ANTI-TUMOUR TREATMENT

Reirradiation of recurrent and second primary headand neck malignancies: a comprehensive review

Johnny Kao1, Michael C. Garofalo1, Michael T. Milano1,

Steven J. Chmura1, Jason R. Citron1 and Daniel J. Haraf1,2

1Department of Radiation and Cellular Oncology, The University of Chicago, 5758 South Maryland MC 9006, Chicago,IL 60637, USA; 2The University of Chicago Cancer Research Center, 5758 South Maryland MC 9006, Chicago, IL

60637, USA

The management of locoregionally recurrent or second primary tumors in a previously irradiated head and neck volumepresents a challenging clinical problem. Only a small subset of patients are candidates for potentially curative surgery. Che-

motherapy alone provides only limited palliation with no long term survivors. Reirradiation, particularly with aggressive con-

comitant chemotherapy, results in prolonged median survival and long term survival for some patients. The toxicity of

reirradiation, while greater than chemotherapy alone or primary irradiation, is lower than expected for the high cumulative

radiation doses. The results of reirradiation in recurrent head and neck cancer and the prognostic factors predicting outcome

in this patient population are reviewed.

sc 2003 Elsevier Science Ltd. All rights reserved.

Key words: Reirradiation; recurrent head and neck cancer; combined modality therapy.

INTRODUCTION

There have been a number of advances in thetreatment of head and neck cancer over the pastdecade resulting in improved tumor control andorgan preservation for early stage disease (1,2).Unfortunately, the majority of patients with headand neck malignancies present with locally ad-vanced disease where expected cure rates, with thetraditional approaches of surgery and radiationtherapy, are approximately 30–50% (2,3). This hasled to the study of more innovative and aggressivetreatment approaches integrating chemotherapyand radiation therapy, which has yielded promis-ing results (4). Nonetheless, local and/or regional

recurrences continue to predominate and are fre-quently the cause of death. Second primary tumorsin the head and neck occur in up to 30% of patientsover 10 years due to field cancerization (1,2). Lo-coregional recurrence of a head and neck cancer ora second primary cancer in the context of a previ-ously irradiated head and neck volume presents theoncologist with a therapeutic dilemma. The stan-dard of care for such patients has been surgicalsalvage. When feasible and agreeable to by thepatient, salvage surgery can be effective (5,6). Dueto the location and extent of the tumor, many ofthose who undergo attempted surgical resection areleft with close or positive margins and a minorityare actually cured of disease.

The standard of care for previously irradiatedunresectable recurrent head and neck cancer hasbeen chemotherapy alone. This approach has offeredlimited palliation and no long term survivors (7–13).While this may be an acceptable option for patientswith clearly incurable widespread metastatic dis-

0305-7372/03/$ - see front matter sc 2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.

CANCER TREATMENT REVIEWS 2003; 29: 21–30

doi:10.1016/S0305-7372(02)00096-8

Correspondence to: Johnny Kao MD, Department of Radiationand Cellular Oncology, The University of Chicago, 5758 SouthMaryland MC 9006, Chicago, IL 60637, USA. Tel.: 1-773-702-6870;Fax: 1-773-702-0610; E-mail: jkao@radonc.uchicago.edu

ease, it may not be the best approach for those pa-tients with only local and/or regionally recurrentdisease.

Reirradiation with curative intent has beencautiously employed by several institutions withvaried success (14–28). Conceptually, it must beassumed that the majority of tumors that recurafter radiation therapy have arisen from selectedradioresistant cells. Therefore, reirradiation alone isnot likely to be as effective, save for a few selectpatients with limited volume recurrence in a fa-vorable site or those with second primary tumors(26–28).

High dose reirradiation with concomitant che-motherapy represents a more aggressive approachto these radioresistant tumors and has afforded en-couraging results with a fraction of long term sur-vivors (14,15,17,20–23,25). This approach representsa potentially curative option for patients with unre-sectable or partially resected disease arising in apreviously irradiated volume. A selected review ofthe reirradiation literature follows.

EPIDEMIOLOGY AND PATTERNS OF FAILURE

In 2001, the incidence of primary head and neckcancer in the United States was approximately40,000 (29). The overall five year, disease specificsurvival rate was 64.0% for treated patients and themost common treatment modality remains surgeryalone (30). Most patients with early stage tumorsare curable with surgery or radiation therapy. Un-fortunately, early stage tumors represent only ap-proximately one-third of newly diagnosed headand neck cancers. For patients who present withadvanced disease at the time of diagnosis, the tra-ditional approach of surgery and radiation therapyhas been largely ineffective with cure rates of 30–50% (2,3). There is ongoing active research withencouraging results exploring combined modalitytherapy to improve survival as well as organpreservation and function in advanced head andneck cancer (1,4,31–33). Altered radiation fraction-ation schemes, particularly hyperfractionation, havedemonstrated improved locoregional control (34).Nonetheless, local and/or regional failure remainsthe predominant pattern of failure and cause ofdeath among the patients that recur after treatmentfor advanced head and neck cancer (3,35). Themajority of patients who succumb to head and neckcancer have persistent or recurrent local and/orregional disease as the sole site of failure and 70–90% of those who develop distant metastatic dis-ease also have local and or regional failure as acomponent of their failure (36,37).

STANDARD OF CARE (SURGERY ORCHEMOTHERAPY ALONE)

For the small subset of patients with resectable localand/or regionally recurrent disease, surgical salvageis the current standard of care. Curative intent sur-gical salvage is feasible and reasonably effective inthis subset of patients with 5 year survival rates from16% to 36% (5,6). However, surgery in the recurrentsetting is often either incomplete or impossible dueto the location and extent of the tumor. For example,only approximately 20% of patients that fail in necknodes will proceed to salvage surgery (38). Manypatients will also be medically unfit for surgery orwill refuse surgery based on fear of morbidity andmortality (38). In such cases, chemotherapy and re-irradiation are the only remaining treatment options.Chemotherapy alone offers limited palliation withresponse rates of approximately 10–40%, mediansurvivals of 5–9 months, and no long term survivorseven with the best multidrug regimens (7–13). Theresponse rate and median survival data from severalrecent studies are summarized in Table 1. There arepromising preclinical and phase I–II data for bio-logically directed therapies. These include EGFRblocking agents ZD1839 and C225, CDK inhibitors,cytotoxic viral agents targeted against p53 deficientcells (ONXY-015), and angiogenesis inhibitors (1).Further investigation of these approaches are war-ranted for patients with clinically apparent distantmetastases. However, the early results of reirradia-tion of unresectable patients suggests that responserates exceed that of chemotherapy alone and thatlong term survival is possible.

REIRRADIATION FEASIBILITY AND RESULTS

There are theoretical concerns of unacceptable normaltissue toxicity in reirradiated patients where cumu-lative radiation doses may reach twice the expectedtolerance of normal tissues, often with doses in excessof 100 Gy (39). Complication rates after reirradiationvary from 7% to 50% but are higher for reirradiation ofthe nasopharynx due to its proximity to brain, cranialnerves, and the orbits (16,40). There are now data fromthe reirradiation of rhesus monkeys that demonstraterecovery of sublethal damage in the spinal cord. In therhesus monkey model, rates of myelitis were far lowerthan expected for reirradiation of the spinal cord.Conservative estimates suggest that at least 60% of theinitial dose effect is repaired by the spinal cord iftreatment courses are separated by 1–3 years (41).Given the potentially devastating consequences oftransverse myelitis, care should be taken to limit

22 J . K A O E T A L .

radiation dose to the spinal cord until more humandata becomes available. However, unresectable pa-tients should not necessarily be denied a potentiallycurative treatment for theoretical concerns of excesstoxicity that have yet to be demonstrated. Normaltissue tolerance data from reirradiation of head andneck cancers are scarce, but some authors have sug-gested that cumulative biologically equivalent dosesof up to 130 Gy in 2 Gy fractions are safe (42).

A review of data from several major academiccenters employing reirradiation for recurrent andsecond primary head and neck cancer reveals sig-nificantly varying outcomes with 5 year survivalsranging from as low as 13% in unselected series to ashigh as 93% in highly selected series (14–26). Theresults from relatively unselected reirradiated pa-tient series are summarized in Table 2.

The differences among published results are inpart attributable to variation in technique, dose ofreirradiation, patient performance status, anatomicsite(s), type of recurrence (primary, nodal, meta-static), use of concomitant chemotherapy, and thenumber of patients treated. While the outcomes ofreirradiation alone are superior to chemotherapyalone, the results from reirradiation are inferior tothe expected control of tumors of similar size andstage treated with primary radiotherapy. For in-stance, in nasopharyngeal carcinoma, reirradiationof recurrent T1-2 disease will result in 38% actuarial5 year survival and reirradiation of recurrent T3-4disease will result in 15% actuarial 5 year survival(26). In contrast, for patients with T1-2 nasopharyn-geal cancers treated at time of first diagnosis with RTalone, 5 year survival ranges from 68% to 76%. ForT3-4 tumors, 5 year survival rates range from 0% to

55%. The reduced effectiveness may be due to thelower reirradiation doses used in some series basedon fear of cumulative toxicity, but it is equally likelyto be the result of more aggressive and radioresistantclonogens that survived initial radiation. This hy-pothesis is supported by in vitro assays of culturedtumor cells from recurrent head and neck squamouscell carcinomas following a curative course of ra-diotherapy (43). The radioresistant population ofcells in a recurrent tumor require a more aggressivetreatment strategy. Concomitant chemotherapy mayrepresent an effective approach due to radiosensiti-zation and direct cytotoxicity.

Reirradiation of local recurrences with brachy-therapy is theoretically attractive for accessible lowvolume disease given that high doses can be deliv-ered to the tumor while sparing surrounding normaltissues. Because potentially microscopic disease insurrounding tissues is not addressed, brachytherapyalone is only appropriate for highly selected patientswith limited recurrences who likely also representexcellent surgical salvage candidates. Local controlis achievable in 60–70% of these selected patients(mostly oropharynx) with 15–30% 5 year survival(44,45). Unfortunately, the majority of recurrenthead and neck cancers are not appropriate candi-dates for brachytherapy alone.

CONCOMITANT CHEMOTHERAPY ANDREIRRADIATION

Hydroxyurea, cisplatin, and 5-fluorouracil (5-FU)are radiosensitizing agents commonly used in head

TABLEABLE 1 Response rates and median survival for recurrent head and neck cancer patients treated with chemotherapy alone

Author Chemotherapy Median survival (mo) Response rate (%)

Murphy et al. (7) CP + 5-FU 8.0 22

TAX + CP 8.0 28

Jacobs et al. (8) CP NR 18

CP + MTX + LV NR 33

Jacobs et al. (9) CP 5.0 17

5-FU 5.5 13

CP + 5-FU 6.1 32

Bendahmane et al. (10) DOC+5-FU 9.6 27 (PR)

Forastiere et al. (11) MTX 5.6 10

CP + 5-FU 6.6 32

CARBO + 5-FU 5.0 21

Burtness et al. (12) CP�C225 6.7 13.7

Liverpool Head and Neck Oncology Group (13) CP NR 28

MTX NR 38

CP+5-FU NR 24

CP+MTX NR 22

Abbreviations: CARBO, carboplatin;CP, cisplatin; DOC, docetaxol; 5-FU, 5-fluorouracil; LV, leucovorin; MTX, methotrexate; NR, not

reported; PR, partial responders; TAX, taxol.

R E I R R A D I A T I O N O F R E C U R R E N T H E A D A N D N E C K C A N C E R 23

TABLEABLE 2 Results of reirradiation in head and neck malignancies

Reported

Series

Number of

patients (type of

treatment)

Median

follow up

(months)

Locoregional

control (%)

Overall survival (%) Chemotherapy Median or range

of reirradiation

dose (Gy)

Fatal or severe

complication

rate (%)

Benchalal et al.

(24)

14 (S + RT) 17 36 64 (1year), 36 (2 years) None 60 NS

5 (CRT) 17 NS NS Cisplatin, 5-FU 60 NS

Dawson et al.

(17)

40 (MIX) 60 19.5 (2 year actuarial) 18 (DFS at 4 years) 35% cisplatin, carboplatin 60 18

De Crevoisier

et al. (22)

169 (MIX) 70 NS 21 (2 years), 9 (5 years) 16% none, 63% 5-FU, hydrea,

21% 5-FU, cisplatin, mitomycin

60 or 65 32

Emami et al.

(18)

48 (S + RT) NS 20.8 20 (5 years) None NS 16

40 (RT) NS 12.5 13 (5 years) None NS NS

Gandia et al.

(21)

33 (CRT) 20 36 23 100% 5-FU, hydroxyurea 40–60 NS

Haraf et al.

(14)

45 (CRT) 41 26 (2 year actuarial),

20 (5 year actuarial)

22 (2 year actuarial),

14.6 (5 year actuarial)

100% 5-FU, hydroxyurea;

some with cisplatin

50 11

Haraf et al.

(15)

48 (CRT� S) 10.8 42 (3 years) 23 (3 years) 100% 5-FU, hydroxyurea,

paclitaxel

60 or 75 21

Pomp et al.

(19)

55 (MIX) (1–120) 33 20 (5 years) 49% (27/55) CTX not specificed 46 NS

RTOG 96-10

(25)

81 (CRT) 16.3 NS 42 (1 year), 16 (2 years) 100% 5-FU, hydroxyurea 60 24

RTOG 99-11 Accruing (CRT) NS NS NS 100% cisplatin, paclitaxel, G-CSF 60 NS

Spencer et al.

(20)

35 (CRT) NS NS NS 100% 5-FU, hydroxyurea 40, 48, or 60 11

Stevens et al.

(16)

100 (RT) (min 13

months)

27 (5 years, recur),

60 (5 years, 2nd pri)

17 (5 year, recurrent),

37 (5 year, 2nd pri)

None 50 9

Wang et al.

(26)

20 (RT) 48 61 93 (5 years, includes

salvage)

None 65–66 NS

Weppelmann

et al. (23)

21 (CRT) 7 NS 56 (1 year) 100% 5-FU, hydroxyurea 40 or 48 NS

RT, reirradiation only; CRT, chemotherapy and radiation therapy; MIX, reirradiation and some patients got chemotherapy; S, surgical debulking; NS, not stated.

24

J.K

AO

ET

AL

.

and neck cancer. This has been established in vitroand in vivo (31,46–50). The addition of concomitantchemotherapy in the primary treatment of head andneck cancer has been associated with improvedoutcomes (31–33,51). Consequently, the use of con-comitant chemotherapy is being investigated inmore aggressive prospective reirradiation protocols.In recently reported relatively unselected series, re-irradiation concomitant with chemotherapy appearsto offer the most promising results (14,15,20–23,25).The results of concomitant chemotherapy and radi-ation therapy are not yet mature with most seriesreporting data with less than 5 years of follow up.

The results of reirradiation with concomitantchemotherapy at the University of Chicago werereported by Haraf et al. (14,15). The initial series re-ported the results of four prospective phase I trials ofconcomitant chemotherapy and reirradiation in 45patients with unresectable tumors. The protocolsallowed for prior chemotherapy as well as patientswith asymptomatic distant metastases who hadbulky local recurrences. Most of these patients re-ceived radiation at 2 Gy/day and concomitant che-motherapy consisting of 5-FU and hydroxyurea.Chemotherapy and radiation were administeredconcomitantly for five consecutive days followed bya nine day break which constituted one cycle oftreatment. Cycles were repeated until the plannedend of reirradiation. The 5 year actuarial survival,progression free survival, and local control rateswere 15%, 14%, and 20%, respectively. Fatal com-plications occurred in 11% of patients, including twopatients with sepsis, one patient with carotid rup-ture, one with respiratory arrest, and one with brain

necrosis which occurred in a patient with recurrentnasopharyngeal cancer (14).

The predominant pattern of failure in the previ-ously described series was locoregional, thereforedose intensity was increased in later protocols in anattempt to improve locoregional control. The resultsof the most recent recurrent head and neck reirra-diation series at the University of Chicago were re-cently reported in which patients were treated withTaxol, 5-FU and hydroxyurea concomitant withtwice daily irradiation. The radiation regimen con-sisted of 1.5 Gy bid to a total dose of 75 Gy in thosepatients who did not undergo surgical debulkingprior to treatment. For the 33% of patients who wereconsidered marginally resectable, treatment con-sisted of optimal surgical debulking prior to radia-tion. The total dose of reirradiation was 60 Gy in2 Gy daily fractions. Treatment was given on alter-nating weeks similar to the first trial, and the resultshave recently been published (15). The treatmentschema used in this trial is illustrated in Figure 1.These data are now matured to a median follow upof 72.5 months and the median survival, 4 yearoverall survival, and 4 year progression free survivalwere 11 months, 22%, and 40%, respectively (re-cently submitted unpublished data).

The RTOG recently reported the results of 86patients treated prospectively at multiple institu-tions treated on alternating weeks with hyperfrac-tionated radiation therapy concomitant withchemotherapy. Patients received 5-FU and hy-droxyurea concomitant with radiation therapy de-livered in 1.5 Gy bid fractions to a total dose of60 Gy. With a median follow up of only 16 months,

Figure 1 University of Chicago reirradiation treatment schema.

R E I R R A D I A T I O N O F R E C U R R E N T H E A D A N D N E C K C A N C E R 25

the 1 year and 2 year overall survival were 42% and16%, respectively (25). Compared with the resultsfrom the University of Chicago protocol, the resultsof RTOG 96-10 may be inferior due to a lower totaldose of reirradiation (60 versus 75 Gy) and the ab-sence of paclitaxel in the chemotherapy regimen. Acurrent prospective multicenter trial (RTOG 99-11) isaccruing patients with recurrent squamous cellcancer of the head and neck to a phase II studyconsisting of paclitaxel and cisplatin in conjunctionwith split course hyperfractionated reirradiation.Longer follow up is needed in these recent studies toadequately assess for long term survival as well aslate toxicity.

Given the suboptimal outcomes and increasedrisk of toxicity with reirradiation, particularly withconcomitant chemotherapy, it is important to iden-tify prognostic factors that can help define thegroups most likely to benefit from reirradiation.Several potentially important prognostic factors thathelp define such groups have been described in theliterature and are reviewed in this manuscript.

PROGNOSTIC FACTORS

Debulking surgery prior to reirradiation

De Crevoisier et al. (52) recently reported the longterm results of salvage surgery prior to reirradiationin a small series of 25 patients. In this series, patientswho had positive margins and/or lymph node in-volvement with extracapsular extension followingattempted salvage surgery were reirradiated withconcomitant chemotherapy. Chemotherapy con-sisted of 5-FU (800mg=m2=d), hydroxyurea (1.5 g/day). Radiation was delivered once daily to a totaldose of 60 Gy in 2 Gy fractions. Treatment was de-livered on a 14 day cycle with five days of treatmentfollowed by a nine day break. These authors re-ported a 43% 4 year survival and 26% 5 year diseasefree survival.

Similar results have been observed by Haraf et al.who reported that effective (removal of all grossdisease) debulking surgery was significantly pre-dictive (p < 0:05) of freedom from progression atany site (recently submitted unpublished data). Inthe same series, the 4 year overall survival was 43%for patients who had undergone debulking surgeryversus 11% for those who had not. The 4 year loco-regional control was 71% for resected patients versus54% for those unresected.

Dawson et al. (17) reported no significant increasein survival on multivariate analysis for patients re-ceiving surgery before irradiation. However, only33% of the patients who proceeded to surgery before

reirradiation had resection of all gross disease. Irre-spective of surgery in the same study, the mediansurvival of patients with non-bulky (< 3cm diame-ter) tumors was 33 months compared with 11.8months for bulky tumors. On multivariate analysis,nonbulky tumors showed a trend (p ¼ 0:10) towardimproved overall survival lending validity to thehypothesis that patients with a low volume of dis-ease prior to reirradiation are most likely to benefitfrom aggressive locoregional treatment.

Anatomic site

Among highly selected series of reirradiation, thebest reported outcomes are seen in patients withlocal recurrences of nasopharyngeal or laryngealcancer. On multivariate analysis, Dawson et al. re-ported that laryngeal and nasopharynx recurrencespredicted for more favorable outcomes (17). Basedon reirradiation of 20 patients with recurrent stage Iand II laryngeal cancer, Wang reported a 5 yearoverall survival of 93% (including surgical salvage)and local control of 60% with no severe complica-tions (27). Several series have reported the results ofreirradiation of nasopharyngeal cancer with 5 yearoverall survival rates of between 20% and 60% andlocal control rates of between 15% and 60%(26,28,40,53,54). The outcomes for these highly se-lected series are encouraging, but they represent avery small portion of the patient population withrecurrent head and neck cancers.

Second primary versus recurrent tumor

New primary cancers should respond better totreatment than recurrent tumors in a previously ir-radiated field due to the inherent aggressiveness andradioresistance of recurrent tumor cell populations.Several studies have reported data which supportthis hypothesis. Based on data from the 81 patientstreated in the RTOG 96-10 study, Spencer et al. re-ported that the 1 year survival rate and mediansurvival for patients with a second primary was 54%and 19.8 months compared with 38% and 7.7 monthsfor patients with recurrent cancers, respectively (25).Stevens et al. analyzed 100 patients treated with re-irradiation alone and reported a 5 year actuarialoverall survival and locoregional control of 17% and27% for recurrent tumors compared with 37% and60% for second primary cancers in a previously ir-radiated field (16). As time to recurrence increases, itis more difficult to distinguish between a laterecurrence and a second primary cancer, therefore

26 J . K A O E T A L .

some institutions have reported on the time intervalto recurrence as a prognostic factor.

Time interval since prior irradiation

Several studies have reported time interval to failureto be an important prognostic factor (16,19,20,25,55,56). Spencer et al. (20) reported that patientswho received their initial course of radiation therapy24 months or more before the repeat course had amedian survival of 15 months versus 6.5 months inpatients who were treated within 1 year of theirtherapy. Stell evaluated 515 recurrent cancers of theupper aerodigestive tract and concluded that alonger disease free interval from initial irradiationcorrelated with better survival after treatment oflocally recurrent disease (57). Based on data from the81 patients treated in RTOG 96-10, Spencer et al. re-ported that the 1 year survival rate for patientstreated within 3 years of prior RT was 35% com-pared with 48% for patients treated greater than 3years out from prior RT (p ¼ 0:017) (25).

Reirradiation: evidence for a dose–responserelationship

Several authors have reported radiation dose as aprognostic factor in reirradiated tumors (14,15,17,56). The argument for high dose reirradiation liesin the hypothesis that recurrent tumor cell popula-tions have arisen from radiation resistant clonogens.There is little reason to believe that doses smallerthan those originally administered will be curative.Almost without exception, studies have shown thathigher doses lead to better control and survival. TheUniversity of Chicago initially reported that the doseof reirradiation strongly correlated (p ¼ 0:005) withsurvival (14). The median and 2 year survival forpatients receiving P58 Gy were 11.3 months and35%, respectively, compared with 6.5 months and8% for patients receiving <58 Gy. In a second pub-lished series, higher radiation doses were againsignificantly predictive of freedom from progressionat any site and freedom from local/regional pro-gression (p < 0:001 in both cases) (15). In both series,radiation dose was the single most important factorassociated with survival, progression free survival,and locoregional control. In the more recent doseescalated protocol, severe/fatal complications in-creased from 11% to 21% but most of the fatalcomplications were unrelated to reirradiation. Em-ami reported benefit for patients treated to doseshigher than 50 Gy (18). In his series, the patients

receiving higher doses had an 80% complete re-sponse rate and 25% eventual control comparedwith 44% and 11% for those receiving lower doses.Despite aggressive therapy with high doses ofreirradiation concomitant with chemotherapy, themajority of failures are still locoregional illustratingthe high proportion of radioresistant cells in recur-rent tumors and the need for high reirradiationdoses.

THE UNIVERSITY OF CHICAGO APPROACHTO REIRRADIATION

Potential reirradiation patients are jointly evaluatedby radiation oncology, medical oncology and oto-laryngology. Eligible patients must have recurrentdisease considered unresectable for cure. Resectedpatients are considered eligible if they have close orpositive margins after definitive surgery. The radi-ation criteria for reirradiation are as follows: theminimum treatment volume must include all grossdisease found on examination or diagnostic study.When considered feasible, the treatment fields alsoinclude areas at risk for microscopic disease. Thecumulative dose to the spinal cord (initial radiationplus reirradiation) should be kept below 50 Gywithout compromising target coverage. Patientswho meet the above criteria are offered entry onphase I/II studies of concomitant combined modal-ity therapy as previously described in this article.

All patients undergo CT based treatment plan-ning in our department and are treated with 3Dconformal therapy. The minimum target volume fortreatment planning includes all gross disease plusmargin to account for setup uncertainty. Video as-sisted setup is used for verification of patient posi-tioning during treatment to reduce setup uncertaintyto 3 mm or less (58). In most patients, it is possible toinclude high risk microscopic disease target volumeswhich include the primary and often the secondaryuninvolved draining lymph nodes. The reirradiationdose for gross disease in unresected patients rangesfrom 70 to 75 Gy. Resected patients typically get 55–60 Gy to the postoperative field. The dose to the ar-eas at risk for microscopic disease ranges from 45 to60 Gy in both resected and unresected patients.

Although we use intensity modulated radiationtherapy (IMRT) on virtually every newly diagnosedhead and neck cancer patient, we have not usedIMRT on the retreatment patient population. Thecurrent commercially available treatment planningsoftware tends to produce plans that are too inho-mogeneous and have poor target coverage whensevere limitations are placed on spinal cord dose.

R E I R R A D I A T I O N O F R E C U R R E N T H E A D A N D N E C K C A N C E R 27

Another concern is leakage through the collimatorduring treatment since the beam-on time for IMRT ismuch greater, adding potential error to spinal corddose calculations. We currently rely on customblocked photon fields with electron field matchingover the spinal cord to ensure that the cumulativedose to the cord does not exceed 50 Gy.

All reirradiation patients receive concomitantchemotherapy. We have studied multiple regimensin the past (14,15). Our current protocols include theaddition of a promising anti-VEGF antibody to ourstandard concomitant chemotherapy radiation regi-men. The combination of angiogenesis inhibitorswith radiation therapy has been shown to be highlyeffective in eradicating radioresistant head and neckcancer cells in vivo (59).

CONCLUSIONS

In patients with an unresectable locoregional recur-rence of a head and neck cancer or a second primarycancer in the context of a previously irradiated vol-ume, high dose reirradiation concomitant with che-motherapy is a potentially curative treatment option.Often, this is the only potentially curative optionavailable. While chemotherapy alone remains thestandard of care, it has limited benefit. Responserates with chemotherapy alone are lower than thoseobserved with concomitant chemotherapy and ra-diation therapy. Additionally, the responses ob-served with chemotherapy alone are short lived andlong term survival is almost never seen. The argu-ment against reirradiation has focused on toxicity.Physicians are often reluctant to offer a secondcourse of radiation to the head and neck due to alack of experience and concern over potential liti-gation. Given that reirradiation often represents theonly curative treatment option, a higher level ofpotential toxicity may be acceptable. There are nowincreasing data suggesting that toxicity, while higherthan with primary irradiation, is significantly lowerthan predicted in reirradiated patients. Any poten-tial serious toxicity associated with reirradiationmust be weighed against the symptoms seen withlocal progression of untreated recurrent head andneck cancers that will ultimately result in death.

It is clear that the overall prognosis remains poorfor patients with recurrent head and neck cancer,even after high dose reirradiation and chemother-apy. Analysis of the available data suggests thatpatients most likely to benefit from reirradiation in-clude recurrences of early stage larynx or naso-pharynx cancer. Irrespective of site, it appears thatlate failures as well as second primary cancers aremore favorable. There are convincing data that in-

creasing intensity of locoregional treatment withhigh doses of reirradiation and maximal surgicaldebulking may be beneficial.

Patients seeking a curative option should be en-rolled in ongoing clinical trials designed to helpdefine the optimal regimen of concomitant chemo-therapy and high dose reirradiation. Reirradiationshould be employed by experienced personnel inacademic centers where such protocols are available.Given the toxicity associated with reirradiation,further studies and analyses of available data shouldfocus on identification and evaluation of prognosticfactors that are potentially useful in defining groupsof patients most likely to benefit from aggressivereirradiation. Prospective quality of life studies areneeded to better define the sequellae of combinedmodality reirradiation. Areas of ongoing investiga-tion include the use of IMRT as a strategy to reduceearly and late toxicity by decreasing the amount ofnormal tissue receiving high dose radiation, noveltreatment regimens with varying chemotherapeuticand biologic agents, and radiotherapy deliverytechniques aimed at optimizing outcomes withoutincreasing complications.

ACKNOWLEDGEMENTS

The authors thank the Robert and Valda SvensenMemorial for its generous support. This work wasalso funded in part by the University of ChicagoCancer Research Center Grant P30CA-14599 and theGeraldi Norton Memorial Corporation.

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