41 toxicity 0% to 9%. We believe this
may represent one of the main causes for the lack of
major soft tissue complications, which, as highlighted in
HEAD & NECK—DOI 10.1002/HED MONTH 2014 5
VARGO ET AL.

TABLE 5. Summary of toxicity by fractionation and dose after stereotactic body radiation therapy for recurrent head and neck cancer.

Study No. of patients Dose range Fractions range TV (cc) Interfraction time Acute grade 4 Late grade 4
5
Comet et al 40 36 6 64.1 QOD 0% 0%
Siddiqui et al6 44 14–18 or 36–48 1 or 6–8 15.5 QOD 4.5% 4.5%*
Heron et al11 31 25–44 5 44.8 QOD 0% 0%
Rwigema et al4 85 15–44 1–5 25.1 QOD 0% 0%
Unger et al7 65 21–35 2–5 75 QOD 0% 9%
Kodani et al8 34 19.5–42 3–8 11.6 QD 0% 17.6%
Roh et al9 36 18–40 3–5 22.6 QD 0% 9.7%
Cengiz et al10 46 18–35 1–5 45 – 0% 17.3%

Abbreviations: TV, tumor volume; QOD, every other day; QD, daily.
* of the 2 patients experiencing severe late toxicity, 1 received 18Gy in single fraction.

this report, is virtually absent from our experience,
despite significantly higher doses in our experience.
Although no accurate formula for the biological effec-
tive dose for the high dose per fraction techniques inher-
ent to SBRT is currently available, using the linear-
quadratic BED formula, the acute and late responding tis-
sue BED for 44 Gy in 5 fractions is 82.7 Gy and 173.1
Gy, respectively. Conventionally, increases in treatment
time have been associated with decreased biological
equivalent dose when accounting for prolongations in
treatment time, potentially decreasing tumor control with
the benefit of reduced acute toxicity.17 The data presented
here suggest lower late toxicity with extended treatment
duration at the expense of potential tumor control and
survival. These results mirror previously reported results
from a phase II study from Stanford University for SBRT
in localized prostate cancer in which the rates of late rec-
tal toxicity were significantly decreased (rates of any rec-
tal problems every other day 0% vs daily 38%; p 5
.0035) by increasing the interfraction interval an every
other day (3 fractions per week) versus daily fractionation
(5 consecutive days) schema.18
The importance of tumor volume on tumor control and
toxicity after SBRT for other extracranial sites has been
well documented.19–22 Prior reports from our institution
have suggested superior tumor control/response for tumor
volume 25 cc with a dose-response model highlighting
the potential importance of dose escalation for larger recur-
rences.14,15 However, previous reports have failed to exam-
ine the impact of tumor volume on toxicity; theoretically,
increases in tumor volume may increase the normal tissue
at risk for radiation-related side effects. The data presented
here suggest that tumor volume and cetuximab predict for
increased acute toxicity but does not affect late toxicity;
and overall acute and late toxicity rates remain low irre-
spective of tumor volume and cetuximab. This supports the
finding that patients with larger tumor volumes may be can-
didates for SBRT with the recognition that dose escalation
6 cetuximab may be necessary to improve tumor control at
the expense of manageable increases in acute (predomi-
nately mucosal/skin) toxicity. Assessment of disease out-
comes is limited by heterogeneity of patient population and
retrospective nature, however, this analysis validates prior
findings of the importance of tumor volume 25 cc and
reirradiation interval (2 years) after SBRT in locally
recurrent head and neck cancer, which represent selective
factors for SBRT efficacy and recurrent disease biology.
The impact of treatment duration is a novel radiobiological
consideration in the SBRT literature with implications for
SBRT fractionation that should prompt further validation to
confirm findings presented herein.8,14,15
CONCLUSIONS
Evaluation of a large retrospective single institutional
series of SBRT 6 cetuximab for locally recurrent head
and neck cancer overall rates of acute and late toxicity
were low. Larger tumor volume and cetuximab accounted
for manageably increased acute toxicity (predominately
skin and mucosal) with no difference in late toxicity. Pro-
longed treatment duration 14 days (planned treatment
course time 7–14 days) accounted for less late toxicity, at
the expense of disease control. Further work should con-
sider implications of treatment duration, reirradiation
interval, and tumor volume as important factors in the
evaluation of SBRT 6 cetuximab as a salvage strategy.
Acknowledgments
We thank Karlotta Ashby for assistance in manuscript
preparation.
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