Postoperative intensity-modulated radiation therapy for cancers of ...

Postoperative intensity-modulated radiation therapy for cancers of ...






Bradford S. Hoppe, MD, 1 Suzanne L. Wolden, MD, 1 Michael J. Zelefsky, MD, 1

James G. Mechalakos, PhD, 2 Jatin P. Shah, MD, 3 Dennis H. Kraus, MD, 3 Nancy Lee, MD 1

1 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York,

New York 10021. E-mail:

2 Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York

3 Department of Head and Neck Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Accepted 9 November 2007

Published online 26 February 2008 in Wiley InterScience ( DOI: 10.1002/hed.20800

Abstract: Background. Our aim was to review Memorial

Sloan-Kettering Cancer Center’s experience with postoperative

intensity-modulated radiotherapy (IMRT) for paranasal sinus,

nasal cavity, and lacrimal gland cancer and report dosimetric

measures, toxicity, and outcomes.

Methods. Between September 2000 and June 2006, 37

patients with paranasal sinus, nasal cavity, or lacrimal gland

cancer underwent postoperative IMRT. Median values were as

follows: prescription dose, 60 Gy (range, 50–70); PTV D95 ,99%

(range, 79–101%); optic nerve Dmax, 53 Gy (range, 2–54); optic

chiasm Dmax, 51Gy (range, 2–55). Acute and late toxicities

were scored by Radiation Therapy Oncology Group morbidity


Results. Median follow-up was 28 months. Two-year local

progression–free and overall survivals were 75% and 80%. No

early- or late-grade 3/4 radiation-induced ophthalmologic toxicity


Correspondence to: N. Lee

Parts of this work were presented at the following conferences and

received awards: 2007 Multidisciplinary Head & Neck Cancer Symposium

Rancho Mirage, CA (ASTRO Travel Grant); 2007 New York Roentgen

Society Meeting (1st prize).

VC 2008 Wiley Periodicals, Inc.

Conclusions. Preliminary results show that adjuvant IMRT in

these patients is feasible, allowed for excellent planning target

volume (PTV) coverage, and minimized dose delivered to optic

structures. Longer follow-up is warranted to assess the extent of

late effects and outcomes. VC 2008 Wiley Periodicals, Inc.

Head Neck 30: 925–932, 2008

Keywords: IMRT; paranasal sinus; lacrimal gland; nasal cavity;


Complete surgical resection followed by postoperative

radiotherapy has the best overall outcome

with respect to overall survival and local control

in patients diagnosed with cancer of the paranasal

sinuses. 1–3 Unfortunately, the high dose of radiation

(60–70 Gy) required to prevent local relapses

often exceeds the optic structure tolerance (45–54

Gy). Studies using conventional radiotherapy

techniques for treating cancers of the paranasal

sinuses have reported severe radiation-induced

visual toxicity in up to 35% of patients with a median

time of 2 years to develop symptoms. 4–6

Postoperative IMRT for Cancers of the Paranasal Sinuses HEAD & NECK—DOI 10.1002/hed July 2008 925

Over the past 2 decades, radiotherapy techniques

have evolved from conventional to 3-dimensional

(3D) conformal radiotherapy (3D-CRT), to

intensity-modulated radiotherapy (IMRT) with

‘‘dose-painting.’’ These newer techniques have

allowed for improved dose distributions with

increased dose to the target volumes and reduced

dose to the surrounding normal tissues, when

compared with conventional treatment. Cancers

involving the paranasal sinuses are a group that

can benefit from these newer treatment modalities.


Our protocol at Memorial Sloan-Kettering

Cancer Center (MSKCC) for the last 7 years has

been to treat these patients with postoperative

IMRT with ‘‘dose painting.’’ In this study, we

report on a group of 37 consecutive patients who

underwent complete surgical resection followed

by IMRT with dose painting, focusing on technique,

preliminary toxicities, and outcomes.


Between November 1999 and June 2006, 151

patients with a diagnosis of paranasal sinus, nasal

cavity, or lacrimal gland cancer were evaluated in

the Department of Radiation Oncology. Patients

were excluded from the analysis if they had

received their radiation at another facility (n 5

39), had received definitive radiotherapy or chemoradiotherapy

only for stage 4b disease (n 5 29),

had been treated with 3D-CRT (n 5 7) or with an

IMRT boost (n 5 7), had a history of prior irradiation

for paranasal sinus cancer (n 5 5), or had melanoma,

which is currently treated on a hypofractionated

protocol (n 5 27). This analysis included

37 patients with tumors located close to the visual

pathways and who underwent surgical resection

followed by postoperative IMRT. Patient characteristics

are listed in Table 1. The median age was

55 years (range, 15–88) and the median Karnofsky

score was 90 (range, 70–100).

Table 1. Patient, tumor, and treatment characteristics.

No. (%)

Patient characteristics


Male 19 (51)


White 27 (73)

Asian 4 (11)

African American 4 (11)

Other 2 (5)

Tumor and treatment characteristics


Squamous cell carcinoma 17 (46)

Sarcoma 5 (14)

Adenoid cystic 4 (11)

Undifferentiated 3 (8)

Adenocarcinoma 3 (8)

Esthesioneuroblastoma 3 (8)

Myoepithelial 2 (5)


Maxillary sinus 20 (54)

Nasal cavity 10 (27)

Ethmoid sinus 4 (11)

Lacrimal gland 1 (3)

Sphenoid sinus 1 (3)

Frontal sinus 1 (3)

AJCC staging (excluding sarcomas), n 5 29

Tumor classification

Recurrent 3 (10)

T1 0 (0)

T2 5 (17)

T3 5 (17)

T4 16 (55)

Node classification

N0 26 (90)

N1 3 (10)

N2 0 (0)

Kadish (esthesioneuroblastoma), n 5 3

A 0 (0)

B 2 (66)

C 1 (33)


Maxillectomy (full/partial) 19 (51)

Craniofacial resection 8 (22)

Both 8 (22)

Other 2 (5)

Orbital exenteration 5 (14)

Surgical margins

Negative 27 (73)

Microscopically positive 10 (27)

Perineural invasion present 15 (41)

Chemotherapy 6 (16)

Evaluation and Staging. Pretreatment evaluation

included a complete history and physical examination,

direct flexible fiberoptic endoscopic examination,

complete blood counts, liver function tests,

chest X-ray, CT scan of the head and neck, and

dental evaluations. Thirty-three patients (89%)

had additional MRI, and 15 (41%) had 18F-fluorodeoxyglucose

positron emission tomography

(PET) scans. For this study, disease was retrospectively

restaged using the 2002 American Joint

Committee on Cancer (AJCC) TNM staging system

(Table 1), 11 with the exception of esthesioneuroblastomas

(Kadish staging) 12 and sarcomas

(not staged). Three patients with local relapses after

surgical resection alone were included in this

analysis, including 1 with squamous cell carcinoma,

1 with adenoid cystic, and 1 with myoepi-

926 Postoperative IMRT for Cancers of the Paranasal Sinuses HEAD & NECK—DOI 10.1002/hed July 2008

thelial carcinoma. At the time of recurrence, these

patients underwent radical surgical resection followed

by postoperative radiation. Tumor characteristics

are listed in Table 1. Clinically involved

cervical lymph nodes were identified in 4 patients

at presentation, consisting of level II adenopathy

in 1 patient with adenocarcinoma of the nasal cavity,

adenoid cystic carcinoma of the maxillary

sinus in 1 patient, esthesioneuroblastoma of the

nasal cavity in 1 patient, and level IV adenopathy

in 1 patient with squamous cell carcinoma of the

ethmoid sinus.

Surgery. All patients underwent gross surgical

resection. The details of the surgical interventions

can be found in Table 1. Surgical techniques

varied depending on the location of the tumor.

Three patients underwent ipsilateral neck dissection

for clinically positive cervical lymph nodes,

whereas 1 patient with a PET-positive cervical

lymph node did not undergo neck dissection or

removal of the involved lymph node. Five patients

underwent orbital exenteration as part of their

primary surgery, due to extension of the tumor to

the orbit. The median time to initiation of postoperative

radiotherapy was 1.8 months (range, 1.1–

3.2 months).

Chemotherapy. Systemic chemotherapy was used

in the initial management of 6 patients. Three

patients received neoadjuvant chemotherapy

prior to treatment, including 1 patient with sinonasal

undifferentiated carcinoma, 1 patient with

sarcoma, and 1 patient with esthesioneuroblastoma.

Three patients received concurrent postoperative

chemoradiation with platinum (CDDP)-

based regimens: 1 patient with squamous cell carcinoma

of the nasal cavity with involvement of the

nasopharynx, 1 patient with adenoid cystic carcinoma

of the lacrimal gland, and 1 patient with

esthesioneuroblastoma, who developed recurrent

disease and lymph node metastasis in the postoperative

period prior to starting radiation therapy.

Radiation Treatment. The use of IMRT at MSKCC

has evolved over the last 8 years. Initially,

patients were treated with an IMRT ‘‘boost’’ of 10

to 14 Gy to a cone down area. More recently,

patients have had their entire course of treatment

delivered using 1 IMRT plan (n 5 37), incorporating

dose painting. The IMRT dose painting

approach delivers differential daily doses prescribed

to higher and lower risk target volumes.

All treatments were administered with 6-MV

photons from a linear accelerator. Patients were

treated in the supine position and were immobilized

with custom Aquaplast masks (Aquaplast,

Wycoff, New Jersey). Currently, we are using

thermoplastic masks that also immobilize the

shoulders when the neck is to be treated. Using

this immobilization strategy, interfraction set-up

error of head and neck treatments have been calculated

as between 1.5 and 3 mm, and intrafraction

set-up error has been found to be up to 2

mm. 13,14 Target localization was accomplished

using CT simulation (AcQSim; Philips Medical

Systems, Andover, Massachusetts). CT images

indexed every 3 mm were obtained, extending

from the vertex of the skull to 5 cm inferior to the

clavicular heads. IMRT treatment planning was

performed using the inverse planning algorithm

of Spirou and Chui, 15 employing the proprietary

MSKCC treatment planning system. 16 IMRT was

delivered with dynamic multileaf collimation on

a Varian accelerator (Varian Medical Systems,

Palo Alto, California). Dynamic leaf sequencing

was accomplished using the algorithm of Spirou

and Chui. 17

Delineation of Target Volumesfor Intensity-Modulated

Radiotherapy. After obtaining planning CT

images in the treatment position, all target volumes

were outlined slice by slice. The clinical tumor

volume (CTV1) was used for patients with residual

disease and included the gross disease with

a margin of 0.3–0.5 cm. CTV2 was included in all

patients and was defined by the surgical bed and

areas at high risk of microscopic spread. Preoperative

MRI and/or PET scans, in addition to the diagnostic

CT scan with contrast of the head and neck,

were used to delineat the CTVs. Image fusion software

was used at the discretion of the treating

physician. To ensure the accuracy of target delineation,

a neuroradiologist and the operating surgeon

would review the CTVs in conjuction with

the treating radiation oncologist. CTV3 encompassed

the lymph node regions at risk, including

those patients who received elective neck irradiation.

Expansion of the CTVs with a margin ranging

from 0.5 to 1 cm created the planning target

volumes (PTV1, PTV2, and PTV3). The PTVs

were further modified to produce expansions as

small as 0.1 cm in areas adjacent to critical normal

structures, to prevent overlap with the PTV. The

surrounding organs at risk, including the brainstem,

spinal cord, optic nerves, optic chiasm,

parotid glands, mandible, and cochlea were also


Postoperative IMRT for Cancers of the Paranasal Sinuses HEAD & NECK—DOI 10.1002/hed July 2008 927

Dose Specifications for IMRT. For dose painting,

the prescription was specified to the normalized

isodose line encompassing the PTV. The median

prescribed dose was 70 Gy to the PTV1 (range,

66–70 Gy), 60 Gy to PTV2, and 54 Gy to PTV3.

The median dose per fraction was 2.12 Gy to PTV1

(range, 2–2.12 Gy), 2 Gy to PTV2 (range, 1.8–2.0

Gy), and 1.8 Gy to PTV3 (range, 1.64–1.80 Gy).

Patients were treated once daily, 5 days per week.

The median number of treatment fields was 5

(range, 3–12).

For PTVs, the volume, dose to 95% of the volume

(D95), minimum dose (Dmin), maximum

point dose (Dmax), mean dose (Dm), volume covered

by 95% of the prescription dose (V95), and

dose to 5% of the volume (D05) were evaluated.

For the critical organs with functional subunits

organized in series, Dmax was examined. When

the Dmax dose constraint could not be met, efforts

were made to keep the D05 below the constraint

dose. Dose constraints included the brainstem

Table 2. Dose-volume histogram summary of patients.



Structure Median Range Median Range


D95, % 99 79–101 – –

Dmin, Gy 45 16–56 – –


Dmax, Gy 45 4–65 31 3–54

D05, Gy 32 3–57 17 2–48

Dmean, Gy 12 2–40 6 1–35

D95, Gy 3 1–28 2 2–43


Dmax, Gy 7 2–44 4 2–45

D05, Gy 6 2–42 3 2–43

Dmean, Gy 5 2–40 2 1–36

D95, Gy 4 1–38 2 1–28

Optic Nerve

Dmax, Gy 53 2–54 41 2–54

D05, Gy 49 2–53 32 2–53

Dmean, Gy 36 2–50 21 1–45

D95, Gy 17 2–46 10 1–39

Optic Chiasm

Dmax, Gy 50 2–55 – –

D05, Gy 46 2–53 – –

Dmean, Gy 34 2–51 – –

D95, Gy 26 1–49 – –

Abbreviations: PTV, planning target volume; D95, dose to 95% of the

volume; Dmin, minimum dose; Dmax, maximum dose; D05, minimum

dose to hottest 5% of the volume; Dmean, mean dose to volume.

99% (range, 79% to 101%). Only 5 patients had a

D95 45 Gy for the ipsilateral eye.

Seven patients had Dmax >45 in the contralateral

eye; however, only 1 patient (48 Gy) had a contralateral

eye D05 >45 Gy.

contralateral optic nerve with a Dmax or D05 > 54


Optic Chiasm. Thirty-six patients had DVH data

for the optic chiasm. Only 1 patient (55 Gy) had a

Dmax >54 Gy; however, no patient had a D05 >54

Gy. This patient had a maxillary sinus sarcoma

that extended into the frontal and sphenoid sinus

and was treated to a dose of 63 Gy.

Treatment Outcome. The median follow-up was

28 months (range, 11–57) for living patients. The

2-year LPFS and OS were 75% and 80%, respectively.

Kaplan-Meier survival curves are shown in

Figure 2.

Local Relapse. Ten patients developed local

relapses with a median time to relapse of 12

months (range, 5–28). Local recurrence was outside

the prior radiation treatment field (or PTV) in

1 patient. In the other 9 patients, tumor was found

both within as well as outside the treated volume.

One patient, who failed to complete radiation

treatment due to psychosocial reasons, received

only 40 Gy and experienced a local relapse.

Regional Relapse. Relapse in cervical nodes was

identified in 3 patients, including 1 patient who

was seen with cervical lymph node involvement

and received neck irradiation. The 2 other

patients who developed neck recurrences include

1 patient with a T4 sinonasal undifferentiated

carcinoma of the ethmoid sinus and 1 patient with

a T4 squamous cell carcinoma of the maxillary

sinus. Two of these 3 patients have subsequently

died of their disease. None of the 3 patients who

received elective neck irradiation developed a cervical


Toxicity. All patients were evaluated for early

radiation toxicities and late (>3 months after fin-

Lens. DVHs for ipsilateral lenses were available

only for 30 patients. Seventeen patients had

Dmax >6 Gy and 15 patients had D05 >6Gy.

Thirty-five patients had DVH curves available for

the contralateral lens. Eleven had Dmax >6Gy

and 11 had D05 >6Gy.

Optic Nerve. Thirty-one patients had DVH data

for ipsilateral optic nerves. No patient had Dmax

or D05 >54 Gy. Thirty-six patients had DVH data

for contralateral optic nerves. No patient had a

FIGURE 2. Kaplan-Meier survival curves for overall survival

and local progression–free survival.

Postoperative IMRT for Cancers of the Paranasal Sinuses HEAD & NECK—DOI 10.1002/hed July 2008 929

Table 3. Radiation morbidity in all patients.*

Acute toxicities,

n 5 37

Late toxicities,

n 5 36


0 1 2 3 4 0 1 2 3 4


2 18 12 5 0 36 0 0 0 0


Salivargy gland 7 23 7 0 0 30 3 3 0 0

Skin 4 23 7 3 0 33 2 1 0 0

Ipsilateral eye 27 3 2 0 0 32 0 0 0 0

Contralateral 36 1 0 0 0 36 0 0 0 0


*Data presented as number of patients with each complication, either

early (

Author Patients Month, f/u

Table 4. Summary of trials using modern radiotherapy techniques.


advanced* SCC* Surgery1RT*






toxicity y *

Padovani et al 20 25 25 25 (84) 12 (48) 22 (88) 30 40 2 (8) 3D

Pommier et al 21 40 19 NA 14 (35) 30 (75) 73 66 1 (3) 3D

Roa et al 22 39 54 39 (54) 16 (41) 24 (62) 75 65 3 (8) 3D

Weber et al 23 36 52 36 (100) 10 (28) 28 (78) NA 90 1 (3) Proton

Duthoy et al 24 39 31 23 (59) 8 (21) 39 (100) 68 59 2 (5) IMRT

Combs et al 25 46 16 41 (89) 6 (13) NA 81 80 0 IMRT

Daly et al 26 36 51 33 (91) 12 (33) 32 (89) 62 69 0 IMRT

Hoppe et al 27 37 28 32 (86) 17 (46) 37 (100) 75 80 0 IMRT

Abbreviations: f/u, follow-up in months; SCC, squamous cell carcinoma; RT, radiotherapy; LPFS, local progression–free survival; 3D, 3D conformal

radiotherapy; NA, not available; IMRT, intensity-modulated radiotherapy.

*In parenthesis are percentage figures.

y Grade 3 or 4.



pathy or optic neuropathy is 2 years after radiotherapy,

6 cataracts typically occur 5 to 8 years

later. 19 Thus, longer follow-up of our patients is

required to properly assess the risk of cataract formation.

The maximum dose to the optic chiasm and

optic nerve was kept below the tolerance (54 Gy)

in all but 1 patient, and no patient has yet been

diagnosed with optic neuropathy. Parsons et al

reported no optic nerve injury for conventional

radiotherapy to doses

may allow future studies of dose escalation, which

was not feasible during the conventional era.

Intensity-modulated proton therapy may emerge

as a critical tool to achieve even better dosimetry

and allow for even further dose escalation. As

data further matures, toxicity outcomes will allow

us to judge whether IMRT and proton therapy are

indeed sparing critical structures and reducing

late visual toxicity, which typically occurs 2 years

following radiation, 5,6 without compromising local

control and overall survival.


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