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Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 1, pp. 110–116, 2007Copyright © 2007 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2006.08.006

LINICAL INVESTIGATION Endometrium

ADJUVANT PACLITAXEL AND CARBOPLATIN CHEMOTHERAPY WITHINVOLVED FIELD RADIATION IN ADVANCED ENDOMETRIAL CANCER:

A SEQUENTIAL APPROACH

KRYSTINE LUPE, M.D.,* JANICE KWON, M.D., M.P.H., F.R.C.S.C.,†

DAVID D’SOUZA, M.D., F.R.C.P.C.,* CHRISTINE GAWLIK, B.PHARM.,‡ LARRY STITT, M.SC.,§

FRANCES WHISTON,� PATRICIA NASCU, M.D.,¶ EUGENE WONG, PH.D.,*AND MARK S. CAREY, M.D., F.R.C.S.C.†

Department of *Radiation Oncology, †Division of Gynecologic Oncology, ‡Department of Pharmacy, §Department of Biostatisticsand Epidemiology, �Clinical Cancer Research Program, ¶Department of Obstetrics and Gynecology, University of Western Ontario

and London Health Sciences Centre, London, Ontario, Canada

Purpose: To determine the feasibility of adjuvant paclitaxel and carboplatin chemotherapy interposed withinvolved field radiotherapy for women with advanced endometrial cancer.Methods and Materials: This was a prospective cohort study of women with Stage III and IV endometrial cancer.Adjuvant therapy consisted of 4 cycles of paclitaxel (175 mg/m2) and carboplatin (350 mg/m2) every 3 weeks,followed sequentially by external beam radiotherapy (RT) to the pelvis (45 Gy), followed by an additional twocycles of chemotherapy. Para-aortic RT and/or HDR vault brachytherapy (BT) were added at the discretion ofthe treating physician.Results: Thirty-three patients (median age, 63 years) received treatment between April 2002 and June 2005.Median follow-up was 21 months. Stage distribution was as follows: IIIA (21%), IIIC (70%), IVB (9%).Combination chemotherapy was successfully administered to 30 patients (91%) and 25 patients (76%),before and after RT respectively. Nine patients (27%) experienced acute Grade 3 or 4 chemotherapytoxicities. All patients completed pelvic RT; 19 (58%) received standard 4-field RT and 14 (42%) receivedintensity-modulated radiotherapy. Ten (30%) received extended field radiation. Four patients (12%)experienced acute Grade 3 or 4 RT toxicities. Six (18%) patients developed chronic RT toxicity. There wereno treatment-related deaths. Two-year disease-free and overall survival rates were both 55%. There wasonly one pelvic relapse (3%).Conclusions: Adjuvant treatment with combination chemotherapy interposed with involved field radiation inadvanced endometrial cancer was well tolerated. This protocol may be suitable for further evaluation in a clinicaltrial. © 2007 Elsevier Inc.

Endometrial cancer, Adjuvant therapy, Paclitaxel and carboplatin, Radiation, Toxicity.

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INTRODUCTION

ndometrial carcinoma is the fourth most common malig-ancy in women and the most common gynecologic malig-ancy in North America (1, 2). While it is recognized that aignificant number of patients are cured by treatment, thereemain a substantial number with adverse prognostic fea-ures who relapse and die of this disease. Those with extra-terine disease (Stage III or IV) have a significant risk of

Reprint requests to: Janice S. Kwon, M.D., M.P.H., F.R.C.S.C.,ynecologic and Surgical Oncology, University of Western On-

ario and London Health Sciences Centre, 800 Commissionersoad East, London, Ontario, Canada, N6A 4G5. Tel: (519) 685-088; Fax: (519) 685-8176; E-mail: Janice.kwon@lhsc.on.caPresented at the Forty Eighth Annual Meeting of the American

ociety for Therapeutic Radiology and Oncology (ASTRO), No-

ember 5–9, 2006, Philadelphia, PA.

110

eath despite current therapies, with 5-year survival ratesanging from 23–72% (1, 3–6). There is need for effectiveherapies that improve cure rates in patients with limitedxtra-uterine disease.

Randall et al. recently reported outcomes from a Gyne-ologic Oncology Group (GOG) study in which chemother-py resulted in significantly improved progression-free andverall survival rates compared to whole abdominal radio-herapy in advanced endometrial cancer (7). However, che-

cknowledgments—The authors wish to acknowledge Dr. Moniqueertrand and Dr. Akira Sugimoto (Gynecologic Oncology) andr. Alex Hammond and Dr. John Radwan (Radiation Oncology)

or accruing patients to this study.Conflict of interest: none.Received July 4, 2006, and in revised from Aug 10, 2006.

ccepted for publication Aug 13, 2006.

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111Adjuvant chemotherapy and radiotherapy in advanced endometrial cancer ● K. LUPE et al.

otherapy alone appears to be associated with high rates ofelvic relapse, ranging from 18 to 47% (7–9). It is wellecognized that pelvic radiation reduces the risk of pelvicelapse in those who have high risk factors such as highrade and deep myometrial invasion (10–12), which areften present in those who have advanced stage disease. Thebservation that chemotherapy is an important componentf treatment for some of these patients but may be insuffi-ient for controlling pelvic relapse therefore provides theationale for using both chemotherapy and radiation indvanced stage disease. Early Phase II trials demonstratedhat paclitaxel and carboplatin chemotherapy resulted inigh response rates in advanced endometrial cancer (13–5). Having considerable experience treating patients withvarian cancer using paclitaxel and carboplatin with veryanageable toxicity, we developed a pilot protocol using

djuvant chemotherapy and radiation for patients with en-ometrial cancer who had limited extra-uterine disease. Therimary aim of this study was to assess toxicity and deter-ine whether a novel protocol comprised of adjuvant car-

oplatin and paclitaxel chemotherapy interposed with in-olved field radiation could be effectively administered toatients with acceptable toxicity. Secondary objectives in-luded assessment of disease-free and overall survival overhe duration of follow-up.

METHODS AND MATERIALS

This was a prospective cohort study in women with advancedndometrial cancer who received treatment at the London Healthciences Centre between April 2002 and June 2005. The Healthciences Research Ethics Board (HSREB) of the University ofestern Ontario granted approval for this study. Women were

ligible only if they had proven extrauterine disease (Stage III orV). Women were ineligible if they had (1) received previousystemic chemotherapy or pelvic radiation, (2) a Karnofsky Per-ormance Scale score of �60, (3) history of previous malignancyithin the last 5 years with the exception of basal cell carcinomar squamous cell carcinoma of the skin, (4) leiomyosarcoma, or (5)epatic or pulmonary metastases.All patients underwent a hysterectomy and bilateral salpingo-

ophorectomy, with or without pelvic and/or para-aortic lymphode dissection and other procedures (peritoneal cytology, randomeritoneal biopsies, omentectomy). Adjuvant treatment consistedf four cycles of i.v. paclitaxel (175 mg/m2 over 3 h) and carbo-latin (350 mg/m2) administered at three-week intervals, followedequentially by delivery of radiation, then an additional two cyclesf paclitaxel and carboplatin chemotherapy. The protocol wasesigned in this manner because it was uncertain at the time howatients would tolerate pelvic radiotherapy after 6 cycles of pac-itaxel and carboplatin. In this study we calculated carboplatin dosesing body surface area (BSA) instead of glomerular filtration rateGFR)-based area under the curve (AUC) dose schedule. We haveeen using this method of carboplatin dosing at our institutionince the early 1990s because the dose is not altered by transienthanges in serum creatinine that are often observed after majorynecologic surgery (16).

Our intent was to administer all adjuvant treatment on an out-

atient basis. For patients who experienced significant paclitaxel- G

nduced peripheral neuropathy during the first three cycles ofhemotherapy, pelvic radiation was administered after the thirdycle (instead of the fourth cycle) at the discretion of the attendingynecologic oncologist or radiation oncologist to allow for “re-pite” from paclitaxel. An attempt was made to resume bothaclitaxel and carboplatin for another three cycles after completingadiation. Patients received standard prophylactic medications (an-iemetics, steroids, and antihistamines) before each cycle of che-otherapy. Blood was drawn for complete blood count (CBC)ith differential, electrolytes, and creatinine before each cycle.hemotherapy was delayed 1 week if the neutrophil count was1.5 � 10 (9)/L, platelet count �100 � 109/L or creatinine was120 �mol/L (Grade 1 or 2 bone marrow or metabolic toxicity).arboplatin dose was reduced by 20% if creatinine was persis-

ently �120 �mol/L after 1 week delay. Paclitaxel was discontin-ed for severe (Grade 3 or 4 hypersensitivity reactions), and theose was reduced by 20% for Grade 3 or 4 peripheral neuropathy.lood transfusions were administered to maintain hemoglobin100 g/L. Acute chemotherapy toxicity was graded as per theommon Terminology Criteria for Adverse Events (CTCAE),ersion 3.0 (17).Involved field radiation consisted of external beam radiation

o the pelvis to a dose of 45 Gy in 25 fractions, delivered 5 daysweek in 1.8 Gy fractions, either by standard four-field tech-

ique (AP-PA and opposed laterals) or intensity modulated archerapy (IMRT), a technique developed at our center and re-orted elsewhere (18). The rationale for using IMRT was basedn the assumption that chemotherapy before radiation mightncrease bone marrow toxicity. Therefore the goal of IMRT waso (1) cover the tumor bed and regional nodes with the pre-cription dose, (2) minimize dose to small bowel and iliac crestsbone marrow), and (3) restrict maximum rectal and bladderose to be less than that received by the tumor bed. Theecision to offer IMRT was left to the discretion of the treatingadiation oncologist. Standard pelvic field borders were applied,ith the superior border at the L5-S1 interspace. Extended field

adiation was provided in the presence of metastatic disease inhe para-aortic or common iliac nodes for both four-field andMRT techniques. The decision to add HDR vaginal vaultrachytherapy was left to the discretion of the treating radiationncologist, but was generally based on risk factors for localelapse including deep myometrial invasion and/or cervicaltromal invasion. The dose of brachytherapy varied between 5y–7.5 Gy per fraction prescribed to a depth of 0.5 cm from the

urface of the applicator. A total of 3 fractions were given, eachraction delivered 1 week apart for a total dose of 15 Gy–22.5y. When a total dose of 22.5 Gy was used, a posterior

ttenuator was added for the second and third fractions. Duringadiation, patients were seen weekly in a review clinic toonitor acute radiation side effects. Acute radiation toxicityas graded as per CTCAE, Version 3 (17).After completion of treatment, patients were seen in regular

ollow-up by the attending radiation oncologist and gynecologicncologist every 3 months for the first 2 years, then every 6 monthsor up to 5 years. Follow-up consisted of history and physical exam-nation, which included speculum and pelvirectal examinations.maging and other investigations were not done unless indicatedy symptomatology or findings on examination. Chronic radiationoxicity, defined as the presence of adverse effects persistingeyond 6 weeks after completion of treatment, was reported as perhe RTOG (Radiation Therapy Oncology Group) Cooperative

roup Common Toxicity Criteria (19).

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112 I. J. Radiation Oncology ● Biology ● Physics Volume 67, Number 1, 2007

RESULTS

atient and tumor characteristicsThirty-three patients with a median age of 63 years

range, 46–83 years) were enrolled in this study. At theime of this analysis, median follow-up was 21 monthsrange, 9–43 months). Table 1 summarizes the differentypes of surgical procedures. Three patients had a hysterec-omy and bilateral salpingo-oophorectomy without pelvic orara-aortic lymphadenectomy; these patients had their surgeryt a community hospital and had Stage IIIA with pathologi-ally documented adnexal metastases. Table 2 summarizesrognostic factors, including age, histopathology, stage, pelvicnd para-aortic node involvement. Twenty-five patients (76%)ad tumors of variant histopathology (i.e., nonendometrioid),ith serous carcinoma (UPSC) being the most common sub-

ype (48%). Six patients had macroscopic residual disease: 3 inhe pelvis and 2 in the para-aortic (peri-renal) nodes, all mea-uring less than 1 cm, and 1 with gross residual measuringore than 2 cm in both the pelvis and upper abdomen. Of the

0 patients who underwent pelvic and/or para-aortic lymphode dissection or sampling, 23 (77%) had metastatic nodalisease.

re-radiation chemotherapy delivery and toxicityThe first cycle of chemotherapy was delivered at a me-

ian of 33 days after surgery. Details of treatment toxicity,ose modifications and delays are presented in Table 3.hirty patients (91%) received all scheduled cycles of pac-

itaxel and carboplatin before radiation. A total of 6 patients18%) experienced 7 Grade 3 or 4 toxicities during pre-adiation chemotherapy. Five patients (15%) had dose re-uctions, including 4 who had dose reductions in botharboplatin and paclitaxel, and 1 who had a dose reductionn carboplatin alone. One patient required a 1 week delay inhemotherapy because of pancytopenia. Complete informa-ion regarding chemotherapy toxicity is missing for 1 pa-ient, as her chemotherapy was administered at a communityospital.

adiation delivery and toxicityAll thirty-three patients completed external beam radia-

ion to the pelvis. Thirty-one (94%) patients received 45 Gy

Table 1. Surgery type and frequency

Surgery type n (%)

BSO, no nodes* 3 (9%)BSO, pelvic nodes �/� staging† 13 (39%)BSO, para-aortic nodes �/� staging† (nopelvic nodes) 1 (3%)

BSO, pelvic � para-aortic nodes �/� staging† 16 (48%)

Abbreviation: HBSO � Hysterectomy and bilateral salpingo-ophorectomy.* Surgery at community hospital.† Staging includes omentectomy, peritoneal cytology and biopsies.

n 25 fractions and 2 patients (6%) received 50.4 Gy in 28

ractions. Nineteen patients (58%) were treated with stan-ard four-field radiation, and 14 patients (42%) were treatedith IMRT. Ten patients (30%) were treated with extendedelds to cover the para-aortic lymph nodes. Of these 10atients, 9 had positive para-aortic nodes and 1 had aathologically positive common iliac node and unconfirmedara-aortic nodal status. The median number of days toomplete external beam radiation was 37 days (range,2–49 days). Radiotherapy was delayed in 3 patients bynly 1 to 4 days because of neutropenia. The median num-er of days between chemotherapy and start of radiationas 31 days and the median number of days between com-letion of external beam radiation and resumption of che-otherapy was 30 days. There was only 1 major protocol

iolation in the timing of radiation; 1 patient received 6ycles of chemotherapy before radiation. She had Stage IVBisease and had persistent disease after her 4th cycle ofhemotherapy, and therefore at the discretion of the attend-ng physician, she received a total of 6 cycles until her CA25 was below 35 IU/L before she received radiation.Thirty-two (97%) patients received HDR vaginal vault

rachytherapy and 1 (3%) refused to complete brachyther-py. Twenty-three (72%) patients received 15 Gy in three 5y fractions, 3 (9%) patients received 18 Gy in three 6 Gy

ractions and 5 (16%) received 22.5 Gy in three 7.5 Gyractions. The variability in fractionation schemes used re-ects a change in practice, with 15 Gy in three 5 Gyractions being our current standard.

Acute radiation toxicity data were available for all pa-ients, as they all received radiation at the London Healthciences Centre. Acute radiation toxicities are presented inable 4. Four patients experienced Grade 3 or 4 acute toxicity

12%); 3 had Grade 4 neutropenia and 1 experienced acuterade 3 proctitis. All patients had normal complete blood

Table 2. Patient characteristics and prognostic factors

Characteristic n (% of total)

ndometrioid histology 8 (24%)Grade 1 1Grade 2 5Grade 3 2

on-endometrioid histology 25 (76%)Uterine papillary serous carcinoma 11 (33%)Clear cell 3 (9%)UPSC and clear cell 5(15%)Adenosquamous carcinoma 3 (9%)Malignant mixed mullerian tumor 3 (9%)

tageIIIA* 7 (21%)IIIC – metastatic pelvic and/or para-aortic

nodes 23 (70%)- positive pelvic nodes/n† 20/29 (69%)- positive para-aortic nodes/n† 10/17 (59%)IVB – peritoneal implants 3 (9%)

Abbreviation: UPSC � uterine papillary serous carcinoma.* All had adnexal disease, without positive cytology or serosal

isease.

† n � total number of patients with that specific node dissection.

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113Adjuvant chemotherapy and radiotherapy in advanced endometrial cancer ● K. LUPE et al.

ount parameters before starting radiation. Only 1 patientith Grade 4 neutropenia required granulocyte-colony stim-lating factor (G-CSF) and had a delay of radiation for

days until the neutrophil count was greater than 1.5.hronic radiation toxicities are presented in Table 5. Fiveatients experienced Grade 3 or 4 chronic toxicity (15%).wo patients developed both radiation proctitis and cystitis.oth of these patients were treated with pelvic fields only,elivered by an IMRT technique. Only 1 patient who re-eived extended field radiation to cover the para-aorticseveloped chronic toxicity. There were no treatment-relatedeaths.

ost-radiation chemotherapy delivery and toxicityAfter radiation, 25 patients (76%) completed all remain-

ng cycles of paclitaxel and carboplatin chemotherapy. Post-adiation chemotherapy toxicity is summarized in Table 6.hree patients (9%) had a total of 4 Grade 3 or 4 toxicitiesuring post-radiation chemotherapy. Three patients hadose reductions, including 1 who had a dose reduction inarboplatin and 2 who had a dose reduction in paclitaxel.

Table 3. Pre-rad

Event Total

Grade 3 or 4 toxicity 7 (22%)

Dose reduction 5 (15%)

Delay 1 (3%)Discontinuation of therapy: 3 (9%)

* All patients experienced these reactionsdiscontinued without attempt at rechallenge.paclitaxel for the remainder of her first cycle an

† Febrile neutropenia during first cycle – likadministered according to schedule without re

†† Chemotherapy dose reduced at the discre§ 80 year old patient who refused further ch

myalgias, prolonged nausea and vomiting, but

Table 4. Frequency of acute radiation toxicities*

Toxicity

Standard 4-field(n � 19)

IMRT(n � 14)

Grade 3 Grade 4 Grade 3 Grade 4

iarrhea 0 0 0 0rinary 0 0 0 0ausea/emesis 0 0 0 0roctitis 1 0 0 0eutropenia 0 3 0 0

Abbreviations: CTCAE � Common Terminology Criteria fordverse Events; IMRT � intensity-modulated radiotherapy.

* Acute radiation toxicity as per CTCAE Version 3.

our patients (12%) required a 1 week delay in chemother-py because of hematologic and neurologic toxicity. Fouratients completed chemotherapy with carboplatin alonend 1 patient received only one cycle of post-radiationhemotherapy.

Acute hematologic toxicity during the initial (pre-ra-iation) phase of chemotherapy did not predict subse-uent hematologic toxicity during radiation or the secondpost-radiation) phase of chemotherapy, nor did it predictncomplete treatment. All patients with Grade 4 neutro-enia either during chemotherapy or radiation were ableo complete treatment as planned, with the exception of 1atient who had Grade 4 neutropenia during radiation andgain after her fifth cycle, which resulted in discontinu-tion of paclitaxel and delay of her sixth cycle of che-otherapy (single agent carboplatin). In total, 13 patients

xperienced Grade 3 or 4 acute chemotherapy or radia-ion toxicity (39%). Two of these and an additional 3atients (for a total of 5) had Grade 3 or 4 chronicoxicity attributed to radiation (15%).

chemotherapy

Reasons

paclitaxel hypersensitivity*neuropathyfatiguenausea/vomitingneutropenia†

paclitaxel and carboplatin (2 advanced age††

and 2 with Grade 2/3 neuropathy)carboplatin (Grade 1 rise in creatinine)ncytopenia (Grade1/2)paclitaxel and carboplatin (patient refusal§)paclitaxel hypersensitivity

the first cycle. Two patients had paclitaxelhird patient was able to continue receivingbsequent cycles by prolonged (12 h) infusion.ated to central line sepsis. Subsequent cyclesn in dose, and no adverse sequelae.

the attending physician.erapy after her first cycle because of fatigue,mplete pelvic radiation.

Table 5. Frequency of chronic radiation toxicities*

Toxicity

Standard 4-field(n � 19)

IMRT(n � 14)

Grade 3 Grade 4 Grade 3 Grade 4

ystitis 0 0 2 0roctitis 1 0 3 0mall bowelobstruction 1 0 0 0

Abbreviations: IMRT � intensity-modulated radiotherapy;TOG � Radiation Therapy Oncology Group.

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114 I. J. Radiation Oncology ● Biology ● Physics Volume 67, Number 1, 2007

utcomesAfter a median follow up of 21 months (range, 9–43onths), 14 patients (42%) have relapsed and 13 of these

ave died of disease. The median time from surgery toelapse was 14 months (range, 7–28 months). Patterns ofelapse are listed in Table 7. There was only one pelvicelapse (3%). Twelve of the 13 deaths were among womenith variant histopathology (UPSC, clear cell carcinoma,MMT, adenosquamous carcinoma). Two year disease-free

urvival and overall survival rates were both 55%.

DISCUSSION

Adjuvant treatment for advanced stage endometrial can-er comprised of paclitaxel and carboplatin chemotherapyith involved-field radiotherapy in a sequential approachas an acceptable toxicity profile. When this protocol wasnitiated in 2002, there was limited published data on theoxicity of adjuvant combined modality therapy for high-isk endometrial cancer. Since then, several studies have

Table 6. Post-ra

Event Total

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† In addition to three chemotherapy discontin(� total discontinuations 8/33 or 24%).

Table 7. Sites and frequency of relapse

Site of relapse n (% of total)

Distant (beyond radiated field) 13 (39%)Bone* 3Lung† 5Liver 2Perihepatic 1Supraclavicular lymph node 1Peritoneal carcinomatosis†† 5Pelvic† 1 (3%)

* 1 patient relapsed in para-aortic nodes, lung, liver, and bone.† 1 patient relapsed in lung and pelvis.†† Includes 2 patients with ascites and no evidence of pelvic/

bdominal mass, peritoneal disease, or retroperitoneal lymphade-opathy (1 patient with ascites and lung metastases, and 1 patient

tith ascites only).

valuated the use of paclitaxel and platinum-based chemo-herapy with involved field radiotherapy. Most are Phase Irials demonstrating considerable rates of toxicity (20–22).reliminary analysis of RTOG 9708 revealed a 62% rate ofrade 4 toxicities during cisplatin and paclitaxel chemo-

herapy (23). Similarly, in a pilot trial of TAC (paclitaxel,oxorubicin and carboplatin) followed by radiation, 50% ofatients reported Grade 3 or 4 neutropenia despite G-CSFupport (21). Finally, in a GOG study of concurrent weeklyisplatin and whole abdominal radiation followed by doxo-ubicin and cisplatin, 100% of patients experienced Grade 4eutropenia during chemotherapy (22). Our protocol wasssociated with a lower overall frequency of acute Grade 3nd 4 toxicities (39%) compared to the studies describedbove. However, we observed a higher rate of peripheraleuropathy, which may be attributed to the higher numberf chemotherapy cycles in our protocol (6 compared to 4ycles). As in other studies (20, 21, 23, 24), radiation wasntegrated into our protocol with a high rate of compliance.he variability in brachytherapy dose fractionation schemessed in the study did not appear to have affected toxicity, asatients treated with the old technique and higher dose didot experience increased toxicity. However, the rate ofuccessful completion of the final 2 cycles of chemotherapyfter radiation was lower than anticipated (76%), but thisas not entirely attributable to treatment toxicity. Overall,ur protocol was reasonably well tolerated compared to thether protocols for advanced stage endometrial cancer asescribed above.The efficacy of IMRT in the treatment of endometrial

ancer remains unclear. The use of IMRT results in aeduction in dose to small bowel and bone marrow and mayelp reduce toxicity in the context of multimodality therapy18). In our series, more chronic radiation toxicities werebserved in patients treated with IMRT, but small boweloxicity was comparable between the 2 groups. There were

chemotherapy

Reasons

thyatin (prolonged Grade 4 neutropenia, paclitaxelinued)el (Grade 2/3 neuropathy)ia (Grade 4)rade 2)

ytopenia (Grade 2)y (Grade 3)el and carboplatin (patient refusal after Grade 3and neuropathy)el (1 prolonged Grade 4 neutropenia ande 3 neuropathy)

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115Adjuvant chemotherapy and radiotherapy in advanced endometrial cancer ● K. LUPE et al.

etween those treated with IMRT vs. a standard four-fieldox technique. Further prospective data needs to be col-ected on IMRT for gynecologic malignancies.

Since inception of this study, the GOG has published 2mportant studies on adjuvant chemotherapy in advancedndometrial cancer. The first study was a Phase III random-zed trial in which cisplatin and doxorubicin (AP) chemo-herapy had a survival benefit compared to whole abdominaladiotherapy (WAI) in Stage III and IV endometrial cancer7). However, toxicity was considerable in this study, as theeaths of 8 patients (4%) in the chemotherapy group and 52%) in the radiotherapy arm were attributed to treatment.nly 63% of patients in the AP group were able to complete

reatment. The second study was a Phase III randomizedrial confirming that the addition of paclitaxel to cisplatinnd doxorubicin chemotherapy improved progression-freend overall survival in advanced and recurrent endometrialancer, but at the expense of considerable toxicity (25).dditional studies have demonstrated high response rates toaclitaxel, and cumulative evidence presently suggests thatarboplatin and paclitaxel may be the chemotherapy regi-en of choice in advanced endometrial cancer (26–30).Our study was not primarily designed to evaluate survival

utcomes. Furthermore, it is difficult to compare outcomesmong various combined modality protocols for endome-rial cancer because the study populations are different.reven et al. reported four-year overall and disease-free

urvival rates of 85% and 81% respectively in RTOG 970831). However, variant histopathology was excluded and4% had Stage I and II disease, a population with annherently better prognosis than in our study with predom-nantly high-risk histopathology and 100% Stage III and IVisease. Preliminary analysis from the pilot trial of TAC

hemotherapy and radiation revealed that 72% were dis- t

REFEREN

8. Mundt AJ, McBride R, Rotmensch J, Waggoner SE, Yamada

1

1

1

ase-free after a median follow-up of 16 months (21). In thatilot trial, 40% had Stage IIIC and 15% had Stage IVisease, whereas in our study, 70% had Stage IIIC and 9%ad Stage IV disease. Apart from this, there is no othervailable information on survival outcomes for combinedhemotherapy and radiation treatment for a similar popula-ion of patients.

Our protocol was associated with a very low rate ofelvic relapse (3%). Greven et al. also reported a low pelvicelapse rate of 2% in patients treated with combined mo-ality treatment RTOG 9708 (31). In contrast, Randall et al.eported an 18% pelvic relapse rate among patients treatedith chemotherapy alone in the context of a large random-

zed GOG trial (7). The chemotherapy arm in this GOGtudy had a greater proportion of women with endometrioidistology (47%) and Stage IV disease (21%) compared tour study. Despite these differences, the low rate of pelvicelapse with combined modality treatment is notable. Thesebservations suggest that women with advanced endome-rial cancer treated by chemotherapy alone still remain atisk for pelvic relapse, and that radiation may significantlyeduce this risk.

There is emerging experience that combined modalityreatment is feasible and that radiation may be more effec-ive in controlling involved field disease compared to che-otherapy alone. Ideally the patient population best suited

or this treatment includes those with documented extrauter-ne metastases and microscopic or minimal residual diseasehat can be encompassed within the planned radiation field.lthough longer follow-up is required to establish survivalutcomes, combined modality treatment appears to be as-ociated with a low rate of pelvic relapse and should beonsidered for further testing against established chemo-

herapy regimens.

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SD, Connell PP. Significant pelvic recurrence in high-riskpathologic stage I–IV endometrial carcinoma patients afteradjuvant chemotherapy alone: implications for adjuvantradiation therapy. Int J Radiat Oncol Biol Phys2001;50:1145–1153.

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1. Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC, et al.Outcome of high-risk stage IC, grade 3, compared with stage Iendometrial carcinoma patients: the Postoperative RadiationTherapy in Endometrial Carcinoma Trial. J Clin Oncol 2004;22:1234–1241.

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