The Role of Intraoperative Radiation Therapy (IORT) in the Treatment of Locally Advanced Gynecologic Malignancies

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1 The Role of Intropertive Rdition Therpy (IORT) in the Tretment of Loclly Advnced Gynecologic Mlignncies MARCELA G. DEL CARMEN, JAMES F. MCINTYRE, b ANNEKATHRYN GOODMAN Vincent Gynecologic Oncology Service, b Deprtment of Rdition Oncology, Msschusetts Generl Hospitl, Boston, Msschusetts, USA Key Words. Intropertive rdition therpy Advnced gynecologic mlignncies Primry disese Recurrent disese Externl bem rdition therpy Brchytherpy ABSTRACT The prognosis in women with loclly dvnced primry or recurrent gynecologic mlignncies is rther poor. Doses of externl bem rdition necessry to tret gross or microscopic recurrence mong ptients surgiclly treted or previously irrdited exceed wht is tolerted by norml structures. In this group of ptients, intropertive rdition therpy (IORT) cn be utilized to mximize locl tumor control, minimizing the rdition exposure of dose-limiting surrounding structures. Review of the vilble literture indictes tht IORT my improve long-term locl control nd overll survivl in women with pelvic sidewll nd/or pr-ortic nodl recurrence. The most encourging results hve been reported in the cses of microscopic residul disese, following surgicl debulking. The Oncologist 2000;5:18-25 INTRODUCTION Women with loclly dvnced primry or recurrent pelvic mlignncies hve rther poor prognosis, especilly in the setting of tumor extension to the pelvic sidewll or lymphtic dissemintion to the pelvic or pr-ortic lymph nodes. Locl filure my be the primry cuse of deth in s mny s 60% of ptients who die from crcinom of the cervix or endometrium [1]. Only selected group of women with loclly recurrent disese confined to the centrl pelvis hve chnce of cure with exentertive surgery [1]. Externl bem irrdition to the pelvis is constrined by dose limittions to norml structures. Rdition doses required to control gross residul or microscopic disese in the pelvis re in excess of those tolerted by norml surrounding structures [2, 3]. Rdition cn be sfely delivered in doses of Gy (in frctions of 1.8 Gy) [1]. However, the externl bem rdition doses needed to tret residul disese fter gross resection would prove to be too morbid [2-4]. This is especilly true in dvnced locl recurrence, where tissue hs either been previously irrdited or surgiclly mnipulted [3]. For ptients with loclly dvnced gynecologic mlignncies, not previously irrdited, preopertive externl bem rdition therpy (EBRT) is lso recommended [1]. This tretment my be in conjunction with chemotherpy. In the cse of previous irrdition, full-dose EBRT is not n option. If further tretment vi this modlity is t ll possible, re-tretment depends on the rdition dose previously used, the time intervl tht hs elpsed from tretment to recurrence, nd the ntomicl loction of recurrence in reltion to norml structures [1]. Intropertive rdition therpy (IORT) llows direct irrdition of tumor bed during plnned surgicl procedure [2, 5, 6]. Irrdition is utilized to sterilize the remining tumor nests fter debulking of resectble lesions [5]. IORT represents unique tretment modlity since it llows direct visuliztion of the trget volume, which in turn results in more precise mpping of the field to be irrdited [5]. Secondly, IORT permits removl or shielding of norml structures from the rdition field. In this wy, the totl dose of rdition tht cn be delivered sfely cn be incresed, while diminishing Correspondence: Mrcel G. del Crmen, MD, VBK 113 Vincent Gynecology, 32 Fruit Street, Boston, Msschusetts 02114, USA. Telephone: ; Fx: ; e-mil: mdelcrmen@prtners.org Accepted for publiction Jnury 24, AlphMed Press /2000/$5.00/0 The Oncologist 2000;5:

2 del Crmen, McIntyre, Goodmn 19 rdition morbidity in norml tissue [5, 7]. Tht is, sufficiently high doses of rdition my be delivered vi IORT to the high-risk pelvic tissues, while minimizing the exposure to other orgns such s the kidneys, bldder, bowel, nd rectum [6]. The biologic effectiveness of single-dose IORT is hypothesized to be two to three times tht of frctionted rdiotherpy. Therefore 15 Gy of IORT is equivlent to giving Gy of frctionted externl bem irrdition [1]. PATIENT SELECTION Both rdition nd gynecologic oncologists should ctively prticipte in the evlution of the ptient who my be cndidte for IORT [1]. The ptient s initil ssessment should include history nd physicl exmintion, s well s ccurte determintion of involvement of the pelvic tumor, which in some instnces my necessitte n exmintion under nesthesi [1]. Lbortory evlution should include comprehensive blood count, liver function tests, nd blood chemistries [1]. Imging studies should include chest x-ry, bdominl/pelvic computed tomogrphy, nd pelvic mgnetic resonnce imging when indicted to evlute tumor extent within the pelvis [1]. The Myo Clinic, through its experience with IORT, hs delineted generl criteri for the selection of women with gynecologic mlignncies for whom IORT my be tretment option [3, 4]: The ptient s medicl condition must permit her to tolerte mjor surgery [1-4]. Surgery lone would not result in cceptble locl control [1-4]. Positive microscopic mrgins would likely exist if surgery lone ws performed [1]. Ptients with distnt metstses, including peritonel seeding, re excluded [1-4]. The ntomicl loction of disese should be one tht is menble to direct intropertive tretment of the tumor bed, minimizing the exposure of norml structures [3]. Dose-limiting tissue such s the smll bowel cn be temporlly displced t the time of rdition so s to mximize the therpeutic rtio between curtive ttempt nd complictions [2]. TREATMENT TECHNIQUE Women suffering from primry loclly dvnced gynecologic mlignncies who re cndidtes for surgicl resection nd IORT should be treted preopertively with EBRT. This pproch mximizes the likelihood of ttining gross totl resection [1]. In women with no previous irrdition history, medin doses rnging from Gy hve been given. This dose hs been delivered in 1.8 Gy frctions, five dys per week, over five- to six-week course [3, 4, 7]. IORT is delivered t the time of surgery, immeditely following surgicl resection. The rdition equipment is locted within the spce of the operting room (Figs. 1 nd 2). The dose of IORT delivered depends on the tumor burden fter surgicl resection, the depth of the trget volume, the loction of dose-limiting norml structures (such s the smll bowel, the rectum, nd the bldder), nd the degree of previous irrdition in the ptient [1, 3, 4]. The IORT dose is generlly clculted t the 90% isodose line. Electron energies vilble rnge from 6-18 MeV. The trget thickness dicttes the electron energy chosen [1-4] (Fig. 3). The IORT dose selected vries ccording to the mount of residul disese nd the mount of EBRT the ptient hs lredy received or will receive postopertively [1, 3, 4]. If EBRT in the rnge of Gy hs been delivered preopertively or is plnned postopertively, microscopic residul disese cn be irrdited with doses of Gy [1, 3, 4]. In the cse of gross residul disese, doses of Gy re recommended [1, 3, 4]. Higher doses of IORT ( 15 Gy) re usully employed in the tretment of women previously irrdited with high-dose EBRT or who cnnot receive full-dose EBRT [3, 4]. BID Witing Are N Blossom Street h A e OR 26 4 IORT Room Gntry rottion plne Isocenter 1 i Electronics Room Stirwell c 2 d E b D g 5 Sterilizer Control Room B 3 C Corridor f Figure 1. Blueprint lyout of the IORT room t the Msschusetts Generl Hospitl. Set-up during IORT consists of dedicted operting room where ll the rdition equipment is lso mintined, llowing for esy conversion into rdition suite. As the rdition is being delivered, the surgeon, rdition oncologist, nesthesi tem, nd rest of the stff move to n djcent shielded room tht llows continuous ptient monitoring.

3 20 Intropertive Rdition Therpy in Advnced Gynecologic Cncer Figure 2. A) Liner ccelertor positioned over field to be irrdited. B) Rdition cone shown secured in plce over incision, immeditely prior to rdition delivery over field. RESULTS AFTER CONVENTIONAL TREATMENT Review of the literture llows for comprison to be mde between ptients with dvnced recurrent nd primry gynecologic mlignncies treted with IORT nd historic controls. Recurrent Disese Locl filure hs been reported s the principl cuse of deth in s mny s 60% of women with recurrent cervicl or endometril cncer [8]. Most uthors cite five-yer Figure 3. The IORT dose is generlly clculted t the 90% iso-dose line. Electron energies vilble rnge from 6 to 18 MeV. The trget thickness dicttes the electron energy chosen. Shown here: A) The iso-doses line for 6 MeV. The first red line is t 100% iso-dose line; first green line is for 90% iso-dose line; second green line is for 70% iso-dose line; blue line is for 50% iso-dose line; nd bottom red line is for 20% iso-dose line. B) The iso-dose lines for 12 MeV. C) The iso-dose lines for 18 MeV. survivl rte of 5% mong ptients with pelvic recurrences of cervicl cncer [9]. Exentertive surgery my present curtive option only mong those with locl recurrence confined to the centrl pelvis. This ltter tretment modlity my led to ftl complictions in s mny s 10% of ptients nd my result in recurrence in nother 30% [10]. One series documented five-yer survivl of 0% mong 143 women with positive mrgins t the time of nterior exentertion for recurrent cervicl cncer [11].

4 del Crmen, McIntyre, Goodmn 21 In ptients who recur fter tretment for endometril cncer, the prognosis is lso poor. The five-yer disese-free survivl nd pelvic control for women with recurrence limited to the vgin hve been reported s 40% nd 59%, respectively [12]. In this series, if ptients hd recurrence involving the pelvis, their five-yer disese-free survivl ws noted to be 20% nd their pelvic control rte 17% [12]. Primry Disese Review of the literture lso permits comprison between results with IORT nd historic controls. For women with stge I cervicl cncer treted surgiclly (vi rdicl hysterectomy) or EBRT plus brchytherpy, the five-yer survivl rte is >90%. This rte is 75%-90% for those with stge II disese [13]. If the pelvic sidewll is involved (stge III), five-yer control rtes re much lower, in the order of 50%-65%. Stge IVA disese hs n estimted five-yer survivl of only 25%-35% [13]. Nodl disese in the setting of primry cervicl cncer confers worse prognosis. The Gynecologic Oncology Group documented nodl disese s the most significnt prognostic fctor ssocited with recurrence [14]. Women with positive pr-ortic lymph nodes hd the worst outcome [14]. One series reported relpse-free survivl of 57% nd pelvic filure rte of 20% in ptients with grossly involved but resectble pelvic lymph nodes [15]. Ptients whose pelvic lymph nodes were unresectble exhibited relpse-free survivl of 0% nd pelvic filure rte of 56% [15]. Unfortuntely, the control rte medited by EBRT lone in the setting of grossly involved pelvic lymph nodes is in the order of 50% [16]. Long-term survivl mong cervicl cncer ptients with positive pr-ortic lymph nodes (microscopic or limited-volume) is reported to be 25%- 50% [17, 18]. Unfortuntely, the doses necessry to chieve control of mcroscopic disese t this level exceed those tolerted by the smll intestines [1]. Kinney t l. reported on series of 117 ptients undergoing rdicl hysterectomy nd pelvic lymph node dissection for stge IB nd IIA cervicl crcinom [19]. Fifty-one of them (44%) hd plpbly involved pelvic lymph nodes. Of these 51 ptients, 29 received djuvnt rdiotherpy [19]. Thirty-two of these 51 ptients nodes hd documented disese recurrence. The site of recurrence included n extrpelvic component in 73% of these ptients [19]. The uthors conclude tht since the doses of rdition required to tret lrge-volume disese often exceed those tolerted by norml structures, resection of mcroscopic nodl disese my ply role in improving locl control [19]. Similrly, lthough only 5%-10% of primry endometril mlignncies present with disese extending beyond the uterus, ptients with unresectble disese hve poor survivls. EBRT nd brchytherpy re ssocited with high rte of pelvic filure. Five-yer survivl with disese confined to the pelvis my be in the order of 12% with locl relpse rte of 37% [20]. Pelvic sidewll disese hs reported five-yer survivl rte of 0% [20]. Women with nodl involvement of their endometril mlignncy, s in the cse of those with cervicl cncer, hve poor five-yer survivl. Most survivors hve only microscopic disese. After extended-field EBRT in the setting of positive pr-ortic lymph nodes, five-yer survivl hs been documented s 40%-60% [1]. RESULTS AFTER TREATMENT WITH IORT The next section provides summry of some of the dt in the literture regrding the role of IORT in treting dvnced gynecologic mlignncies. Ptients with both primry nd recurrent disese hve been treted with IORT. The mjority of the experience with IORT hs been obtined from treting isolted nodl or loclly recurrent gynecologic mlignncies. The ppliction of IORT in the setting of primry disese hs been much more limited. Tble 1. IORT nd disese relpse in recurrent loclly dvnced gynecologic mlignncies Series [Ref.] Site n of Ptients Locl Relpse (%) Centrl Relpse (%) Distnt Relpse (%) Myo [3, 4, 22] All sites 55 43/5-yr 31/5-yr 48/5-yr Cervix 36 50/5-yr 40/5-yr 58/5-yr Endometrium 10 22/5-yr 0 33/5-yr Others 9 50/5-yr 42/5-yr 33/5-yr Frnce [23, 24] Cervix 70 75/3-yr 33/3-yr Univ. Nvrre [26, 27] Cervix (prior ERBT) 14 60/4-yr 22/4-yr 20/4-yr Cervix (no prior ERBT) 24 16/4-yr 5/4-yr 11/4-yr Others b 10 44/4-yr 33/4-yr 67/4-yr Three vgin, four uterine srcom, two ovry. b Four endometrium, four ovry, two vulv.

5 22 Intropertive Rdition Therpy in Advnced Gynecologic Cncer Tble 2. IORT nd survivl results in recurrent loclly dvnced gynecologic mlignncies Series Site n of Medin Survivl Survivl Disese-Free [Ref.] Ptients (months) (%) Survivl (%) Myo [3, 4, 22] All sites /5-yr 21/5-yr Cervix /5-yr 21/5-yr Endometrium /5-yr 17/5-yr Others /5-yr 22/5-yr Frnce [23, 24] Cervix /3-yr (overll) Univ. Nvrre [26, 27] Cervix (prior EBRT) /4-yr (overll) Cervix (no prior EBRT) /4-yr (overll) Others b /4-yr (overll) Three vgin, four uterine srcom, two ovry. b Four endometrium, four ovry, two vulv. Recurrent Disese The initil experience t the Msschusetts Generl Hospitl suggested tht IORT hd pplictions in the tretment of loclly recurrent disese [21]. Five ptients with recurrent cervicl crcinom were treted with IORT. Three of these women were lso treted with EBRT. A survivl of 40% ws noted t the time of publiction [21]. Tbles 1 nd 2 summrize review of the literture regrding rtes of relpse nd survivl dt for loclly dvnced recurrent disese. The Myo Clinic hs documented series tht includes 55 ptients with recurrent gynecologic cncers [3, 4, 22]. Thirtysix of them (65%) were lso treted with either preopertive or postopertive EBRT. Re-irrdition, in the dose rnge of 9-50 Gy, ws lso used to tret 9 of the 28 (32%) women who hd disese recurrence fter previous irrdition. Eleven of these 28 ptients (39%) lso received preopertive chemotherpy with methotrexte, vinblstine, doxorubicin, nd cispltin. In seven of them (64%), gross totl resection ws chieved. This chemotherpy regimen preopertively resulted in higher disese-free intervl. However, the p vlue did not rech sttisticl significnce. The medin IORT dose used in the Myo series ws 15 Gy for microscopic residul disese nd 20 Gy for gross residul tumor [3, 4, 22]. At five yers, locl relpse ws seen in 43%, centrl relpse in 31%, nd distnt relpse in 48% [1]. Medin survivl ws 20 months. Five-yer survivl ws 29%, with reported disese-free survivl t five yers of 21% [1]. In the Europen literture, the French hve one of the lrgest series. They hve reported their experience with IORT in 70 ptients with recurrent cervicl crcinom [23, 24]. This represents the lrgest series evluting the role of IORT in the tretment of recurrent cervicl crcinom. Men follow-up fter IORT ws 11 months. Tretment modlities consisted of IORT lone in 40 out of 70 ptients. Thirty of the women lso received EBRT. Additionl chemotherpy in the form of 5-fluorourcil (5-FU) nd cispltin or cispltin-contining regimen ws given to 20 of the ptients. The men IORT dose dministered ws 18 Gy. With men follow-up of 15 months, the French Intropertive Group found medin survivl to be 11 months nd locl control to be 21%. The reported overll survivl (t three yers) ws 8%. One nd two-yer survivls were 47% nd 17%, respectively. Locl relpse ws seen in 50 (75%) of the 70 ptients. Distnt relpse ws noted in 33% of the women [23]. It is importnt to note tht 40 of these women did not receive EBRT nd 37 of them hd gross residul tumor [23]. The poor results documented in this study my be reflection of inclusion of ll ptients without selecting for tumor volume nd site of recurrence [25]. A series from the University of Nvrre, Spin, included 31 ptients with loclly dvnced or recurrent cervicl crcinom [26, 27]. These ptients were treted with both chemotherpy (cispltin nd 5-FU) nd EBRT (40-46 Gy) followed by surgery with or without IORT to high-risk res for recurrence [26]. Complete nd qusi-complete response ws documented pthologiclly in 74% of the surgicl specimen [26]. A prtil response ws noted in 26% [26]. Medin follow-up ws 27 months, with n cturil disese-free survivl of 80% nd locoregionl control rte of 93.4% [26]. Primry Disese Although there hs been rther limited experience with IORT in the tretment of primry loclly dvnced gynecologic mlignncies, ptients who hve disese extending to the pelvic sidewll or loclly dvnced nodl metstses re idel cndidtes for IORT. Tble 3 summrizes the survivl dt from some of the vilble series. In one series, 16 ptients who hd loclly dvnced cervicl cncer were treted with IORT to the pr-ortic region

6 del Crmen, McIntyre, Goodmn 23 Tble 3. IORT nd survivl results in primry gynecologic mlignncies Series n of Medin Survivl Survivl Disese-Free [Ref.] Ptients (months) (%) Survivl (%) Myo [3, 4, 22] /5-yr 14/5-yr Konski b [28] /2-yr Lyon c [29] /1-3 yrs Four cervix, two vgin, one endometrium, one uterine srcom. b Eight cervix. c Twenty cervix. [6]. Eleven of them (69%) hd involvement of the pr-ortic nodes. Two ptients (12%) received pr-ortic EBRT. IORT doses rnged from Gy. In the 10 to 36 months following IORT, 4 of the 11 women with positive nodes (36%) were live, 2 of them (36%) with no evidence of disese [6]. The experience t the Myo Clinic includes tretment with IORT in eight ptients with primry loclly dvnced cncers [3, 4, 22]. Seven of them (88%) were lso treted with either preopertive or postopertive EBRT. The pttern of filure noted in this group of ptients ws s follows: 62% hd locl relpse t five yers; 43% relpsed centrlly t five yers; nd 36% demonstrted distnt relpse t five yers [1]. Among these women, medin survivl time ws 12 months. Fourteen percent of them survived t five yers, while the sme percentge demonstrted disese-free survivl t five yers [1]. It is importnt to recognize the improvement in survivl nd locl control when mximl tumor resection is chieved surgiclly. A five-yer survivl of 42% ws documented in the Myo Clinic series in cses of microscopic residul tumor [1]. In contrst, only 11% of ptients with gross residul disese survived this sme time intervl [1]. These ptients were lso more likely to demonstrte distnt metstses. Seventy-eight percent of women with gross residul disese hd evidence of distnt metstses t the five-yer intervl (in contrst with only 31% mong those with microscopic residul disese) [1]. Medin survivl in the group with gross residul disese ws 19 months, while it ws reported s 36 months for those with only microscopic tumor [1]. Tble 4. Toxicity of IORT Site of Toxicity (%) Peripherl nerves 5%-30% TOXICITY Gstrointestinl 8%-16% There hs not Ureterl obstruction 3% been n incresed Soft tissue 1%-2% morbidity to the surgicl procedure per- Hemtologic 1%-2% Vsculr tissue <1% formed when IORT is Bone <1% dded. Complictions were noted in 35% of ptients receiving preopertive EBRT only. This ws comprble to 32% ssocited risk in those women receiving EBRT nd IORT [7]. Tble 4 lists the most common toxicities of IORT. The dose-limiting structures for IORT in both the pelvis nd the pr-ortic regions seem to be peripherl nerves [1, 6]. Reports of pinful neuropthy rnge from 5%-30% [1]. One of the Myo Clinic series quotes rte of 48% of tretment-relted toxicities (surgery, IORT, EBRT) [3]. In 29% of them (6 of 21 ptients), IORT ws directly responsible for the toxicity suffered. One ptient suffered from vsculr tissue toxicity, two from gstrointestinl trct toxicity, one from soft tissue, two from ureterl toxicity, nd two from peripherl neuropthy [3]. Another series from the Myo Clinic noted tretmentrelted (surgery, IORT, EBRT, chemotherpy) grde 3 or higher toxicity in 36% of the ptients [4]. Twelve ptients suffered from complictions in the gstrointestinl trct, six from soft tissue toxicity, four from hemtologicl ones, one from bone, one from vsculr tissue, nd two from peripherl nerve toxicity [4]. The cumultive dt gthered from the experience t the Myo Clinic indicte 17% risk of grde 3 or higher toxicity (11 of 63 women) [22]. Gstrointestinl obstruction or fistul formtion occurred in 8% of ptients, soft-tissue injury ws reported in 3%, while ureterl obstruction ws seen in 3% [22]. Some recommend tht ureterl stent should be plced in the IORT field either s prophylxis or with the development of ureterl obstruction whenever tumor is dherent to the ureter prior to surgicl resection [1]. CONCLUSIONS Ptients dignosed with loclly dvnced primry or recurrent gynecologic mlignncies hve rther poor prognosis. The doses of externl bem rdition necessry to tret either gross or microscopic recurrence in those who hve been surgiclly treted or previously irrdited exceed wht is tolerted by norml structures [1-4]. IORT hs been dded to the tretment rmmentrium in this group of ptients. This tretment modlity llows mximizing locl tumor control chievble with rdition, while minimizing

7 24 Intropertive Rdition Therpy in Advnced Gynecologic Cncer the rdition exposure of dose-limiting surrounding structures. IORT hs demonstrted the potentil for improving both the long-term locl control nd the overll survivl in women with pelvic sidewll nd/or pr-ortic nodl recurrence [1, 3, 4]. Perhps the most encourging results cn be seen in the cses of microscopic residul disese, following surgicl debulking [3]. The experience with IORT hs served to further document the importnce of optiml surgicl resection. Higher five-yer disese-free nd overll survivl rtes re seen in women with microscopic residul disese, when compred to those with gross residul disese [1, 4]. Review of institutionl experiences with IORT, especilly mong those institutions with the most experience, my serve to estblish guidelines for ptient selection. These criteri my in turn be utilized in the design of future clinicl trils. The construction, execution, nd evlution of clinicl trils re despertely needed in order to dequtely ssess the role of IORT in the tretment of ptients with dvnced primry nd recurrent gynecologic mlignncies. REFERENCES 1 Hddock MG, Mrtinez-Monge R, Petersen IA et l. Loclly dvnced primry nd recurrent gynecologic mlignncies. EBRT with or without IOERT or HDR-IORT. In: Gunderson LL, Clvo F, Hrrison LB et l., eds. Current Clinicl Oncology: Intropertive Irrdition: Techniques nd Results. New Totow, NJ: Humn Press, 1999: Gunderson LL. Rtionle for nd results of intropertive rdition therpy. Cncer 1994;74: Grton GR, Gunderson LL, Webb MJ et l. Intropertive rdition therpy in gynecologic cncer: the Myo Clinic experience. Gynecol Oncol 1993;48: Grton GR, Gunderson LL, Webb MJ et l. Intropertive rdition therpy in gynecologic cncer: updte of the experience t single institution. Int J Rdit Oncol Biol Phys 1997;37: Abe M. Intropertive rdiotherpy: pst, present nd future. Int J Rdit Oncol Biol Phys 1984;10: Delgdo G, Goldson AL, Ashyeri E et l. Intropertive rdition in the tretment of dvnced cervicl cncer. Obstet Gynecol 1984;63: Tepper, JE, Gunderson LL, Orlow E et l. Complictions of intropertive rdition therpy. Int J Rdit Oncol Biol Phys 1984;10: Brdy LW, Perez CA, Bedwinek JM. Filure ptterns in gynecologic cncer. Int J Rdit Oncol Biol Phys 1986;12: Thoms GM, Dembo AJ, Blck B et l. Concurrent rdition nd chemotherpy for crcinom of the cervix recurrent fter rdicl surgery. Gynecol Oncol 1987;33: Htch KD, Shingleton HM, Soong SJ et l. Anterior pelvic exentertion. Gynecol Oncol 1988;31: Shingleton HM, Soong SJ, Gelder MS et l. Clinicl nd histopthologicl fctors predicting recurrence nd survivl fter pelvic exentertion for cncer of the cervix. Obstet Gynecol 1989;73: Kuten A, Grigsby PW, Perez C et l. Results of rdiotherpy in recurrent endometril crcinom: retrospective nlysis of 51 ptients. Int J Rdit Oncol Biol Phys 1989;17: Mrcil VA, Mrcil LV. Rdition therpy of cervicl cncer. Cncer 1993;71: Stehmn FB, Bundy BN, DiSi PJ et l. Crcinom of the cervix treted with rdition therpy. I. A multivrite nlysis of prognostic vribles in the Gynecologic Oncology Group. Cncer 1991;67: Potish RA, Downey GO, Adcock LL et l. The role of surgicl debulking in cncer of the uterine cervix. Int J Rdit Oncol Biol Phys 1989;17: Fletcher GH. Subclinicl disese. Cncer 1984;55: Bermn ML, Keys H, Cresmn W et l. Survivl nd ptterns of recurrence in cervicl cncer metsttic to periortic lymph nodes. Gynecol Oncol 1984;19: Lovecchio JL, Averette HE, Donto D et l. 5-yer survivl of ptients with periortic nodl metstses in clinicl stge IB nd IIA cervicl crcinom. Gynecol Oncol 1989;34: Kinney WK, Hodge DO, Egorshin EV et l. Surgicl tretment of ptients with stge IB nd IIA crcinom of the cervix with plpbly positive pelvic lymph nodes. Gynecol Oncol 1995;57: Dnoff BF, McDy J, Louk M et l. Stge III endometril crcinom: nlysis of ptterns of filure nd therpeutic implictions. Int J Rdit Oncol Biol Phys 1980;6: Dosoretz DE, Tepper JE, Shim DS et l. Intropertive electronbem irrdition in gynecologic mlignnt disese. Appl Rdiol 1984;13: Hddock MG, Petersen IA, Webb MJ et l. Intropertive rdiotherpy for loclly dvnced gynecologicl mlignncies. Front Rdit Ther Oncol 1997;31: Mhe MA, Gerrd JP, Dubois JB et l. Intropertive rdition therpy in recurrent crcinom of the uterine cervix: report of the French Intropertive Group on 70 ptients. Int J Rdit Oncol Biol Phys 1996;34: Mhe MA, Romesting P, Gerrd JP et l. Prognostic fctors for locl control in recurrent cervicl crcinom treted with IORT: report of the French IORT group. Front Rdit Ther Oncol 1997;31: Abe M, Shibmoto Y. The usefulness of intropertive rdition therpy in the tretment of pelvic recurrence of cervicl cncer. Int J Rdit Oncol Biol Phys 1996;34:

8 del Crmen, McIntyre, Goodmn Mrtinez-Monge R, Jurdo M, Azinovic I et l. Preopertive chemordition nd djuvnt surgery in loclly dvnced or recurrent cervicl crcinom. Rev Med Univ Nvrr 1997;41: Mrtinez-Monge R. IORT in the mngement of loclly dvnced or recurrent gynecologic cncer t high risk of locoregionl relpse [doctorl thesis]. University of Nvrro, Spin, Konski A, Neisler J, Phibbs G et l. The use of intropertive electron bem rdition therpy in the tretment of pr-ortic metstses from gynecologic tumors: pilot study. Am J Clin Oncol 1993;16: Gerrd JP, Drgent D, Rudrnt D et l. Plce de l rdiotherie preopertoire dns le tritement des cncer de l uterus. Esperience lyonnise preliminire. Bull Cncer Rdiother 1994;81: