Cancer Al Ovario-2013

Does Modality of Adjuvant Chemotherapy After IntervalSurgical Debulking Matter in Epithelial Ovarian Cancer?

An Exploratory Analysis

Nashmia Joudallah Al Mutairi, MD and Tien Le, MD

Objectives: This article aimed to study the role of adjuvant intraperitoneal (IP) chemo-therapy after neoadjuvant chemotherapy and optimal interval surgical debulking.Method: All patients with epithelial ovarian cancer treated with neoadjuvant chemother-apy were retrospectively reviewed from 2007 to 2009. Demographics, related diseases, andsurvival outcome data were abstracted from the medical records. W2 statistics were applied tocategorical variables. Cox regression was used to model progression-free survival (PFS),adjusting for age, residual status, and use of adjuvant IP chemotherapy. All P values less than0.05 were considered statistically significant.Results: Sixty-five patients were reviewed. The median age was 63.3 years. The majorityhad stage III disease with serous histology. Optimal residual (G1 cm) after interval debulkingwas achieved in 34 (54%) of 63 patients. Sixteen patients chose to receive adjuvant IPchemotherapy. The median follow-up was 26.2 months. Fifty-one patients had progressed,with a median PFS of 17.5 months. Adjuvant IP chemotherapy was not predictive of PFS(hazard ratio, 0.91; 95% confidence interval [CI], 0.24Y3.44; P = 0.89). The estimatedmedian overall survival was 37.8 months (95% CI, 29.9Y45.7) in the intravenous groupversus 48.1 months (95% CI, 37.9Y58.3) in the IP-treated patients (P = 0.162).Conclusions: Adjuvant IP chemotherapy was not predictive of survival after neoadjuvantchemotherapy in our small exploratory study. The role of IP chemotherapy in this settingneeds to be further studied in a larger prospective patient cohort.

Key Words: Intraperitoneal chemotherapy, Interval debulking, Neoadjuvantchemotherapy

Received June 5, 2013, and in revised form November 15, 2013.Accepted for publication November 17, 2013.

(Int J Gynecol Cancer 2014;24: 461Y467)

Epithelial ovarian cancer (EOC) is the second most commongynecologic cancer in North America, causing more

deaths than all other gynecologic cancers combined.1 Thehigh case-fatality rate is related to the relative absence of spe-cific signs and symptoms in early stages. As a result, the ma-jority of patients will present at an advanced stage (III/IV) atthe time of diagnosis.2

The standard management for metastatic EOC consistsof an initial maximal cytoreductive effort, followed by adjuvantintravenous (IV) platinum- and taxane-based chemotherapy.3Y6

Despite this aggressive therapeutic approach, most patientswith advanced ovarian cancer will eventually relapse and die ofprogressive disease. Many studies have demonstrated that one

ORIGINAL STUDY

International Journal of Gynecological Cancer & Volume 24, Number 3, March 2014 461

Division of Gynecologic Oncology, Department of Obstetrics,Gynecology and Newborn Care, University of Ottawa, Ottawa,Ontario, Canada.Address correspondence and reprint requests to Nashmia

Joudallah Al Mutairi, MD, Division of Gynecologic Oncology,Ottawa General Hospital, 501 Smyth RdVRoom 8130,Ottawa, Ontario, Canada K1H 8L6.E-mail: [email protected]; [email protected].

The research project was funded by an educational research grantfrom Roche Pharmaceuticals.

The authors declare no conflicts of interest.Copyright * 2014 by IGCS and ESGOISSN: 1048-891XDOI: 10.1097/IGC.0000000000000066

Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

of the strongest predictors of survival is the achievement ofoptimal residual disease after primary surgical debulking, mostcommonly defined as having no tumor nodule larger than1 cm.7Y9 Because ovarian cancers are often widely metastatic atthe time of the presentation and commonly associatedwith poorperformance status, radical tumor debulking procedures toobtain optimal residuals can be quite challenging. In Canadiancenters, the optimal primary debulking rate was reported to beonly approximately 44% in a recently completed prospectivetrial.10 A higher rate of optimal resection has been achievedwhen radical upper abdominal surgical procedures are routinelyused with acceptable morbidity,5 but this is not commonlypracticed in Canada. Patients’ poor performance status alsomight preclude extended radical tumor debulking efforts at thetimeof the presentation for concerns of prolongedpostoperativerecovery and delays in starting adjuvant chemotherapy.

To address these management challenges, neoadjuvantchemotherapy followed by interval surgical debulking has beenproposed as a potential alternative strategy to primary surgicaldebulking.10 A meta-analysis of 21 studies on the use ofneoadjuvant chemotherapy published in 2009 suggested thatthis was associated with an increased rate of optimal debulkingin patients with a high risk for suboptimal debulking at pre-sentation. However, the improved surgical outcome did nottranslate into a better overall survival (OS).11 In addition,2 recent meta-analyses further suggested that neoadjuvantchemotherapy seemed to be inferior to primary surgicaldebulking.12,13 However, these analyses mostly includedstudies where patients were commonly triaged toward neo-adjuvant treatment because of the presence of significantmedical comorbidities or the presence of large bulky tumors,making selection bias unavoidable and proper comparisonwith standard treatment difficult.

In 2010, the European Organisation for Research andTreatment of Cancer published the matured results of a pro-spective randomizedphase 3 trial comparingprimarydebulkingsurgery followed by standard platinum- or taxane-based che-motherapy with neoadjuvant chemotherapy followed by inter-val debulking surgery (IDS) in women with bulky stage IIICand IV EOCs.10 Consistent with other retrospective reports,postoperative morbidity and mortality were lower in the neo-adjuvant group compared with those in the control (primarydebulking surgery) group. The OS and progression-free sur-vival (PFS) were not inferior between the study and controlgroup in the intention-to-treat analysis.10

The survival benefits of adjuvant intraperitoneal (IP)chemotherapy after optimal primary cytoreductive surgery(PCRS) have been well established. A meta-analysis of 6 ran-domized clinical trials (SWOG-8501/ECOG/GOG-104,14

GOG-172,15 NWOG,16 UCSD,17 SWOG/ECOG/GOG-114,18

and Yen et al19) on the efficacy of adjuvant IP chemotherapyafter optimal primary debulking surgery has shown consis-tent significant improvement in both PFS andOS. The pooledhazard ratio (HR) for PFS for IP cisplatin treatment ascompared with that for IV treatment was 0.792 (95% con-fidence interval [CI], 0.688Y0.912; P = 0.001). The pooledHR for the OS of IP cisplatin treatment as compared with thatof IV treatment was 0.799 (95% CI, 0.702-0.910; P =0.0007). As expected, treatment-related toxicities were more

commonly seen in the IP comparedwith the IV chemotherapygroup.20

To date, few studies have examined the benefits of IPchemotherapy after optimal IDS in a neoadjuvant setting.21,22

Currently, The National Cancer Institute of Canada Clini-cal Trials Group is accruing patients on a large multicenterprospective randomized phase 3 clinical trials (OV21) to in-vestigate the potential benefit of IP versus IV chemotherapyto address this question.

We evaluated the impact of IP adjuvant chemotherapyin unselected, consecutive, neoadjuvantly treated patients withEOC compared with that of IV adjuvant therapy after optimalinterval surgical debulking.

METHODOLOGYA retrospective chart review was performed to identify

all consecutive unselected patients diagnosed with epithelialovarian/peritoneal or fallopian tube carcinoma from 2007 to2009, who were treated on the neoadjuvant protocol at theOttawa Regional Cancer Centre. The Ottawa Hospital re-search ethics board granted ethical approval for the study.

According to our protocol, all patients with clinicaland radiographic findings consistent with stage III/IV dis-ease without evidence of acute abdomen or gastrointestinal/genitourinary obstruction would undergo a diagnostic corebiopsy of the most accessible lesion under computed tomog-raphy guidance for tissue diagnosis, with the intention to startneoadjuvant chemotherapy. A histologic confirmation of aprimary gynecologic malignancy supported by immunohis-tochemistry is a prerequisite for the initiation of neoadjuvantchemotherapy. Three to 4 cycles of neoadjuvant chemother-apy consisting of carboplatin (area under the curve [AUC], 6)and paclitaxel (175 mg/m2) were administered intravenouslyevery 21 days. An IDS was scheduled approximately 4 weeksafter the third or fourth cycle, regardless of the observedclinical or biochemical responses to neoadjuvant therapy.Before the surgery, patients were counseled about the po-tential risks and benefits of IP chemotherapy and offeredadjuvant IP treatment if optimal debulking (G1-cm residuals)was achieved. Radical upper abdominal debulking procedureswere not routinely used in our center during the study period.

Patients were reassessed approximately 4 weeks afterthe surgery with the intention to continue with an additional3 to 4 more cycles of chemotherapy to complete their primarytreatment. Those left with suboptimal residuals and those withoptimal residuals who chose not to receive IP chemotherapybased on preoperative counseling were given additional 3 to 4more cycles of IV chemotherapy, similar to the regimen in theneoadjuvant phase. Optimally debulked patients given con-sent for adjuvant IP chemotherapy were administered 3 IPchemotherapy cycles using a regimen similar to the GOG-172study protocol consisting of IV paclitaxel (135 mg/m2) over24 hours on day 1, followed by IP cisplatin (100 mg/m2) onday 2, and paclitaxel (60 mg/m2) on day 8, to be repeatedevery 3 weeks.

After the completion of all prescribed frontline thera-pies, patients were seen every 3months during the first 3 yearsand every 6 months thereafter, with CA-125 measurement

Al Mutairi and Le International Journal of Gynecological Cancer & Volume 24, Number 3, March 2014

462 * 2014 IGCS and ESGO


and clinical assessment at each visit. Computed tomographyimaging is considered only if there is a strong suspicion fordisease progression based on CA-125 elevation and/or sus-picious clinical signs or symptoms.

Patients’ demographics, surgical pathologic data, andsurvival outcomes were manually abstracted from paper-based

medical records and cross-referenced to patients’ electronicmedical records to ensure accuracy.

Descriptive statistics were used to summarize the pa-tients’demographics and surgical pathologic data. W2 tests wereperformed to detect significant associations between categor-ical variables. Cox proportional hazard regression models were

TABLE 1. Cohort’s Demographics Summary

Age, Median(Range), y

ECOGPerformanceStatus, n (%)

Disease Stageat Diagnosis,

n (%)

CA-125 Levelat Diagnosis,

Median (Range)

CA-125 LevelBefore IntervalDebulking,

Median (Range)

Overall cohort 63.3 (25.8Y85.4) 0: 24/65 (37) 3: 56/65 (86) 1221 (72Y36,963) 72 (6Y1980)1: 34/65 (52) 4: 9/65 (14)2: 7/65 (11)

Suboptimallydebulked group

59.2 (25.8Y81.1) 0: 8/30 (27) 3: 27/30 (90) 1131 (128Y36,963) 176 (12Y1980)1: 19/30 (63) 4: 3/30 (10)2: 3/30 (10)

Optimally debulkedgroupVadjuvantIV treated

69.8 (44.5Y85.4) 0: 9/18 (50) 3: 12/18 (67) 1500 (303Y13,000) 84 (6Y456)1: 6/18 (33) 4: 6/18 (33)2: 3/18 (17)

Optimally debulkedgroupVadjuvantIP treated

64.1 (48.4Y72.6) 0: 2/16 (13) 3: 16/16 (100) 809 (72Y9369) 54 (13Y737)1: 14/16 (87) 4: 0/16 (0)2: 0/16 (0)

TABLE 2. Surgical Pathologic Findings Based on Available Data

Tumor Grade,n (%)

Histology,n (%)

Residual DiseaseDistribution,

n (%)

Modality of AdjuvantTherapy PostsurgicalDebulking, n (%)

Overall cohort 1: 1/63 (1.5) Serous: 58/65 (89) Microscopic: 20/63 (32) None: 2/65 (3)2: 3/63 (5) Nonserous: 7/65 (11) Micro to G1 cm: 14/63 (22) IV: 47/65 (72)3: 59/63 (93.5) 1Y2 cm: 9/63 (14) IP: 16/65 (25)

92 cm: 20/63 (32)Suboptimallydebulked group

1: 0/30 (0) Serous: 27/30 (90) Microscopic: 0/30 (0) None: 2/30 (7)2: 2/30 (7) Nonserous: 3/30 (10) Micro to G1 cm: 0/30 (0) IV: 28/30 (93)

3: 28/30 (93) 1Y2 cm: 9/30 (30) IP: 0/30 (0)92 cm: 21/30 (70)

Optimally debulkedgroupVadjuvantIV treated

1: 1/18 (6) Serous: 15/18 (83) Microscopic: 11/18 (61) IV: 18/18 (100)2: 1/18 (6) Nonserous: 3/18 (17) Micro to G1 cm: 7/18 (39) IP: 0/18 (0)

3: 16/18 (89) 1Y2 cm: 0/18 (0)92 cm: 0/18 (0)

Optimally debulkedgroupVadjuvantIP treated

1: 0/16 (0) Serous: 15/16 (94) Microscopic: 9/16 (56) IV: 0/16 (0)2: 0/16 (0) Nonserous: 1/16 (6) Micro to G1 cm: 7/16 (44) IP: 16/16 (100)

3: 16/16 (100) 1Y2 cm: 0/16 (0)92 cm: 0/16 (0)

International Journal of Gynecological Cancer & Volume 24, Number 3, March 2014 Modality of Adjuvant Chemotherapy

* 2014 IGCS and ESGO 463


built to model the time to first progression, taking into accountthe effects of age, residual status (optimal vs suboptimal), andtype of adjuvant chemotherapy (IP vs IV). The backward

stepwise variable selection strategywas used to obtain the mostparsimonious model. Kaplan-Meier analysis allowed for theestimation of OS for each cohort. Log-rank statisticswere used

FIGURE 1. Kaplan-Meier survival estimates for PFS and OS in the entire study cohort (optimal and suboptimalresiduals, regardless of treatment received).

FIGURE 2. Kaplan-Meier PFS estimates in optimally debulked patients stratified by adjuvant chemotherapy regimen.




to compare survival curves. All P values less than 0.05 wereconsidered to be statistically significant. Statistical analyseswere performedusingSPSSversion16 forWindows (SPSS Inc,Chicago, Ill; 2007).

RESULTSSixty-five patients were identified from the Division of

Gynecologic Oncology surgical database. The median age atthe time of diagnosis was 63.3 years (range, 25.8Y85.4 years).Of the 65 patients, 47 (75%) presented with significant ab-dominal distension as their presenting complaint. The ma-jority of the cohort had stage III disease (86%), serous histology(89%), and grade 3 tumors (94%).ThemedianCA-125 levels atdiagnosis and immediately before the IDS were 1221 and 72,respectively. Themedian number of neoadjuvant chemotherapycycles administered was 3. Tables 1 and 2 summarize the rel-evant demographic and surgical pathologic data for the overallstudy cohort and the subgroups, respectively.

All but one patient underwent an attempt at IDS re-gardless of his or her response to neoadjuvant chemotherapy.This patient was deemed to be at a very high risk for lapa-rotomy and was analyzed with the subgroup having sub-optimal residual disease based on her follow-up assessmentafter 3 cycles of chemotherapy. No grade 3 or 4 postoperativecomplication was encountered. An optimal residual of lessthan 1 cm was achieved in 34 (54%) of 63 patients. Of these34 patients, 20 (32%) had amicroscopic residual disease, withthe remaining 14 (22%) having a macroscopic disease of lessthan 1 cm. Twenty-nine patients (46%) had suboptimal residualdisease. Sixteen patients with optimal residual disease receivedadjuvant IP chemotherapy with the other half continuing onwith additional IV chemotherapy postoperatively, as per theirpreoperative decision. Twopatients did not receive any adjuvantchemotherapy because of poor performance status.

The median follow-up time was 26.2 months. Diseaseprogression occurred in 51 (86%) of 59 patients, with anestimated median PFS of 17.5 months for the whole cohort.Elevation of CA-125 level was the first sign of recurrence in36 (61%) of 59 patients. Figure 1 shows the Kaplan-Meiercurves for OS and PFS in the whole cohort. Figures 2 and 3show similar estimates in patientswith optimal residuals treatedwith IP and IV adjuvant chemotherapy, respectively. Appro-ximately half of the patients with recurrent disease had aprogression-free interval of at least 6 months. They were all re-treated with platinum-based chemotherapy. The overall re-sponse rate (complete and partial response) to the subsequentsecond-line therapy was 44%.

Progression-free survival was modeled using Cox re-gression, adjusted for age, residual disease status, and typeof adjuvant chemotherapy (IP vs IV). The use of adjuvantIP chemotherapy was not significantly predictive of im-proved survival, with an HR of 0.91 (95% CI, 0.24Y3.44; P =0.89). Only suboptimal residual disease was of borderline

FIGURE 3. Kaplan-Meier OS estimates in optimally debulked patients stratified by adjuvant chemotherapyregimen (IV/IP).

TABLE 3. Follow-up Survival Outcome at Last Visit

Follow-up time, median (range), mo 26.2 (1Y66)Progression-free interval, median (range), mo 17.5 (6Y45)Disease progression, n (%)

Yes 51/59 (86.0)No 8/59 (14.0)

Patient status at last follow-up, n (%)No evidence of disease 8/65 (12.3)Alive with disease 31/65 (47.7)Died of disease 26/65 (40.0)




significance in predicting a shortened time to progressivedisease, with an HR of 2.19 (95% CI, 0.94Y5.14; P = 0.07).

At the last follow-up, 21 (40%) of 47 patients had diedof the disease in the IV group and 5 (31.3%) of 16 patients haddied in the IP-treated group (P = 0.56). Table 3 summarizesthe survival outcomes observed at the last follow-up. Theestimated median survival time was 41.3 months (95% CI,32.9Y49.5) in the IV group versus 51.3 months (95% CI,41.9Y60.8) in the IP cohort (P = 0.18). Figure 3 plots theoverall estimated survival curve for the 2 study groups (ad-juvant IV vs IP chemotherapy).

DISCUSSIONThe survival benefit of IP chemotherapy over IV che-

motherapy in patients with optimal residual disease afterprimary debulking surgery has been well established based ona number of prospective randomized clinical trials.14Y20

Theoretically, this benefit is derived from the exposure oftumor cells to a very high concentration of chemotherapydrugs in the peritoneal cavity for a prolonged period, en-hancing tumor cell kill activity.23

It is uncertain if a similar benefit can be extrapolated topatients started on neoadjuvant chemotherapy, who had un-dergone an optimal interval surgical debulking. In 2009, theSouthwest Oncology Group conducted a phase 2 study ofneoadjuvant chemotherapy followed by interval debulking inwomen with stage III and IVepithelial ovarian, fallopian tube,or primary peritoneal cancer. In this study, women with ad-enocarcinoma on biopsy or peritoneal cytology consistentwith stage III/IV (pleural effusions only) epithelial ovarian,fallopian tube, or primary peritoneal carcinoma were treatedwith neoadjuvant IV paclitaxel at 175 mg/m2 combined withcarboplatin (AUC, 6) every 21 days for 3 cycles, followed bydebulking surgery. If optimally debulked, patients received IVpaclitaxel (175 mg/m2) and IP carboplatin (AUC, 5) on day 1as well as IP paclitaxel (60 mg/m2) on day 8, every 28 days for6 cycles. At a median follow-up of 21 months, the observedPFS and OS for the 26 patients who received IV and IP ad-juvant chemotherapy were 29 and 34 months, respectively.24

In contrast to this study, the median PFS for our patients whoreceived IP adjuvant chemotherapy was only 17.5 months.This difference might be due to the differences in dose in-tensity, use of different platinum drugs, number of chemo-therapy cycles performed after surgery (3 vs 6), and treatmentinterval (21 vs 28 days) between the 2 IP protocols. Similar toour study, Nelson et al21 compared 38 patients treated with IPchemotherapy after neoadjuvant chemotherapy and optimalIDS with 29 patients who had optimal PCRS, also receivingIP chemotherapy. The recurrence rates for patients whocompleted 4 or more cycles of IP chemotherapy in the IDSand PCRS groups were 58% and 35%, respectively. Themedian time to recurrence was shorter than expected with theuse of IP chemotherapy after neoadjuvant chemotherapy,compared with those in previous trials.15

We observed that adjuvant IP chemotherapy was notpredictive of survival after neoadjuvant chemotherapy in oursmall exploratory study. We hypothesize the following rea-sons for these findings. First, it is conceivable that after

exposure to neoadjuvant chemotherapy, the residual tumorcells at the time of interval surgery would be expected to berelatively more platinum resistant compared with residualtumor cells left after primary up-front surgery, thereby de-creasing the expected benefit of increased dose intensity asprovided by the IP route. This is supported by Matsuo et al25

who studied the prevalence of platinum and taxane resistancein epithelial ovarian, fallopian, and primary peritoneal car-cinomas. In this report, platinum resistance was documentedto be more common after neoadjuvant chemotherapy com-pared with PCRS without previous chemotherapy (odds ratio,5.4; 95% CI, 1.3Y23.2; P = 0.027). Second, the benefits of IPchemotherapy are theorized to be dependent largely on directtumor cell exposure to a very high concentration of cytotoxicdrugs. Because of the commonly observed extensive tumorfibrosis after neoadjuvant chemotherapy and adhesions afterradical debulking surgery, this might result in suboptimaldrug distribution and absorption in residual tumor masses,decreasing the anticipated benefit. Third, the number of IPchemotherapy cycles to achieve optimal benefits has not yetbeen defined in a neoadjuvant setting. After the primaryinitial optimal debulking surgery, all IP protocols had re-commended at least 6 cycles of adjuvant treatment. In ourcohort, the median number of IP cycles given was 3.Wemightnot have fully exploited the full benefit of IP chemotherapybecause of the limited treatment in our current protocol. Asreported by the study of Tewari et al26 on the long-term out-comes of patients treated with IP chemotherapy on GOGprotocols 172 and 114 presented at the Society of GynecologicOncologist 2013 annual meeting, patients who completed 5 or6 cycles of IP therapy had a 5-year OS of 59%, compared with18% versus 33%, with 1 or 2 versus 3 or 4 cycles, respectively(P G 0.001), suggesting that at least 6 cycles of chemotherapywould be preferred to maximize the benefits. Lastly, a recentreport had suggested that there exists a significant risk ofunderestimating the residual disease after neoadjuvant che-motherapy secondary to the chemotherapy effect causing in-flammation and fibrosis.27 This can potentially result in the useof IP chemotherapy in patients with more than 1 cm of residualdisease in our IP cohort, leading to a lower observed survivalbecause these poor prognostic patients would have been in-cluded with good prognosis patients, diluting the potentialadditional benefit of IP chemotherapy.

There are a number of important limitations in ourstudy. As with any retrospective review, there are unavoidableselection biases and unknown confounders that cannot beidentified and corrected. Our follow-up time was relativelyshort, and our small sample size provided only limited sta-tistical power for a comprehensive statistical analysis. Wecannot make a definitive conclusion or recommendationsbased on the current exploratory analysis. The roles of IPchemotherapy after neoadjuvant chemotherapy will need tobe further studied and defined in a larger prospective cohort.Currently, the National Cancer Institute of Canada is accruingpatients to prospective randomized phase 3 trials (OV21) toevaluate the survival benefit of IP versus IV adjuvant che-motherapy in patients treated with neoadjuvant chemotherapy,which will further guide oncologists on the application of IPchemotherapy in this patient cohort.




Future research on IP chemotherapy in the neoadjuvantsetting will need to address a number of important unresolvedissues such as the optimal number of IP cycles to be givenafter neoadjuvant therapy, the use of IP carboplatin instead ofcisplatin to limit toxicities, the role of concurrent consoli-dation bevacizumab in combination with IP therapy, and theincorporation of dose-dense strategy into the current standardof care.

REFERENCES1. SEER. Cancer Statistics, 2012. http://seer.cancer.gov/statfacts/

html/ovary.html. Accessed December 12, 2013.2. Cannistra SA. Cancer of the ovary. N Engl J Med.

2004;351:2519Y2529.3. Mutch DG. Surgical management of ovarian cancer. Semin

Oncol. 2002;29:3Y8.4. Vermorken JB. The integration of paclitaxel and new platinum

compounds in the treatment of advanced ovarian cancer. Int JGynecol Cancer. 2001;11:21Y30.

5. Chi DS, Liao JB, Leon LF, et al. Identification of prognosticfactors in advanced epithelial ovarian carcinoma. GynecolOncol. 2001;82:532Y537.

6. Hoskins WJ, McGuire WP, Brady MF, et al. The effect ofdiameter of largest residual disease on survival after primarycytoreductive surgery in patients with suboptimal residualepithelial ovarian carcinoma. Am J Obstet Gynecol.1994;170:974Y979; discussion 979Y980.

7. Covens AL. A critique of surgical cytoreduction in advancedovarian cancer. Gynecol Oncol. 2000;78:269Y274.

8. Dauplat J, Le Bouedec G, Pomel C, et al. Cytoreductive surgeryfor advanced stages of ovarian cancer. Semin Surg Oncol.2000;19:42Y48.

9. Boente MP, Chi DS, Hoskins WJ. The role of surgery in themanagement of ovarian cancer: primary and intervalcytoreductive surgery. Semin Oncol. 1998;25:326Y334.

10. Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapyor primary surgery in stage IIIC or IVovarian cancer. N Engl JMed. 2010;363:943Y953.

11. Kang S, Nam BH. Does neoadjuvant chemotherapy increaseoptimal cytoreduction rate in advanced ovarian cancer?Meta-analysis of 21 studies. Ann Surg Oncol.2009;16:2315Y2320.

12. Bristow RE, Eisenhauer EL, Santillan A, et al. Delaying theprimary surgical effort for advanced ovarian cancer: a systematicreviewof neoadjuvant chemotherapy and interval cytoreduction.Gynecol Oncol. 2007;104:480Y90.

13. Bristow RE, Chi DS. Platinum-based neoadjuvantchemotherapy and interval surgical cytoreduction for advancedovarian cancer: a meta-analysis. Gynecol Oncol.2006;103:1070Y1076.

14. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatinplus intravenous cyclophosphamide versus intravenouscisplatin plus intravenous cyclophosphamide for stage IIIovarian cancer. N Engl J Med. 1996;335:1950Y1955.

15. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitonealcisplatin and paclitaxel in ovarian cancer. N Engl J Med.2006;354:34Y43.

16. Gadducci A, Carnino F, Chiara S, et al. Intraperitoneal versusintravenous cisplatin in combination with intravenouscyclophosphamide and epidoxorubicin in optimallycytoreduced advanced epithelial ovarian cancer: a randomizedtrial of the Gruppo Oncologico Nord-Ovest. Gynecol Oncol.2000;76:157Y162.

17. Kirmani S, Braly PS, McClay EF, et al. A comparison ofintravenous versus intraperitoneal chemotherapy for the initialtreatment of ovarian cancer. Gynecol Oncol. 1994;54:338Y344.

18. Markman M, Bundy BN, Alberts DS, et al. Phase III trial ofstandard-dose intravenous cisplatin plus paclitaxel versusmoderately high-dose carboplatin followed by intravenouspaclitaxel and intraperitoneal cisplatin in small-volume stage IIIovarian carcinoma: an intergroup study of the GynecologicOncology Group, Southwestern Oncology Group, and EasternCooperative Oncology Group. J Clin Oncol.2001;19:1001Y1007.

19. Yen MS, Juang CM, Lai CR, et al. Intraperitonealcisplatin-based chemotherapy vs. intravenous cisplatin-basedchemotherapy for stage III optimally cytoreduced epithelialovarian cancer. Int J Gynaecol Obstet. 2001;72:55Y60.

20. Hess LM, Benham-Hutchins M, Herzog TJ, et al. Ameta-analysis of the efficacy of intraperitoneal cisplatin for thefront-line treatment of ovarian cancer. Int J Gynecol Cancer.2007;17:561Y570.

21. Nelson G, Lucero CA, Chu P, et al. Intraperitonealchemotherapy for advanced ovarian and peritoneal cancers inpatients following interval debulking surgery or primarycytoreductive surgery: Tom Baker Cancer Centre experiencefrom 2006 to 2009. J Obstet Gynaecol Can. 2010;32:263Y269.

22. Le T, Latifah H, Jolicoeur L, et al. Does intraperitonealchemotherapy benefit optimally debulked epithelial ovariancancer patients after neoadjuvant chemotherapy? GynecolOncol. 2011;121:451Y454.

23. Schneider JG. Intraperitoneal chemotherapy. Obstet GynecolClin North Am. 1994;21:195Y212.

24. Tiersten AD, Liu PY, Smith HO, et al. Phase II evaluation ofneoadjuvant chemotherapy and debulking followed byintraperitoneal chemotherapy in women with stage III and IVepithelial ovarian, fallopian tube or primary peritoneal cancer:Southwest Oncology Group Study S0009. Gynecol Oncol.2009;112:444Y449.

25. Matsuo K, Eno ML, Im DD, et al. Chemotherapy time intervaland development of platinum and taxane resistance in ovarian,fallopian, and peritoneal carcinomas. Arch Gynecol Obstet.2010;281:325Y328.

26. Tewari D, Java J, Salani R, et al. Long-term survival advantageof intraperitoneal chemotherapy treatment in advancedovarian cancer: an analysis of a Gynecologic Oncology Groupancillary data study. Los Angeles, CA: Society of GynecologicOncology (SGO): 2013 Annual Meeting on Women’sCancer; 2013.

27. Hynninen J, Lavonius M, Oksa S, et al. Is perioperative visualestimation of intra-abdominal tumor spread reliable in ovariancancer surgery after neoadjuvant chemotherapy? GynecolOncol. 2013;128:229Y232.




Cancer Al Ovario-2013

Documents

Transcript of Cancer Al Ovario-2013