Brachytherapy 5 (2006) 32–40

Perioperative high-dose-rate brachytherapy (PHDRB)in previously irradiated head and neck cancer: Initial

results of a Phase I/II reirradiation study

Rafael Martınez-Monge1,*, Juan Alcalde2, Carlos Concejo3,Mauricio Cambeiro1, Cristina Garran1

1Department of Oncology, University of Navarra Clinic, University of Navarra, Pamplona, Spain2Department of Otolaryngology, University of Navarra Clinic, University of Navarra, Pamplona, Spain

3Department of Maxillofacial Surgery, University of Navarra Clinic, University of Navarra, Pamplona, Spain

ABSTRACT BACKGROUND: This study was undertaken to determine the feasibility of salvage surgery andperioperative high-dose-rate brachytherapy (PHDRB) at the dose/fractionation schedule proposedin patients with previously irradiated, recurrent head and neck cancer or second primary tumorsarising in a previously irradiated field.METHODS AND MATERIALS: Twenty-five patients were treated with surgical resection andPHDRB. The PHDRB dose was 4 Gy b.i.d.� 8 (32 Gy) for R0 resections and 4 Gy b.i.d.� 10(40 Gy) for R1 resections. Further external beam radiotherapy or chemotherapy was not given.RESULTS: Resections were categorized as R0 (negative margins of at least 10 mm) in 3 patients(12.0%) and R1 (negative margins of less than 10 mm or microscopically positive margins) in 22(88.0%). Twelve patients with R1 resections had microscopically positive margins (48%), and 10 pa-tients had close margins (40%), with a median of 2.0 mm. Ten patients (40.0%) developed RadiationTherapy Oncology Group Grade 3 or greater toxicity. Seven patients (28%) presented complicationsrequiring a major surgical procedure. Four of these complications appeared in the immediate post-operative period and were surgical in nature (flap failure, n 5 2; fistula, n 5 2), and the other threewere mainly related to the brachytherapy procedure (n 5 2) or the radiation dose delivered(n 5 1). One patient died on postoperative day 11 due to bleeding. After a median followup of 14months, the 4-year local control rate and overall survival were 85.6% and 46.4%, respectively.CONCLUSIONS: Surgical salvage and PHDRB at the dose/fractionation proposed are feasible inthis high-risk population. Toxicity is high, but not substantially different from other reirradiationseries. Four-year local control results are encouraging taking into account that 22 of 25 pa-tients (88%) had either close or microscopically positive margins. � 2006 American BrachytherapySociety. All rights reserved.

Keywords: Head and neck cancer; Prior radiation therapy; Reirradiation; Perioperative; High-dose-rate; Brachytherapy

Introduction

Patients with previously irradiated, recurrent head andneck cancer or second primary tumors arising in a previ-ously irradiated field have a poor prognosis. Salvage sur-gery is the standard ofcare but can be performed in only

Received 29 September 2005; received in revised form 10 November

2005; accepted 17 November 2005.

* Corresponding author. Department of Oncology, University of Nav-

arra Clinic, University of Navarra, Avda Pıo XII s/n., Pamplona, Navarra,

Spain E-31080. Tel.: 134-948-255400; fax: 134-948-255500.

E-mail address: rmartinezm@unav.es (R. Martınez-Monge).

1538-4721/06/$ – see front matter � 2006 American Brachytherapy Society. A

doi:10.1016/j.brachy.2005.11.003

a minority of cases. Reirradiation can be effective, butmeaningful doses are only rarely delivered due to the con-cern for increased late toxicity. As a result, most patientsare finally treated on a palliative basis.

Upfront reirradiation has been evaluated in patientsdeemed unresectable or unsuitable for salvage surgery (1–21). Although external beam radiation therapy (EBRT) (1,11, 12) or low-dose-rate brachytherapy (LDR) (19–21)has been used as the sole treatment in some studies, mostof the published studies reported the use of EBRT in com-bination with concurrent chemotherapy. The chemotherapyagents most frequently used, alone or in combination, have

ll rights reserved.

33R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

been hydroxyurea, cisplatin, and 5-fluorouracil (4–9, 13,15–17). More recent chemo-reirradiation trials also reportthe combined use of newer drugs such as gemcitabineand paclitaxel (5, 7). With a few exceptions, survival resultsare disappointingly low, with median survival times be-tween 8 and 12 months (4–6, 9, 16, 17) and 2-year survivalrates almost invariably below 50%.

Only a few trials describe the use of postoperative reir-radiation after salvage surgery. In these studies, reirradia-tion was delivered by means of postoperative EBRT (22),postoperative chemoradiation (23, 24), intraoperative elec-tron beam radiotherapy (IOERT) (25, 26), intraoperativehigh-dose rate brachytherapy (IOHDR) (27) and LDR(28–32), pulsed dose-rate (PDR) (33), or high-dose-rate(HDR) brachytherapy (34). Two-year survival rates higherthan 50% have been reported in at least six of the studiesreferenced above (23–25, 28, 33).

The use of salvage surgery and postoperative reirradia-tion carries a considerable risk of postoperative complica-tions (25) and severe late tissue damage. However, it isnot clear whether the overall complication rate among sur-gical and nonsurgical reirradiation series is substantiallydifferent. The rate of Grade 3–5 late complications in sev-eral postoperative reirradiation studies ranged from 4.7% to38%, including some fatal events (23, 25, 26, 28, 29, 33, 34).Similarly, reirradiation-only series have reported high com-plication rates, with documented moderate to severe toxic-ity in 9–30% of the patients (5, 7, 9–11, 15, 17, 21),including some fatal cases (5, 7, 9–11, 15, 17, 21).

Perioperative high-dose-rate brachytherapy (PHDRB)may have several theoretical advantages over other typesof radiation techniques. Some advantages of PHDRBcompared to IOERT and intraoperative high-dose-rate bra-chytherapy (25–27, 35) are as follows: (1) use of computer-ized axial tomography (CT) scan-based treatment planningand optimization, (2) determination of the brachytherapydose based upon the amount of residual disease as de-scribed in the final pathology report, and (3) fraction-ation-improved therapeutic ratio. In addition, PHDRBtreats a smaller tissue volume than does EBRT (22–24)and, therefore, severe late toxicity could be minimizeddue to the dose–volume effect.

We have initiated this prospective, nonrandomized, con-trolled, Phase I or II, clinical study to determine the feasi-bility of salvage surgery and PHDRB at the dose/fractionation schedule proposed in patients with previouslyirradiated, recurrent head and neck cancer or second pri-mary tumors arising in a previously irradiated field.

Methods and materials

Eligibility criteria

From February 2001 to January 2005, 25 patients withpreviously irradiated, recurrent head and neck cancer orsecond primary tumors arising in a previously irradiated

field were treated with salvage surgical resection and peri-operative HDR brachytherapy. Only patients with histolog-ically documented head and neck cancer without metastaticdisease below the clavicles and in whom surgery wasplanned with curative intent were included. Metastaticworkup included CT scan of the chest and upper abdomenin all cases and positron emission tomography scan in pa-tients with recurrent disease. Prior treatment (whether withsurgery, radiation therapy, and/or chemotherapy) was notconsidered an exclusion criterion. All patients gave writteninformed consent before study entry. Patient and tumorcharacteristics are shown in Tables 1 and 2, respectively.

Treatment protocol

The brachytherapy dose was planned at three differentlevels corresponding to the presumed amount of residualdisease as described in the final pathology report, whichwas usually available within 48 h after surgery. Surgicalmargins equal to or greater than 10 mm were classified asR0 resections. Close (!10 mm) or microscopically positivesurgical margins or the presence of extracapsular nodal ex-tension were classified as R1 resections. The brachytherapydose was 4 Gy b.i.d.� 8 (32 Gy total dose) for R0 resec-tions and 4 Gy b.i.d.� 10 (40 Gy total dose) for R1 resec-tions. The number of patients included in each dose level isshown in Table 3. The brachytherapy dose was prescribedto the implant minimum target dose (MTD) as per Interna-tional Commission on Radiation Units and Measurements(ICRU) No. 58 recommendations (36). Further EBRT wasnot administered. Total radiation doses equivalent to stan-dard fractionation regimens delivered with 2 Gy daily frac-tions and calculated with the linear quadratic formulationwithout time correction (i.e., BED 5 nd[1 1 d/(a/b)]) (37)for the ICRU No. 58 parameters MTD and mean centraldose are shown in Fig. 1.

Intraoperative target definition

The surgical and the radiation oncology teams used thepreoperative physical examination and imaging tests/surgi-cal findings, frozen sections where necessary, and gross

Table 1

Patient characteristics

n %

Gender

Male 17 68.0

Female 8 32.0

Age

Mean 64.1

Range 37–82

Prior therapy

Surgery 19 75.0

External beam radiation 25 100.0

Brachytherapy 4 16.0

Chemotherapy 10 40.0

34 R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

examination of the surgical specimen to jointly determinethe area to be implanted.

All surgical field areas presumed to belong to RadiationTherapy Oncology Group (RTOG) risk category 2 (i.e., twoor more positive nodes or extracapsular nodal extensionwith negative margins) or risk category 3 (positive margins)were implanted. In most cases, the implanted area coveredthe CTV around the primary tumor and the lymphaticchains with nodes greater than 2–3 cm in diameter, whichhave a substantial probability of extracapsular extension.

Brachytherapy technique

The CTV was covered with a set of plastic cathetersplaced as parallel as possible at 1.0–1.5 mm intervals witha margin of 1 cm in all directions. The lateral margins wereprovided with additional catheters extending beyond the

Table 2

Tumor characteristics

n %

Histology, type

Undifferentiated carcinoma 1 4.0

Squamous cell carcinoma 22 88.0

Lymphoepithelioma 1 4.0

Paraganglioma 1 4.0

Histology, grade

Well differentiated 2 8.0

Moderately differentiated 12 48.0

Poorly differentiated 4 16.0

Not stated 7 28.0

Tumor largest diameter (cm)

Mean 2.8 –

Range 1.0–8.0 –

Implanted site

Dorsal surface of the tongue 1 4.0

Border of the tongue 4 16.0

Floor of the mouth 2 8.0

Base of the tongue 4 16.0

Tonsillar fossa 2 8.0

Supraclavicular fossa 1 4.0

Meningeal surface 1 4.0

Lymph nodes 10 40.0

Stage at PHDRB

T1–2N0 3 12.0

Recurrent disease 22 88.0

Table 3

Treatment characteristics

n %

Type of resection

R0 3 12.0

R1 22 88.0

Close margins (median 2.0 mm) 10 40.0

Positive margins 12 48.0

R2 – –

CTV (Fig. 2). In recurrences involving the mucosal surface,the longitudinal margins were covered by setting the blindend of the catheters at 1.0–1.5 cm above the mucosal sur-face with the aid of a plastic spacer using a nonloopingtechnique described previously (38). Catheters were in-serted no more than 5 mm deep into the tumor bed to avoidunderdosage of the surgical surface. This arrangementavoided catheter displacement and resulted in an improvedgeometry. Furthermore, the surgical surface remained cath-eter-free, making surgical reconstruction easier. In caseswhere the catheters could not be inserted below the surface,reabsorbable sutures were used to secure the catheters ontothe surgical surface. In addition, catheters were attached atthe skin exit points with plastic buttons and silk sutures.Single plane implants were the preferred techniques forboth the primary tumor bed and the neck (Fig. 2).

Once the implant was completed, any necessary recon-struction of the surgical defect was performed immediatelywith regional flaps (infrahyoid and pectoralis major myocu-taneous flaps) or microvascular free flaps including radialflap, lateral arm flap, abdominis flap, and fibula.

3D dosimetry guidelines

A CT scan for verification was performed during thesecond or third postoperative day, once the patient was instable condition and ready for transportation (Fig. 3). TheCT study was transferred to the Radiation Treatment Plan-ning System (Abacus US module, version 3.55, Gam-mamed; Varian Medical Systems, Palo Alto, CA) fordosimetry. The treatment planning process followed therules of the Paris System with manual optimization for eachof the CT slices. Additional rules included that the CTV beencompassed by the 4 Gy isodose line (MTD ICRU No.58). An MTD to mean central dose ICRU No. 58 ratio ofat least 70% was accepted, provided that the volume en-compassed by the 6 Gy isodose (V150) was not greater than50% of the volume encompassed by the 4 Gy isodose(V100). Automatic optimization algorithms provided by

R0

HDR 32Gy

R1

HDR 40Gy

R2

HDR 48Gy

MTD 37.3Gy

MCD 50.0Gy

MTD 46.7Gy

MCD 62.5Gy

MTD 56.0Gy

MCD 75.0Gy

No EBRT

PRIOR XRT

Fig. 1. Treatment scheme.

35R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

Fig. 2. Operative view of different perioperative high-dose-rate brachytherapy implants in the head and neck region: (a) lateral border of the tongue; (b)

parotid bed; (c) floor of the mouth; and (d) pterygoid fossa.

the Treatment Planning System were not used. Once thetreatment plan was approved, it was transferred to the after-loader unit control console where the dwell positions andtreatment times were double-checked by the radiation tech-nologist. Brachytherapy parameters are detailed in Table 4.

Statistical analysis

Survival results were calculated using the Kaplan–Meier(39) method from the date of surgery to the last followupvisit and differences evaluated with the log-rank test. Dis-crete variables were compared with the Fisher’s exact testmethod.

Local failure was defined as the occurrence of tumor re-growth in the area treated with brachytherapy or in an ad-jacent region (i.e., unsuccessful target definition). Anyother failure above the clavicles was considered regionaland any failure below was considered distant failure.

Acute toxicities were defined as those occurring fromthe date of surgery to 90 days after the completion of thetreatment. Toxicities were classified as late if they occurredmore than 90 days after the completion of the treatment.Toxicities were documented according to the RTOG mor-bidity scoring criteria.

Results

Protocol compliance

All patients but one received the assigned radiation doselevel as per the protocol. The patient who did not receivethe assigned dose level died before the completion of thePHDRB course and during the postoperative period dueto bleeding.

Toxicity

Ten patients (40.0%) developed RTOG Grade 3 orgreater toxicities. Complications requiring a major surgicalprocedure included two cases: one with graft failure and fis-tula and another with soft tissue necrosis. Only the lattercomplication seemed to be directly related to PHDRB. Inaddition, 2 patients needed reoperation for relocation of in-advertedly displaced catheters (n 5 1) and bleeding uponremoval (n 5 1). All the toxic events observed are listedin Table 5. As mentioned above, 1 patient died on postop-erative day 11 due to catastrophic bleeding. This patienthad undergone an extensive resection of a recurrent tumorinvolving the base of the tongue without flap reconstruc-tion. Surprisingly, the necropsy did not reveal any bleedingpoint.

36 R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

Fig. 3. Computerized axial tomography sections of different perioperative high-dose-rate brachytherapy implants in the head and neck region: (a) lateral

border of the tongue; (b) parotid bed; (c) peristomal area; and (d) right carotid vessels.

Outcome analysis: Patterns of failure

A preliminary analysis of patterns of failure after a me-dian followup of 14 months (4–491) for living patientsshows 4-year actuarial local and regional control estimatesof 84.7% and 76.4%, respectively. A detailed description ofthe failures observed is given in Table 6.

Survival

After a median followup of 14 months (4–491), the 4-year actuarial overall survival rate was 46.4%. A descrip-tion of the current status of the patients is shown in Table7. Six patients died of tumor progression, and five died ofother causes, while apparently free of disease, listed as fol-lows: postoperative bleeding (n 5 1), soft tissue necrosisthat was not surgically repaired due to advanced age(n 5 1), diagnosis of a second tumor (n 5 1), liver failure(n 5 1), and cerebrovascular hemorrhage (n 5 1). Threemore patients are alive with disease at the time of this anal-ysis. None of the patients who failed has undergone suc-cessful salvage treatment.

Discussion

This prospective, nonrandomized, controlled, Phase I orII, clinical trial was undertaken to determine the feasibilityof surgical resection and PHDRB as salvage treatment forpatients with previously irradiated, recurrent head and neckcancer or second primary tumors arising in a previously ir-radiated field. Given that 22 of the 25 patients included hadpositive or close (median 2.0 mm) margins and were there-fore at a very high risk of local relapse, the final results ob-served should help to evaluate the effectiveness of PHDRBat the dose/fractionation schedule proposed.

The toxicity observed in this trial has been very high. Infact, 40% of the patients treated experienced Grade 3 orhigher toxic events. Although this figure includes any com-plication observed and not merely those that can be directlyattributable to radiation, the favorable dose-volume effectresultant from smaller brachytherapy-treated volumes hasnot been observed in this previously irradiated population.However, comparison with other surgery-plus-reirradiationseries is difficult due to the lack of standardized reportingof complications in many of the earliest reports, as well

37R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

as in others. In addition, some studies report only ‘‘radia-tion-related’’ complications, but not the overall rate, whichundoubtedly reduces the actual complication rate. A thor-ough review of the literature reveals that six series of pa-tients treated with surgery plus brachytherapy reportmoderate to severe or Grade >3 complications in 4.7–36% of the cases (28–31, 33, 34). In addition, five seriesof patients treated with surgical resection and IOERT orEBRT report moderate to severe complications in 8–38%of the cases (22–26). However, if only toxic deaths (a muchmore easily traceable event) are accounted for, the 4% fatalcomplication rate of the present series is quite comparableto those reported in the literature, which ranges from 0% to8.5% (22–27, 30, 31, 33, 34), the majority of which werecaused by vascular blowout (25, 29), obstruction (23), orfistula (26). Of interest, a number of nonsurgical

Table 5

Toxicity

n %

Highest toxicity observed in the high-dose region

RTOG Grade 3 2 8.0

RTOG Grade 5 1 4.0

Individual toxic events observed

Bone damage Grade 3 1 4.0

Nerve damage Grade 3 1 4.0

Graft failure Grade 4 2 8.0

Technical problems Grade 4a 2 8.0

Soft tissue necrosis Grade 4 1 4.0

Fistula Grade 4 2 8.0

Bleeding Grade 5 1 4.0

a One patient presented arterial bleeding upon catheter removal that

required emergency surgery. Another patient required a reoperation to re-

locate a displaced catheter.

Table 4

Brachytherapy parameters

n

Number of catheters

Median 5

Range 3–9

Surgery to brachytherapy gap (days)

Median 4

Range 1–9

Brachytherapy duration (days)

Median 6

Range 4–15

TV100 (cc)

Median 47.0

Range 7.6–164.4

TV150 (cc)

Mean 17.1

Range 3.3–54.5

TV100: treatment volume encompassed by the prescription isodose

(4 Gy).

TV150: treatment volume encompassed by 150% of the prescription

isodose (6 Gy).

reirradiation series have also reported moderate to severelate toxicity in the 9–37% range (1, 7, 10–12, 19–21) andtoxic deaths in 0–8% (1, 5, 7, 9, 15, 17, 21) of the patients.A description of the most relevant series of patients treatedwith surgical salvage and reirradiation is shown in Table 8.

The local control rate of 84.7% observed in the presentstudy at a maximum followup of 4 years (median followupof 14 months) is high, although followup is not matureenough to provide firm conclusions. Also, if regional fail-ures are accounted for, the locoregional failure rate dropsto 76.4%. Comparison with other reirradiation series is dif-ficult due to the different criteria used to describe patterns offailure. Local control rates sometimes refer to ‘‘in-field’’failures (i.e., failure within the boundaries of the implantedvolume) whereas others refer to locoregional failures (i.e.,failure above the clavicles). In addition, it should be realizedthat locoregional control may not be an ideal surrogatemarker to measure the efficacy of the treatment delivered.Previously irradiated head and neck areas, especially afterone or more surgeries and flap reconstruction, may be ex-tremely difficult to evaluate for locoregional control. On av-erage, previous reports of patients treated with surgicalresection and reirradiation describe 2- to 4-year local controlrates ranging from 25% to 80% (22–25, 28, 29, 31, 33, 34).

Survival rate may be the most reliable indicator of treat-ment appropriateness for this patient population at a veryhigh-risk of both tumor relapse and treatment toxicity. Inpatients with previously irradiated, recurrent head and neckcancer or second primary tumors arising in a previously ir-radiated field, treatment efficacy may be counterbalancedby a high number of noncancer deaths, both treatment

Table 6

Patterns of failurea

n %

Local 3 12.0

Regional 5 20.0

Distant 6 24.0

4 years local control 85.6

4 years regional control 77.5

4 years distant control 62.5

Median followup 14 months (4–491)

a Patterns of failure censored as first failure observed.

Table 7

Patient outcome

n %

NED 13 52.0

AWD 3 12.0

DFD 5 15.0

DWD 6 24.0

4 years disease-free survival 33.6

4 years overall survival 46.4

NED: alive, no evidence of disease; AWD: alive, with disease; DFD:

dead, free of disease; DWD: dead because of disease.

T

P

A Toxicity

S

V Fatal events 4.8%; overall rate of Grade >3 events: 14.3%

Individual events: Grade 3 necrosis 14.3%

P Fatal events: 8.5%; overall rate of Grade >3 events: 36%

Individual events: partial flap necrosis 56%; fistula 8%;

other wound infection 10%; carotid blowout 5%;

osteoradionecrosis 3%; septic death 3%

M Fatal events: none; overall rate of Grade >3 events: 33%

Individual events: hematoma 6.6%; seroma 6.6%;

wound separation 6.6%; orocutaneous fistula 13.3%

D Fatal events 6.6%; overall rate of Grade >3 events: 18.7%

Individual events: orocutaneous fistula 6.6%; partial flap

failure 6.6%; postoperative death 6.6%

C Severe complications 46% (fibrosis, necrosis and

contractures. Decreased to 12% with the use of skin

resurfacing)

Z Severe complications

S Fatal events: none; overall rate of Grade >3 events: 4.7%

Individual events: soft tissue necrosis Grade 3 4.7%

S

R Fatal events: 8.5%; overall rate of Grade >4 events: 19.1%

Individual events: fistula Grade 4 6.4%; osteoradionecrosis

Grade 4 4.2%; respiratory insufficiency Grade 5 6.4%;

carotid blowout Grade 5 2.1%

N Fatal events: 2.6%; overall rate of Grade >3 events: 16%

Individual events: orocutaneous fistula 5.2%; tracheal

dehiscence 2.6%; wound dehiscence 2.6%; carotid

occlusion 2.6%; fatal tracheovascular fistula 2.6%

S

B Fatal events: none; overall rate of Grade >3 events: 8%

Individual events: dry eye syndrome, 4%;

bone necrosis, 4%

38

R.

Ma

rtınez-M

on

ge

eta

l./

Bra

chyth

erap

y5

(20

06

)3

2–

40

able 8

reviously irradiated head and neck cancer

uthor/institution Year # Treatment F/up median LRC OS

urgery 1 brachytherapy

ikram, Montefiore,

NY (28)

1985 21 S 1 LDR 48 Gy192Ir or 75 Gy 125I

35 months IF 2 years 81% 2 years 55%

ark, Johns

Hopkins (29)

1991 35 S 1 LDR 125I 28 months 40% (crude) 5 years 29%

oscoso, Mount

Sinai, NY (30)

1994 15 S 1 LDR 50 Gy192Ir or 125I 160 Gy

n/a n/a n/a

onath, McGill U (34) 1995 15 S 1 HDR 3 Gy� 8 max 16 months !1 year 50% DFS 1 year 25%

ornesa, Royal

Marsden (31)

1996 39 S 1 LDR 1 year 65%

elefskyb,

MSKCC (32)

1998 100 S 1 LDR or LDR alone

(125I 171 Gy, 192Ir 40.2 Gy)

9.5 months 2 years 26% 2 years 20%

trnad,

Erlangen U (33)

2003 43 PDR 27–54 Gy G EBRT

30% G ChT 37% G HT

47% G Surgery 65%

24 months All 2 years 68%

TFC 2 years 80%

All 2 years 49%

TFC 2 years 66%

urgery 1 IORT

atec

Indiana (25)

1991 47 S 1 IORT 20 Gy 14 months 2 years 62% 2 years 55%

ag, OSU (26) 1998 38 S 1 IORT 15–20 Gy 30 months LRC 3 years 4%

IF 3 years 13%

3 years 8%

MST 7 months

urgery 1 EBRT G chemotherapy

enchalal,

Toulouse (22)

1995 14 S 1 EBRT 60 Gy

(45.6–60 Gy) @ 1.2 Gy BID

17 months IF ~4 years 25% 1 year 64% 2 years

36% ~4 years 10%

39R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

D

eC

revo

isie

rd,

IGR

(24

)

20

01

25

S1

EB

RT

60

Gy

(50

–70

Gy

)

Hy

dro

xy

ure

a1

.5g

r/d�

55

FU

80

0m

g/m

2/d�

5o

nal

tern

ate

wee

ks

66

mo

nth

sD

FS

~4

yea

rs3

0%

Cru

de1

5/2

5

2y

ears

43

%

4y

ears

43

%

Fat

alev

ents

:n

on

e;ov

eral

lra

teo

fG

rad

e>

3ev

ents

:n

/a

Ind

ivid

ual

even

ts:

ost

eora

dio

nec

rosi

sG

rade

36

%;

ost

eora

dio

nec

rosi

sG

rade

46

%;

cerv

ical

fib

rosi

sG

rad

e

2–

34

4%

;m

uco

sal

nec

rosi

s2

0%

;tr

ism

us

24

%

Mac

hta

y,

UP

enn

(23

)

20

04

16

S1

EB

RT

54

–6

6G

y

@1

.5G

yB

IDw

1,2

,4,5

CD

DP

25

mg/

m2/d�

3w

1,5

5F

U5

00

mg/

m2/d�

4w

1,5

35

mo

nth

s3

yea

rs8

1%

3y

ears

63

%F

atal

even

ts:

6.2

%;

over

all

rate

of

Gra

de

>3

even

ts:

38

%

Ind

ivid

ual

even

ts:

fib

rosi

sG

rade

33

7.5

%;

dy

sph

agia

Gra

de

33

1.2

%;

vasc

ula

rev

ents

Gra

de3

12

.5%

;va

scu

lar

even

ts

Gra

de

56

.2%

Su

rger

y1

Rei

rrad

iati

on

seri

es.

#:

Nu

mb

ero

fp

atie

nts

;L

RC

:lo

core

gio

nal

con

tro

l;O

S:

over

all

surv

ival

;S

:su

rger

y;

LD

R:

low

-do

se-r

ate

bra

chy

ther

apy

;IF

:in

-fiel

dfa

ilur

e;IO

RT

:in

trao

per

ativ

eel

ectr

on

bea

mra

diat

ion;

EB

RT

:ex

tern

al

bea

mra

dia

tion;

DF

S:

dis

ease

-fre

esu

rviv

al;

TF

C:

trea

ted

for

cure

;M

ST

:m

edia

nsu

rviv

alti

me;

~:

taken

from

surv

ival

plo

ts.

aA

llp

atie

nts

had

R2

rese

ctio

ns.

bE

igh

typ

erce

nt

of

the

pat

ien

tsh

adg

ross

resi

du

ald

isea

se.

cA

llth

ep

atie

nts

had

pT

3,4

and

/or

N1

.d

All

the

pat

ien

tsh

adp

osi

tive

mar

gin

san

d/o

rE

CS

1n

/a:

no

td

escr

ibed

.

related and unrelated. In the present series, the 4-year over-all and disease-free survival rates were 46.4% and 33.6%,respectively, with 5 patients alive and without evidence ofdisease beyond 2 years of followup. However, the medianoverall survival was only 11 months, which probably re-flects an insufficient followup. Only a longer observationperiod will determine if the excellent local control resultswill translate into improved long-term survival rates. Thesurvival rates reported by other reirradiation series do notdiffer substantially from the data shown in the present re-port. Nonsurgical reirradiation series usually report 2-yearsurvival rates below 50% with median survival times be-tween 8 and 12 months (4–6, 9, 16, 17). However, in theseries of patients treated with combined surgical resectionand reirradiation slightly higher survival rates are reported,with about half of the series reporting 2-year survival ratesabove 50% (23, 23–25, 28, 33). Although this may reflecta greater treatment intensity, a strong case selection biasmust be invariably suspected.

Conclusion

The PHDRB at the dose/fractionation proposed is feasi-ble and useful in this high-risk population. Four-year localcontrol results are encouraging, considering that 88% of thepatients had either close (median 2.0 mm) or microscopi-cally positive margins. Toxicity was high, but not substan-tially different from other reirradiation series.

Acknowledgments

We thank Mr. David Carpenter for his editorial assistance.

References

[1] Langlois D, Eschwege F, Kramar A, et al. Reirradiation of head and

neck cancers. Presentation of 35 cases treated at the Gustave Roussy

Institute. Radiother Oncol 1985;3:27–33.

[2] Dawson LA, Myers LL, Bradford CR, et al. Conformal re-irradiation

of recurrent and new primary head-and-neck cancer. Int J Radiat

Oncol Biol Phys 2001;50:377–385.

[3] Ohizumi Y, Tamai Y, Imamiya S, et al. Prognostic factors of reirra-

diation for recurrent head and neck cancer. Am J Clin Oncol 2002;

25:408–413.

[4] Gandia D, Wibault P, Guillot T, et al. Simultaneous chemoradiother-

apy as salvage treatment in locoregional recurrences of squamous

head and neck cancer. Head Neck 1993;15:8–15.

[5] Kramer NM, Horwitz EM, Cheng J, et al. Toxicity and outcome anal-

ysis of patients with recurrent head and neck cancer treated with hy-

perfractionated split-course reirradiation and concurrent cisplatin and

paclitaxel chemotherapy from two prospective phase I and II studies.

Head Neck 2005;27:406–414.

[6] Nagar YS, Singh S, Datta NR. Chemo-reirradiation in persistent/re-

current head and neck cancers. Jpn J Clin Oncol 2004;34:61–68.

[7] Milano MT, Vokes EE, Salama JK, et al. Twice-daily reirradiation

for recurrent and second primary head-and-neck cancer with gemci-

tabine, paclitaxel, and 5-fluorouracil chemotherapy. Int J Radiat

Oncol Biol Phys 2005;61:1096–1106.

40 R. Martınez-Monge et al. / Brachytherapy 5 (2006) 32–40

[8] Schaefer U, Micke O, Schueller P, et al. Recurrent head and neck

cancer: Retreatment of previously irradiated areas with combined

chemotherapy and radiation therapy-results of a prospective study.

Radiology 2000;216:371–376.

[9] De Crevoisier R, Bourhis J, Domenge C, et al. 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.

[10] Ohizumi Y, Tamai Y, Imamiya S, et al. Complications following

re-irradiation for head and neck cancer. Am J Otolaryngol 2002;23:

215–221.

[11] Stevens KR Jr, Britsch A, Moss WT. High-dose reirradiation of head

and neck cancer with curative intent. Int J Radiat Oncol Biol Phys

1994;29:687–698.

[12] Emami B, Bignardi M, Spector GJ, et al. Reirradiation of recurrent

head and neck cancers. Laryngoscope 1987;97:85–88.

[13] Weppelmann B, Wheeler RH, Peters GE, et al. Treatment of recur-

rent head and neck cancer with 5-fluorouracil, hydroxyurea, and

reirradiation. Int J Radiat Oncol Biol Phys 1992;22:1051–1056.

[14] Spencer S, Wheeler R, Peters G, et al. Phase 1 trial of combined che-

motherapy and reirradiation for recurrent unresectable head and neck

cancer. Head Neck 2003;25:118–122.

[15] Haraf DJ, Weichselbaum RR, Vokes EE. Re-irradiation with concom-

itant chemotherapy of unresectable recurrent head and neck cancer:

A potentially curable disease. Ann Oncol 1996;7:913–918.

[16] Spencer SA, Wheeler RH, Peters GE, et al. Concomitant chemother-

apy and reirradiation as management for recurrent cancer of the head

and neck. Am J Clin Oncol 1999;22:1–5.

[17] Spencer SA, Harris J, Wheeler RH, et al. RTOG 96-10: Reirradiation

with concurrent hydroxyurea and 5-fluorouracil in patients with squa-

mous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys

2001;51:1299–1304.

[18] Krull A, Friedrich RE, Schwarz R, et al. Interstitial high dose rate

brachytherapy in locally progressive or recurrent head and neck can-

cer. Anticancer Res 1999;19:2695–2697.

[19] Mazeron JJ, Langlois D, Glaubiger D, et al. Salvage irradiation of

oropharyngeal cancers using iridium 192 wire implants: 5-year re-

sults of 70 cases. Int J Radiat Oncol Biol Phys 1987;13:957–962.

[20] Housset M, Barrett JM, Brunel P, et al. Split course interstitial bra-

chytherapy with a source shift: The results of a new technique for sal-

vage irradiation in recurrent inoperable cervical lymphadenopathy

greater than or equal to 4 cm diameter in 23 patients. Int J Radiat

Oncol Biol Phys 1992;22:1071–1074.

[21] Puthawala A, Nisar Syed AM, Gamie S, et al. Interstitial low-dose-

rate brachytherapy as a salvage treatment for recurrent head-and-neck

cancers: Long-term results. Int J Radiat Oncol Biol Phys 2001;51:

354–362.

[22] Benchalal M, Bachaud JM, Francois P, et al. Hyperfractionation in

the reirradiation of head and neck cancers. Result of a pilot study.

Radiother Oncol 1995;36:203–210.

[23] Machtay M, Rosenthal DI, Chalian AA, et al. Pilot study of post-

operative reirradiation, chemotherapy, and amifostine after surgical

salvage for recurrent head-and-neck cancer. Int J Radiat Oncol Biol

Phys 2004;59:72–77.

[24] De Crevoisier R, Domenge C, Wibault P, et al. Full dose reirradiation

combined with chemotherapy after salvage surgery in head and neck

carcinoma. Cancer 2001;91:2071–2076.

[25] Rate WR, Garrett P, Hamaker R, et al. Intraoperative radiation ther-

apy for recurrent head and neck cancer. Cancer 1991;67:2738–

2740.

[26] Nag S, Schuller DE, Martinez-Monge R, et al. Intraoperative elec-

tron beam radiotherapy for previously irradiated advanced head

and neck malignancies. Int J Radiat Oncol Biol Phys 1998;42:

1085–1089.

[27] Nag S, Schuller DE, Rodriguez-Villalba S, et al. Intraoperative high

dose rate brachytherapy can be used to salvage patients with previ-

ously irradiated head and neck recurrences. Rev Med Univ Navarra

1999;43:56–61.

[28] Vikram B, Strong EW, Shah JP, et al. Intraoperative radiotherapy in

patients with recurrent head and neck cancer. Am J Surg 1985;150:

485–487.

[29] Park RI, Liberman FZ, Lee DJ, et al. Iodine-125 seed implantation as

an adjunct to surgery in advanced recurrent squamous cell cancer of

the head and neck. Laryngoscope 1991;101:405–410.

[30] Moscoso JF, Urken ML, Dalton J, et al. Simultaneous interstitial

radiotherapy with regional or free-flap reconstruction, following

salvage surgery of recurrent head and neck carcinoma. Analysis of

complications. Arch Otolaryngol Head Neck Surg 1994;120:965–

972.

[31] Cornes PG, Cox HJ, Rhys-Evans PR, et al. Salvage treatment for in-

operable neck nodes in head and neck cancer using combined iridium-

192 brachytherapy and surgical reconstruction. Br J Surg 1996;1996:

1620–1622.

[32] Zelefsky MJ, Zimberg SH, Raben A. Brachytherapy for locally ad-

vanced and recurrent lymph node metastases. J Brachyther Int 1998;

14:123–130.

[33] Strnad V, Geiger M, Lotter M, Sauer R. The role of pulsed-dose-rate

brachytherapy in previously irradiated head-and-neck cancer. Bra-

chytherapy 2003;2:158–163.

[34] Donath D, Vuong T, Shenouda G, et al. The potential uses of high-

dose-rate brachytherapy in patients with head and neck cancer. Eur

Arch Otorhinolaryngol 1995;252:321–324.

[35] Martinez-Monge R, Azinovic I, Alcalde J, et al. IORT in the manage-

ment of locally advanced or recurrent head and neck cancer. Front

Radiat Ther Oncol 1997;31:122–125.

[36] International Commission on Radiation Units and Measurements.

Dose and volume specification for reporting interstitial therapy.

ICRU report 58. Bethesda, MD: International Commission on Radi-

ation Units and Measurements; 1997. a. 1997.

[37] Douglas BG, Fowler JF. The effect of multiple small doses of x rays

on skin reactions in the mouse and a basic interpretation. Radiat Res

1976;66:401–426.

[38] Nag S, Martinez-Monge R, Zhang H, et al. Simplified non-looping

functional loop technique for HDR brachytherapy. Radiother Oncol

1998;48:339–341.

[39] Kaplan EL, Meier P. Non parametric estimation from incomplete

observations. J Am Stat Assoc 1958;53:457–481.