A Multi-institutional Survey of the Effectiveness of Chemotherapy Combined with Radiotherapy for Patients with Nasopharyngeal Carcinoma

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1 Jp J Cli Ocol 2004;34(10) doi: /jjco/hyh111 Origial Articles A Multi-istitutioal Survey of the Effectiveess of Chemotherapy Combied with Radiotherapy for Patiets with Nasopharygeal Carcioma Mitsuhiko Kawashima 1, Nobukazu Fuwa 2, Miyako Myoji 3, Katsumasa Nakamura 4, Takafumi Toita 5, Shigeru Saijo 6, Nobuyuki Hayashi 7, Hiroshi Ohishi 8, Naoto Shikama 9, Makoto Kao 10 ad Michiori Yamamoto 11 1 Divisio of Radiatio Ocology, Natioal Cacer Ceter Hospital East, Kashiwa, Chiba, 2 Departmet of Radiatio Ocology, Aichi Cacer Ceter, Nagoya, 3 Departmet of Radiatio Ocology, Natioal Sapporo Hospital, Sapporo, 4 Departmet of Cliical Radiology, Kyushu Uiversity, Fukuoka, 5 Departmet of Radiatio Ocology, Uiversity of the Ryukyus, Okiawa, 6 Departmet of Head ad Neck Surgery, Miyagi Cacer Ceter, Sedai, 7 Departmet of Radiatio Ocology, Nagasaki Uiversity, Nagasaki, 8 Departmet of Radiatio Ocology, Uiversity of Yamaashi, Kofu, 9 Departmet of Radiology, Shishu Uiversity, School of Medicie, Matsumoto, Nagao, 10 Departmet of Otolarygology, Fukushima Medical Uiversity, Fukushima ad 11 Departmet of Radiatio Ocology, Natioal Kure Medical Ceter, Kure, Hiroshima, Japa Received May 26, 2004; accepted August 16, 2004 Backgroud: Previous radomized trials have show a survival advatage of cocurret platium-based chemoradiotherapy with or without adjuvat chemotherapy for advaced asopharygeal cacer. Applicability of these data to a Japaese populatio is a importat issue which remais to be solved. Methods: A retrospective survey of treatmet of patiets with asopharygeal cacer i 17 istitutios i Japa was doe with special referece to the relatioship betwee the type of chemotherapy ad survival outcome. Chemotherapy used was classified accordig to: (i) whether >2 courses of platium plus 5-fluorouracil (FP) was give; or (ii) whether platium was admiistered cocurretly with radiotherapy (RT). This resulted i three groups beig produced cosistig of (i)/(ii) = YES/YES, other miscellaeous (MISC) ad RT aloe. Results: Of 333 evaluable replies, 67 patiets (20%) correspoded to the YES/YES, 192 (58%) to the MISC ad 74 (22%) to the RT aloe group. The YES/YES group achieved a better overall survival tha RT aloe for patiets with itermediate stage (T3N0 or T1 3N1, 81.9 versus 60.7% at, P = 0.042) ad advaced stage (T4 or N2/3, 56.6 versus 31.5%, P = 0.017) disease. The MISC group achieved a almost idetical survival rate to that i the YES/YES group for patiets with itermediate stage disease (81.9% at, P = 0.968), whereas it was ot sigificatly differet from that of the RT aloe group for patiets with advaced stage disease (44.0%, P = 0.261). Coclusio: The results of this survey mirrored the data from previous radomized trials for patiets with itermediate ad advaced stage asopharygeal cacer i Japa. However, cofirmatory prospective trials are required to test the efficacy of less toxic approaches for patiets with itermediate stage disease. Key words: asopharygeal cacer radiotherapy chemotherapy survey For reprits ad all correspodece: Mitsuhiko Kawashima, Divisio of Radiatio Ocology, Natioal Cacer Ceter Hospital East, 6-5-1, Kashiwaoha, Kashiwa, Chiba , Japa. mkawashi@east.cc.go.jp INTRODUCTION Although asopharygeal cacer ofte respods well to radiotherapy (RT), the cure rate i patiets with advaced stage disease has ot bee satisfyig (1,2). Local recurrece at the periphery of the irradiated area receivig a isufficiet RT # 2004 Foudatio for Promotio of Cacer Research

2 570 Survey of CRT for asopharygeal cacer dose due to its proximity to critical orgas ad a high propesity for distat metastasis have bee the two major causes of treatmet failure (3). The additio of chemotherapy to RT for patiets with advaced disease has bee studied extesively durig the last 2 decades (4 12). These results have idicated the followigs: (i) i compariso with treatmet with RT aloe, cocurret chemoradiotherapy with or without adjuvat chemotherapy showed a sigificat survival beefit i two radomized studies (6,11); (ii) sequetial (eoadjuvat ad/ or adjuvat) chemotherapy with RT failed to achieve survival advatage i seve radomized studies (4,5,7 10,12), although some showed a loger relapse-free survival whe eoadjuvat chemotherapy was used (5,8). Nasopharygeal cacer is a relatively rare disease i Japa, compared with coutries i which it is edemic, ad, to our kowledge, o large-scale cliical reports have bee published from our coutry. We therefore coducted a multi-istitutioal questioaire survey to look at patters of treatmet ad outcome of this disease, givig special attetio to the effect of RT combied with chemotherapy o survival outcome. The pricipal purpose of this study was to evaluate the applicability of results of previously reported radomized trials coducted i the USA ad edemic coutries to the Japaese populatio with this disease. SUBJECTS AND METHODS SURVEY A questioaire was set i August 2002 to 17 istitutios (seve uiversities, four affiliated hospitals ad six atioal or regioal cacer ceters i Japa) participatig i the study group of chemoradiotherapy for head ad eck cacer supported by Grat-Aided Cacer Research 14-15, Miistry of Health, Labor ad Welfare of Japa. It requested iformatio about the treatmet ad outcome for all patiets with biopsyprove asopharygeal carcioma. The data collected icluded age, geder, histology, cliical stage, RT dose, cotets ad timig (eoadjuvat, cocurret, alteratig or adjuvat) of chemotherapy, patters of failure ad survival outcome. Collected data were aalyzed i autum The followig defiitios were applied to the iitial treatmet give, with these defiitios ot chagig eve where salvage chemotherapy was ultimately used for failure of respose to the iitial treatmet give: eoadjuvat therapy = chemotherapy followed by RT; adjuvat therapy = chemotherapy after completio of RT; cocurret therapy = simultaeous admiistratio of chemotherapy ad RT; ad alteratig therapy = repetitive sequetial admiistratio of chemotherapy ad RT (e.g. chemo RT chemo RT). To be icluded i the assessmet, the patiet must have had pre-treatmet computed tomography (CT) ad/or magetic resoace imagig (MRI), ad the diseases were restaged accordig to the 1997 UICC TNM stagig system. Tumor histology was divided ito two categories oly (i.e. keratiizig or o-keratiizig), istead of the World Health Orgaizatio (WHO) types 1 3, because of the iteristitutioal variatio of the diagostic criteria employed. Total RT dose/fractioatio to the primary tumor, grossly ivolved cervical lymph odes ad other odal areas were described separately. The dates of first detectio of recurrece of the primary tumor, ivolvemet of cervical lymph odes ad distat orga metastasis were surveyed to aalyze patters of failure. The date of patiet death (or last follow-up for survivig patiets) was also surveyed. REPLIES All of the 17 istitutios replied to the questioaire, ad iformatio o the treatmet of 385 patiets for whom treatmets had started betwee Jauary 1989 ad July 2001 was received. The umber of patiets i each istitutio raged from three to 90 (media 18 patiets), ad eight istitutios had 20 or more patiets durig this study period. Thirty-three patiets were excluded for the followig reasos: 19 were lost to follow-up withi 2 years without evidece of disease recurrece; eight did ot allow distictio betwee keratiizig or o-keratiizig disease o histological examiatio; three had orga metastases at the time of first presetatio; two had palliative treatmet aloe; ad i oe patiet stagig was ot possible from the data provided. A additioal 19 patiets were excluded because they had bee give itraarterial ifusio chemotherapy via the superficial temporal artery before commecemet of RT (stage II, four; stage III, eight; stage IV, seve) accordig to their istitutioal policy. I this treatmet, the cisplati was eutralized with sodium thiosulfate immediately after eterig the systemic circulatio from the locoregioal area, removig its systemic activity (13). The outcome i the remaiig 333 patiets is the basis for the subsequet aalysis, the patiet characteristics of which are show i Table 1. The media follow-up period for survivig patiets was 69 moths (rage ). CLASSIFICATION OF CHEMOTHERAPY PROCEDURES Based o the previous radomized trials which showed positive results for asopharygeal cacer (6,11) ad a metaaalysis of the effect of addig chemotherapy to RT for o-asopharygeal cacer (14), two assumptios were made: (i) the key chemotherapeutic agets for asopharygeal cacer were platium ad 5-fluorouracil (5-FU; the FP regime); ad (ii) cocurret use of platium might be more effective tha sequetial use. Cosequetly, the type of chemotherapy used was classified based o the followig two items: (i) whether the FP regime was admiistered for two or more cycles; ad (ii) whether the platium was admiistered cocomitatly with RT. Patiets were the classified ito the followig five groups regardig (i)/(ii) = YES/YES, YES/NO, NO/YES, NO/NO ad RT aloe. Because a multi-istitutioal phase II study of alteratig chemoradiotherapy for advaced asopharygeal cacer had bee coducted durig this study period, 45 patiets who participated i this study were icluded i our data set (15).

3 Jp J Cli Ocol 2004;34(10) 571 Table 1. Characteristics of patiets Number % Age (years) Rage Media 55 Male:female 252:81 Histology Keratiizig No-keratiizig T classificatio T T T T N classificatio N N N N Stage (UICC, 1997) Stage I 24 7 Stage II Stage III Stage IV Total I additio, 19 patiets who had received alteratig chemoradiotherapy because of their physicia s discretio were also icluded. These 64 patiets who received alteratig chemoradiotherapy were regarded as cocurret chemoradiotherapy i the aalysis. STATISTICAL ANALYSIS Overall (OAS) ad progressio-free (PFS) survival rates from the start of RT were calculated from the replies. To calculate OAS, death from ay cause was cosidered as a evet ad cesored at the time of last follow-up for a survivig patiet; however, patiets who were lost to follow-up after tumor recurrece ( = 17) were cosidered as dead at the date of last follow-up. Recurrece of the tumor at ay sites or death from ay cause were defied as evets for calculatio of PFS. Tumor recurrece at the primary site ad/or cervical lymph odes was cosidered as a evet to calculate the locoregioal cotrol rate (LRC), ad cesored at the time of the last follow-up or patiet death whe there was o evidece of either of these evets. Distat failure was cosidered as a evet for calculatio of distat metastasis-free rate (DMF), ad cesored at the time of locoregioal failure, patiet death or date of the last follow-up visit whe there was o evidece of distat metastasis. Time to evet was calculated usig the Kapla Meier method (16), ad the sigificace of ay differece was estimated usig the log-rak test. Multivariate aalysis was doe usig Cox s proportioal hazards model (17). RESULTS RADIOTHERAPY Of 333 patiets, 23 (7%) received twice daily fractioatio RT ad 12 (4%) uderwet a brachytherapy boost. Otherwise all patiets uderwet exteral beam RT with oce daily fractioatio admiisterig Gy (media 2.0 Gy) per fractio. Differeces i fractioatio ad the use of brachytherapy were ot take ito accout i the followig aalysis because of the small umber of patiets havig such variatios. Oe patiet could ot receive ay RT because of the toxicity due to eoadjuvat chemotherapy; however, this patiet was icluded i the survival aalysis because of the radical itet of the treatmet. The total dose of RT to the primary tumor raged from 0 to 84.6 Gy (media 69.4 Gy). Metastatic cervical lymph odes ad elective odal areas received Gy (media 66.0 Gy) ad Gy (40.0 Gy), respectively. All but two patiets received a total dose of >50 Gy, ad 325 (98%) patiets received >60 Gy to the primary tumor ad metastatic cervical lymph odes. CHEMOTHERAPY A total of 259 (78%) patiets received chemotherapy as a part of their iitial treatmet. Of 24 patiets with stage I disease, 15 (63%) uderwet RT aloe. O the other had, 74 out of 100 (74%), 86 out of 100 (86%) ad 90 out of 109 (83%) patiets with stage II, III ad IV, respectively, received chemotherapy combied with RT. Of these 259 patiets, 248 (96%) received platium-based regimes ad 161 (62%) received two or more cycles of systemic ifusios of the FP regime, mostly by meas of bolus ifusios of platium o day 1 ad 4 5 days of cotiuous ifusio of 5-FU. Otherwise pepleomyci ( = 33), vitami A ( = 27), adriamyci ( = 11), methotrexate ( = 5) or vica alkaloids ( = 2) were used with or without platium ad/or 5-FU accordig to istitutioal protocols or physicias discretio. Accordig to the treatmet classificatio described above, 67 patiets correspoded to the YES/YES, 94 to the YES/NO, 56 to the NO/YES, 42 to the NO/NO ad 74 to the RT aloe group. For patiets i YES/YES or YES/NO groups ( = 161), the total dose of cisplati give raged from 75 to 100mg/m 2, with the dose of 5-FU beig mg/m 2 i each cycle of the FP regime, with idividual dose modificatio as ecessary. Carboplati (>400mg/m 2 ) was used istead of cisplati i the FP regime for 10 patiets. Thirtee patiets i these groups received other chemotherapeutic agets i additio to FP.

4 572 Survey of CRT for asopharygeal cacer I the YES/YES group, two or more cycles of FP were admiistered cocurret or alterated with RT i 59 patiets (four followed by additioal FP i the adjuvat settig). Six patiets received oe cycle of FP cocurret with RT, followed by 1 2 cycles of adjuvat FP i three or preceded by 2 3 cycles of eoadjuvat FP i three. Two patiets received cocurret sigle aget cisplati, followed by three cycles of adjuvat FP. I the YES/NO group, 53 received 2 4 cycles (media, two cycles) of FP i the adjuvat settig, ad 37 received 2 3 cycles (media, two cycles) i the eoadjuvat settig. The other four patiets received both eoadjuvat ad adjuvat FP. For 56 patiets i the NO/YES group, 28 patiets received sigle aget platium at various doses cocurret with RT (four received additioal adjuvat chemotherapy usig oe course of FP regime) ad six received platium with drugs other tha 5-FU cocurret with RT (three received adjuvat chemotherapy usig oral FU derivatives). Fiftee received FUbased cocurret chemotherapy with split-course RT i combiatio with alteratig chemotherapy usig platium ad pepleomyci based o istitutioal policy. Seve received a sigle cycle of FP cocurret with RT without further chemotherapy. The NO/NO group (42 patiets) icluded 17 patiets who uderwet miscellaeous platium-based eoadjuvat ( = 17) or adjuvat ( = 9) chemotherapy other tha the FP regime. The remaiig 16 patiets received FU-based chemotherapy without platium cocurret with RT i 12, ad sequetially i four. There were o statistically sigificat differeces i total RT dose to the primary tumor, grossly ivolved odes ad elective odal areas amog these five groups (data ot show). SURVIVAL OUTCOMES The OAS ad PFS rates at for all patiets were 59% (95% cofidece iterval 53 65%) ad 50% (44 56%), respectively. The OAS for patiets with stage I ( = 24), II ( = 100), III ( = 100) ad IV ( = 109) disease was 87% (73 100%), 75% (66 84%), 56% (46 67%) ad 41% (30 51%), respectively, whereas the PFS was 79% (63 96%), 61% (51 71%), 48% (37 58%) ad 37% (28 47%) at. Table 2 shows LRC, DMF, PFS ad OAS accordig to the stage ad histology of the disease. T4 ad/or N2 3 were statistically sigificat factors associated with a poor progosis. Cumulative total RT dose to the primary tumor (>66 Gy versus <66 Gy) did ot have a sigificat ifluece o OAS (58 versus 60% at, P = 0.746). The results of uivariate ad multivariate aalyses to evaluate the progostic Table 2. Tumor cotrol ad survival rate at accordig to the stage group ad histology Stage Locoregioal cotrol rate Distat metastasis-free rate Relapse-free survival rate Overall survival rate No-keratiizig T ( ) 84.2 ( ) 60.4 ( ) 75.2 ( ) T ( ) 79.9 ( ) 50.5 ( ) 64.9 ( ) T ( ) 73.8 ( ) 54.5 ( ) 65.7 ( ) T ( ) 60.4 ( ) 38.0 ( ) 44.2 ( ) NS T1 3 versus T4, P < T1-3 versus T4, P = T1 3 versus T4, P = N ( ) 96.0 ( ) 70.3 ( ) 78.0 ( ) N ( ) 80.8 ( ) 59.0 ( ) 73.5 ( ) N ( ) 63.3 ( ) 43.8 ( ) 56.5 ( ) N ( ) 67.4 ( ) 36.3 ( ) 48.4 ( ) NS N0 versus N1, P = N0/1 versus N2/3, P < N0/1 versus N2/3, P = N1 versus N2/3, P = Stage I ( ) 94.7 ( ) 84.7 ( ) 89.4 ( ) Stage II ( ) 89.5 ( ) 66.7 ( ) 82.9 ( ) Stage III ( ) 74.0 ( ) 47.1 ( ) 60.9 ( ) Stage IV ( ) 62.7 ( ) 38.0 ( ) 47.6 ( ) Overall ( ) 76.6 ( ) 53.0 ( ) 62.2 ( ) Keratiizig ( ) 90.0 ( ) 38.6 ( ) 44.7 ( ) No-keratiizig versus keratiizig P < P = P = P = Numbers i paretheses represet 95% cofidece itervals.

5 Jp J Cli Ocol 2004;34(10) 573 Table 3. Ui- ad multivariate aalysis of progostic factors for overall ad progressio-free survival Factors No. of patiets OAS at (%) PFS at (%) OAS PFS Uivariate P Multivariate P Uivariate P Multivariate P Geder Male Female Age (years) < <0.001 < > Histology Keratiizig <0.001 < No-keratiizig T T <0.001 < T N N <0.001 <0.001 <0.001 <0.001 N >2 courses of FP Yes No Cocurret or alteratig use of platium Yes No OAS, overall survival; PFS, progressio-free survival; FP, chemotherapy usig platium combied with 5-FU. sigificace of the patiet s age (<60 versus >60 years), T-stage (T1 3 versus T4), N-stage (N0/1 versus N2/3), histology (keratiizig versus o-keratiizig), geder, umbers of admiistered cycles of FP chemotherapy (<1 cycle versus >2 cycles) ad cocurret platium-based chemotherapy (yes versus o) for OAS ad PFS are show i Table 3. Although the receipt of >2 cycles of FP did have progostic sigificace, cocurret or alteratig use of platium did ot. Multivariate aalyses revealed that age, T ad N stage, histology, ad umbers of cycles of FP were idepedet progostic factors for both OAS ad PFS (P < 0.05). DEFINITION OF STAGE SUBGROUPS AND PATTERNS OF TREATMENTS Based o the results of the multivariate aalyses, it seemed reasoable to divide the patiets ito two risk groups accordig to the T ad N classificatio: favorable risk group (T1 3 ad N0 1) ad ufavorable risk group (T4 or N2 3). I additio, the pricipal target populatios for the previously reported radomized trials approximately correspoded to patiets with ode-positive stage II or stage III/IV disease i terms of the 1997 AJCC stagig system. Therefore, patiets with T1 2 ad N0 were aalyzed separately i order to facilitate a estimatio of the applicability of the data origiatig from previous radomized trials to the Japaese populatio. Cosequetly, we tetatively classified patiets ito the followig three stage subgroups: early stage, T1 2 ad N0; itermediate stage, T1 3 ad N0 1 excludig the early stage; ad advaced stage, T4 or N2 3. The distributio of the chemotherapy give i cacer ceters ad uiversities accordig to the stage subgroups is show i Table 4. It was sigificatly differet betwee cacer ceters ad uiversities, i.e. the cacer ceters selected RT aloe for more patiets with early stage disease, ad the combied FP ad RT regime for patiets with itermediate ad advaced stage disease, tha were used i the uiversities (P < 0.020, c 2 test). PATTERNS OF FAILURE The LRC rate for patiets with early, itermediate ad advaced stage disease were 72, 72 ad 61% at, respectively, with o sigificat differece of LRC accordig to the stage subgroups beig observed (P > 0.100). However, there was a cosiderable differece i the LRC rate betwee okeratiizig ad keratiizig tumors as show i Table 2. O

6 574 Survey of CRT for asopharygeal cacer the other had, the DMF rates were 97, 88 ad 68% at, respectively, ad statistically sigificat differeces i DMF rates were observed betwee patiets with itermediate ad advaced stage disease (P < 0.001). Table 4. Treatmet procedures accordig to category of istitutios >2 courses of FP Yes No RT aloe Total Cocurret or alteratig use of platium Early stage (T1 2/N0) Yes No Yes No Cacer ceter Uiversity ad affiliated hospitals Total Itermediate stage (T3N0 or T1 3N1) Cacer ceter Uiversity ad affiliated hospitals Total Advaced stage (T4 or N2/3) Cacer ceter Uiversity ad affiliated hospitals Total Overall Cacer ceter Uiversity ad affiliated hospitals Total DIFFERENCE IN SURVIVAL ACCORDING TO THE CHEMOTHERAPY GIVEN Detailed comparisos of OAS ad PFS at accordig to types of chemotherapy give are show i Tables 5 ad 6, respectively. For patiets with early stage disease, o sigificat survival advatage of combiig chemotherapy with RT was observed without takig otice of patiet selectio, which was ot thoroughly surveyed. Sice oe of the comparisos of OAS ad PFS betwee the two groups from amog the YES/NO, NO/YES ad NO/NO groups showed statistically sigificat differeces (P > 0.05), these three groups were combied ito a MISC group (patiets who received miscellaeous chemotherapy) i the followig aalyses. OAS ad PFS for 287 patiets with itermediate or advaced disease give chemotherapy/rt are show i Figs 1 ad 2. The YES/YES group achieved sigificatly better OAS ad PFS rates tha the RT aloe group, whereas the MISC group showed itermediate results betwee the other two groups. The OAS ad PFS rates for patiets with itermediate ad advaced stage disease give chemotherapy/rt are show i Figs 3 6. The YES/YES group achieved sigificatly better OAS rates ad/or PFS rates tha the RT aloe group for both itermediate ad advaced stage disease. The OAS ad PFS rates i the MISC group were almost idetical to those i the YES/YES group i the itermediate stage, while there were o sigificat differeces of OAS ad PFS betwee the MISC ad the RT aloe group i advaced stage disease. Whe the patiets with Table 5. Overall survival at accordig to the type of chemotherapy combied with radiotherapy >2 courses of FP Yes No RT aloe Total Cocurret or alteratig Yes No Yes No use of platium Male/female 49/18 71/23 46/10 34/8 52/22 252/81 Media age, (rage), years 52 (14 78) 51 (16 77) 55 (17 79) 60 (22 79) 60 (19 85) 55 (14 85) 5 year OAS (%) OAS (%) OAS (%) OAS (%) OAS (%) No-keratiizig T1/2N T3N0 or T1 3N T4 or N Keratiizig T1/2N * * T3N0 or T1 3N { T4 or N z Overall T1/2N T3N0 or T1 3N T4 or N Total OAS (%) OAS, overall survival; RT, radiotherapy; FP, chemotherapy usig platium combied with 5-FU, *at 2 years, { at 3 years, z at 4 years. Numbers i the paretheses idicate 95% cofidece itervals.

7 Jp J Cli Ocol 2004;34(10) 575 Table 6. Progressio-free survival at accordig to the type of chemotherapy combied with radiotherapy >2 courses of FP Yes No RT aloe Total Cocurret or alteratig use of platium Yes No Yes No PFS (%) PFS (%) PFS (%) PFS (%) PFS (%) No-keratiizig T1/2N T3N0 or T1 3N T4 or N Keratiizig T1/2N * * T3N0 or T1 3N { T4 or N z Overall T1/2N T3N0 or T1 3N T4 or N Total PFS (%) PFS, progressio-free survival; RT, radiotherapy; FP, chemotherapy usig platium combied with 5-FU, *at 2 years, { at 3 years, z at 4 years. Figure 1. Overall survival for patiets with ode-positive ad/or T3/4 disease, accordig to the use of combiatio chemotherapy with radiotherapy. YES/YES represets patiets who received >2 courses of platium + 5-FU i combiatio with cocurret platium-based chemoradiotherapy. MISC represets patiets receivig miscellaeous chemotherapy other tha the YES/YES procedure, ad RT aloe represets patiets who were treated with radiotherapy aloe.

8 576 Survey of CRT for asopharygeal cacer Figure 2. Progressio-free survival for patiets with ode-positive ad/or T3/4 disease, accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1. Figure 3. Overall survival for patiets with itermediate stage disease (T3N0 or T1 3/N1), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1.

9 Jp J Cli Ocol 2004;34(10) 577 Figure 4. Progressio-free survival for patiets with itermediate stage disease (T3N0 or T1 3/N1), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1. Figure 5. Overall survival for patiets with advaced stage disease (T4 or N2/3), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1.

10 578 Survey of CRT for asopharygeal cacer Figure 6. Progressio-free survival for patiets with advaced stage disease (T4 or N2/3), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1. Figure 7. Locoregioal cotrol for patiets with itermediate stage disease (T3N0 or T1 3/N1), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1.

11 Jp J Cli Ocol 2004;34(10) 579 o-keratiizig disease oly were aalyzed, these comparative results accordig to the stage subgroups were uchaged. EFFECTS OF CHEMOTHERAPY ON LOCOREGIONAL AND SYSTEMIC TUMOR CONTROL The LRC ad DMF rates accordig to the chemotherapy used i patiets with itermediate stage disease are show i Figs 7 ad 8, ad those i patiets with advaced stage disease are show i Figs 9 ad 10. Differeces i LRC ad DMF rates i the YES/YES, MISC ad RT aloe group were ot statistically sigificat i the itermediate stage, as show i Figs 7 ad 8, while the differeces became more distict i the advaced stage disease favorig the YES/YES group, as show i Figs 9 ad 10, although the differeces i DMF rates i advaced stage disease was margially sigificat as oted i Fig. 10. Whe the patiets with o-keratiizig disease oly were aalyzed, these comparative results of LRC ad DMF accordig to the stage subgroups were uchaged. SURVIVAL AFTER DISEASE RECURRENCE Of 105 patiets who experieced locoregioal recurrece without distat failure, 43 received salvage treatmet that resulted i 24 moths of media survival time ad 43% of OAS at 3 years after detectio of first failure. Otherwise media survival time ad 3year OAS were 10 moths ad 14%, respectively. Of 47 patiets who experieced distat metastasis as the first site of failure, three patiets who had a solitary lug metastasis received salvage surgery. Two of them were treated successfully with 57 moths ad 48 moths of failure-free period thereafter, but oe developed a boe metastasis 1 year after salvage surgery. Otherwise media survival was 7 moths ad the 3 year OAS rate was 8% after detectio of distat failure. DISCUSSION Although some sigle istitutioal studies employig sequetial chemoradiotherapy or RT aloe showed comparable, or eve better, results of OAS compared with that i both arms i the itergroup study (18,19), RT with cocurret use of platium-based chemotherapy is becomig accepted as a stadard treatmet for patiets with advaced asopharygeal cacer (20 22). However, compliace with this treatmet had bee a problem maily due to its ivariably severe acute mucosal ad hematological toxicity (6,11). Because of their broad eligibility criteria with limited sample size precludig subgroup aalysis with sufficiet statistical power, the curretly available data have ot aswered the questio as to whether further adjustmet of the chemotherapy procedures is required for patiets with itermediate stage disease, although their actual defiitio had ot bee clearly established. Differeces i distributio of histological subtypes betwee trials further cofuses their iterpretatio, because these have a cosiderable ifluece o LRC ad survival (Table 2) (23). Figure 8. Locoregioal cotrol for patiets with advaced stage disease (T4 or N2/3), accordig to the use of combiatio chemotherapy with radiotherapy. Abbreviatios are as defied i Fig. 1.

12 580 Survey of CRT for asopharygeal cacer Figure 9. Distat metastasis-free rate for patiets with itermediate stage disease (T3N0 or T1 3/N1), accordig to the use of combiatio chemotherapy with radiotherapy. Patiets who experieced locoregioal recurrece or death without evidece of distat failure were cesored. Abbreviatios are as defied i Fig. 1. Figure 10. Distat metastasis-free rate for patiets with advaced stage disease (T4 or N2/3), accordig to the use of combiatio of chemotherapy with radiotherapy. Patiets who experieced locoregioal recurrece or death without evidece of distat failure were cesored. Abbreviatios are as defied i Fig. 1.

13 Jp J Cli Ocol 2004;34(10) 581 Table 7. Compariso of overall survival rates betwee previous phase III trials ad this study for patiets with advaced asopharygeal cacer Study origi Year Stage Histology Treatmet No. of patiets Rossi (4) 1988 Stage II IV (UICC, 1978) 73.3% udifferetiated carcioma, 26.7% squamous cell carcioma Overall survival (% years) RT RT + ADJ VUMCA I (5) 1996 Ay T, N >2 (UICC, 1987) 100% udifferetiated RT NAC + RT Al-Sarraf (6) 1998 Stage III/IV (UICC, 1987) 28% WHO type I RT % WHO type I CRT + ADJ 78 78* Chua (7) 1998 Ho s stage III/IV or eck ode >3 cm 100% WHO type II/III RT NAC + RT Ma (8) 2001 Stage IV (Chiese, 1992) 97% WHO type II/III RT % WHO type II/III NAC + RT Hareyama (12) 2002 Stage I IV (UICC, 1987) 95% WHO type II/III RT % WHO type II/III NAC + RT Chi (9) 2002 Stage IV (UICC, 1987) 100% WHO type II/III RT % WHO type II/III RT + ADJ Cha (10) 2002 Ho s N2/3 or ode >4 cm 99% WHO type II/III RT { CRT { Li (11) 2003 Stage III/IV (UICC, 1987) 96% WHO type II/III RT % WHO type II/III CRT * This survey N(+) stage II, stage III/IV (UICC, 1997) 20% WHO type I RT aloe % WHO type I MISC % WHO type I YES/YES WHO type II/III RT aloe MISC YES/YES NAC, eoadjuvat chemotherapy; ADJ, adjuvat chemotherapy; CRT, cocurret chemoradiotherapy; RT, radiotherapy; YES/YES ad MISC, see leged for Fig. 1. { Progressio-free survival, *P < Accordig to the assumptios regardig chemotherapy that we made i this study, cocurret platium-based chemoradiotherapy combied with >2 courses of FP, which was classified as the YES/YES group, was expected to be the most efficacious treatmet for this disease. However, for patiets with itermediate or advaced disease, oly 63 (27%) out of 236 patiets who received chemotherapy were i the YES/YES group. Sice sigificat differeces i treatmet strategy were observed betwee cacer ceters ad uiversities as show i Table 4, the differeces are probably due to differeces i istitutioal policies rather tha the result of idividual modificatio of therapeutic programs. O the other had, oly 51 out of 287 (17.8%) patiets with itermediate or advaced stage disease received RT aloe. This suggests that the pricipal approach for this disease had bee combiig chemotherapy ad RT i the istitutios we surveyed, ad that there had bee a relatively ufavorable backgroud for patiets receivig RT aloe. Although our study was udoubtedly affected by these iheret drawbacks of a retrospective survey of this kid, it should be oted that the MISC group, which was cosidered as a less itesive treatmet, had a idetical OAS to that i the YES/YES group for patiets with itermediate stage disease, whereas this was idetical to that of the RT aloe group for those who had advaced stage disease. Prologed survival after salvage treatmet for tumor recurrece is ot uusual i asopharygeal cacer ad, therefore, differeces of OAS accordig to the chemotherapy used might be obscured compared with the differece of PFS (8). Overall survival i this study ad previous trials is compared i Table 7. Although cautio must be exercised whe acceptig the results of a retrospective study, there were o remarkable differeces i the OAS rate betwee our results ad those i previous radomized trials, eve whe the differeces of distributio of histological subtypes were take ito accout. I other words, there is a possibility that the differece i chemotherapy effect betwee the itermediate ad advaced stage

14 582 Survey of CRT for asopharygeal cacer disease might have ideed existed i the previous radomized trials, which should be cofirmed i future trials. Chua et al. reported egative results i their radomized study testig the efficacy of eoadjuvat chemotherapy employig cisplati ad epirubici i additio to RT aloe; however, they showed a o-sigificat tred of OAS i favor of the eoadjuvat chemotherapy arm for patiets with odal metastasis of >6 cm i size (73 versus 37% at 3 years, P = 0.057) (7). Cha et al. also reported results of a subgroup aalysis demostratig sigificat differeces i PFS i favor of a cocurret cisplati ad RT arm compared with RT aloe for patiets with Ho s T3 disease, although the etire study showed a egative result (10). Cosiderig our results as show i Figs 7 10, tumor cotrol above the clavicle might be the pricipal goal for itermediate stage disease, whereas miimizig both locoregioal ad distat failure usig itesive radiosesitizig ad systemic chemotherapy is madatory for the advaced stage disease. The ovel RT techique, itesity-modulated RT (24), is oe of the promisig tools to resolve the former issue, ad the efficacy of less toxic approaches compared with that employed i the previous trials (6,11) should be tested i future prospective studies i patiets with itermediate stage disease. I coclusio, the superiority of a treatmet approach usig cocurret platium-based chemoradiotherapy combied with >2 cycles of FP over RT aloe was show i this group of patiets with ode-positive or T3/4 disease i terms of overall ad progressio-free survival. These results are cosistet with the data obtaied i previous radomized studies, although the feasibility of this itesive approach for Japaese patiets remais to be ivestigated. I additio, three importat clues arose from this survey which should ifluece the future directio of cliical trials for asopharygeal cacer: (i) this itesive approach seems more importat for patiets i the advaced stage disease tha for those who have itermediate stage disease; (ii) a less toxic approach usig adjuctive chemotherapy combied with RT aimig at improvemet of LRC should be tested for patiets with itermediate stage disease; ad (iii) differet treatmet approaches i order to improve LRC should be plaed for patiets with keratiizig disease cosiderig their remarkably poor LRC. Ackowledgmets The authors are most appreciative of the kid cooperatio they received from the followig doctors: Akiko Egawa MD, Departmet of Radiology, Nagasaki Uiversity, Nagasaki; Takashi Matsuzuka MD, Departmet of Head ad Neck Surgery, Fukushima Medical Uiversity, Fukushima; Natsuo Tomita MD ad Professor Yuta Shibamoto MD, Departmet of Quatum Radiology, Nagoya City Uiversity, Nagoya; Shuichi Ishihara MD, Departmet of Radiatio Ocology, Toyohashi Muicipal Hospital, Toyohashi; Hiroshi Oishi MD, Departmet of Radiatio Ocology, Narita Red Cross Hospital, Narita; Kazukiyo Arakawa MD, Departmet of Radiology, Iida Muicipal Hospital, Iida ad Nagao Red Cross Hospital, Nagao; ad Yoshikazu Kagami MD, Divisio of Radiatio Ocology, Natioal Cacer Ceter Hospital, Tokyo. This study was supported by Grat-Aided Cacer Research 14-15, Miistry of Health, Labor ad Welfare of Japa. Refereces 1. Lee AWM, Poo YF, Foo W, Law SCK, Cheug FK, Cha DKK et al. 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