A Gynecologic Oncology Group Study of serum CA-125 levels in patients with stage III optimally debulked ovarian cancer treated with intraperitoneal compared to intravenous chemotherapy: an analysis of patients enrolled in GOG 172. Intraperitoneal cisplatin-based chemotherapy vs. intravenous cisplatin-based chemotherapy for stage III optimally cytoreduced epithelial ovarian cancer. Phase II Study of Intraperitoneal Carboplatin With Intravenous Paclitaxel in Patients With Suboptimal Residual Epithelial Ovarian or Primary Peritoneal Cancer: A Sankai Gynecology Cancer Study Group Study High volume intraperitoneal chemotherapy (“Belly bath”) for ovarian cancer A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer. A randomized Phase II/III trial of 3 weekly intraperitoneal versus intravenous carboplatin in combination with intravenous weekly dose-dense paclitaxel for newly diagnosed ovarian, fallopian tube and primary peritoneal cancer. Importance of delivered cycles and nomogram for intraperitoneal chemotherapy in ovarian cancer. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. Three ongoing intraperitoneal chemotherapy trials in ovarian cancer Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group Study. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. Phase ii/iii study of intraperitoneal chemotherapy after neoadjuvant chemotherapy for ovarian cancer: ncic ctg ov.21. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. First-line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long-term follow-up. A Comparative Study of Intraperitoneal Carboplatin versus Intravenous Carboplatin with Intravenous Cyclophosphamide in Both Arms as Initial Chemotherapy for Stage III Ovarian Cancer Intraperitoneal cisplatin versus no further treatment: 8‐year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum‐based intravenous chemotherapy [Polychemotherapy of ovarian cancer via combined intravenous and intraperitoneal routes. Technic and preliminary results]. Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase-II trial. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Gr
OBJECTIVE Serum CA-125 values have been advocated in the monitoring of ovarian cancer patients receiving intravenous ( IV ) chemotherapy .  This evaluation sought to determine if the CA-125 test can be used to monitor treatment effect among patients receiving intraperitoneal chemotherapy ( IP ) .  METHODS Patient charts from a phase III clinical trial ( GOG 172 ) were retrospectively review ed . Serum CA-125 levels prior to each cycle of therapy were collected and compared between the IV and IP chemotherapy delivery . The association between CA-125 and progression-free survival ( PFS ) or overall survival ( OS ) was estimated and the homogeneity of the results between IP and IV chemotherapy was assessed . RESULTS A total of 177 patients were treated with IV chemotherapy and 165 patients with IP chemotherapy with CA-125 data available were included in this analysis . The observed difference was not statistically significant in median CA-125 levels between the IV and IP arms at any time point ( P>0.05 for all ) . Following surgery and adjuvant chemotherapy , patients with an abnormal CA-125 > 35 U/ml were 2.45 times more likely to have disease progression ( 95 % CI : 1.52 - 3.95 , P<0.001 ) and 2.78 times more likely to die of disease ( 95 % CI : 1.66 - 4.65 , P<0.001 ) , compared to those with a CA-125 < 35 U/ml . These results were consistent with IP and IV chemotherapy . CONCLUSION Serum CA-125 levels decrease in a similar manner during IP chemotherapy when compared to IV chemotherapy . Serum CA-125 algorithms for monitoring treatment effect that have been established for IV chemotherapy may also be applied for patients receiving IP chemotherapy OBJECTIVE To compare the survival between intraperitoneal cisplatin-based chemotherapy ( IPCT ) and intravenous cisplatin-based chemotherapy ( IVCT ) in stage III epithelial ovarian cancer with minimal residual disease ( < 1 cm ) after primary debulking surgery . METHOD One hundred and thirty-two patients with stage III epithelial ovarian cancer after optimal primary debulking surgery with minimal residual disease between April 1990 and March 1995 were entered into a r and omized clinical trial in which IPCT or IVCT was administered at 3-week intervals . Patients in the IPCT arm received cisplatin-based ( 100 mg/m(2 ) ) intraperitoneal chemotherapy . Patients in the IVCT arm received cisplatin-based ( 50 mg/m(2 ) ) intravenous chemotherapy . The tumor response was assessed every 3 months . The hematological toxicity using the South West Oncology Group ( SWOG ) toxicity criteria was assessed . Catheter complications associated with intraperitoneal chemotherapy were also analyzed . RESULT The estimated median survival in the IPCT group was 43 months ( 95 % confidence interval , 34 - 54 ) and IVCT group was 48 months ( 95 % confidence interval , 37 - 59 ) . The hazard ratio of death was not statistically significant between IPCT and IVCT ( hazard ratio , 1.13 ; 95 % CI , 0.69 - 1.86 ; P=0.317 ) . The frequencies of hematological toxic effects were significantly lower in the IPCT group than in the IVCT group . CONCLUSION Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery Purpose : To assess the antitumor efficacy and safety of 2 treatment modalities : intraperitoneal carboplatin combined with intravenous ( IV ) paclitaxel . Patients and Methods : Eligible patients were those with epithelial ovarian carcinoma or primary peritoneal carcinoma stages II to IV who underwent initial surgery and had a residual tumor size of 2 cm or larger . Patients received IV paclitaxel 175 mg/m2 followed by intraperitoneal carboplatin AUC6 . The primary end point was a response . Secondary end points were toxicity , progression-free survival , and overall survival . Results : Twenty-six patients were enrolled , and 24 patients were eligible for assessment . The response rate was 83.3 % ( 95 % CI , 62.6%-95.3 % ; Table 4 ) . The median progression-free survival was 25 months . The median overall survival had not been reached . Incidences of grade ( G ) 3/4 hematological toxicities were absolute neutrophil count , 96 % ; hemoglobin , 29 % ; and thrombocytopenia , 16 % . Nonhematological toxicities included G2 liver function , 4 % ; G3 sensory neuropathy , 8 % ; and G3 myalgia and arthralgia , 4 % . Conclusions : Intraperitoneal administration of carboplatin combined with IV paclitaxel was well tolerated and showed satisfactory response in the patients with bulky residual tumor . Large-scale phase III trial comparing with IV carboplatin is warranted in this patient population Summary The currently accepted therapies for ovarian cancer have produced only limited numbers of extended complete remissions in advanced-stage disease . Studies of high-volume intraperitoneal chemotherapy have been initiated to define the toxicology , pharmacokinetics , and the therapeutic effectiveness of this treatment modality . This technique has been virtually ignored until recently , because little success has been achieved with it except in one study ( Rutledge , 1966 ) , in which large intraperitoneal fluid volumes were used . The general lack of success probably reflects inadequate attention to physiologic and pharmacologic principles of drug distribution and absorption in a space as large as the peritoneal cavity . Biomedical engineers , pharmacologists , and clinicians at the NCI have cooperated in the development of a rational chemotherapy for ovarian cancer . Following mathematical pharmacokinetic modeling and toxicologic studies in rat , a Phase I clinical trial of intraperitoneal methotrexate administered in large volumes of dialysis fluid was initiated . Results in three patients confirm the practicality of this approach , and further investigation is warranted A phase III study was conducted comparing intraperitoneal ( ip ) versus intravenous ( iv ) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate .  Twenty-nine patients were r and omized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks ; thirty-three patients were r and omized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks . Patients were stratified by stage ( IIC-IV ) and size of residual disease ( > or < or = 1 cm ) . The study was conducted in a community-wide setting . The complete response in evaluable patients was 48 % in the ip group and 52 % in the iv group . The surgical complete response rate for all patients on study , underestimated because not all patients in complete clinical remission had a second-look laparotomy , was 31 % in the ip group and 33 % in the iv group . There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm . With a median follow-up of 46 months ( range 21 - 70 months ) there is no difference in response duration or survival . Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity Retrospective studies and a Phase II trial demonstrated the promising efficacy and safety of intraperitoneal administration of carboplatin in ovarian , fallopian tube and primary peritoneal cancer . A Japanese Gynecologic Oncology Group 3016 r and omized Phase III trial for these cancers showed dose-dense weekly administration of paclitaxel significant improvement of progression-free survival and overall survival over every 3-week administration . From June 2010 , we have been conducting a r and omized Phase II/III trial of intravenous versus intraperitoneal administration of carboplatin every 3 week in combination with dose-dense weekly administration of paclitaxel . The purpose of this trial is to prove the superiority of intraperitoneal administration of carboplatin over intravenous administration . Primary endpoint is progression-free survival and secondary endpoints include overall survival , quality of life assessment and cost-benefit .  The first 120 patients will be evaluated for the feasibility of intraperitoneal arm and a total of 746 patients will be enrolled in a Phase III study OBJECTIVE Intraperitoneal ( IP ) chemotherapy has gained enthusiasm in the treatment of ovarian cancer . Despite having a better survival advantage than intravenous ( IV ) chemotherapy , IP chemotherapy still poses significant morbidity and complications . Identifying the subset of patients who could best benefit from IP chemotherapy  , and those who would least benefit from this treatment , thus avoiding potential complications , is critical . METHODS Between January 2001 and December 2007 , 367 patients with stage III epithelial ovarian cancer underwent r and omized trial for IP/IV chemotherapy  were recruited to construct a nomogram , which is a graphical representation of Cox proportional hazards model adopting six weighted risk factors including age , CA125 , IP/IV delivery , stage , histology , and upper abdominal metastases . The nomogram was internally vali date d for discrimination and calibration . The concordance index was used for quantifying the predictive ability of overall survival with bootstrapping to correct for bias . RESULTS The cycles of completed IP chemotherapy had an impact on overall survival ( > or = 5 vs. < or = 4 cycles , P=0.02 ) . A nomogram for predicting median survival and 5-year survival probability was constructed with a concordance index of 0.72 . Upper abdominal tumor metastases ( P<0.001 ) and colon resection ( P=0.02 ) predicted increased chances for early discontinuation of IP chemotherapy . CONCLUSIONS At least five IP cycles are needed to achieve better survival . Nomogram can help to identify the subset of patients who can least benefit from IP chemotherapy , thus avoiding potential IP complications and help to facilitate discussion between patient and physician , risk stratification , and help to guide clinical care BACKGROUND Despite considerable improvement in the treatment of advanced ovarian cancer , the optimization of efficacy and tolerability remains an important issue . Therefore , we performed a r and omized , phase III non-inferiority trial comparing paclitaxel plus cisplatin ( PT ) with paclitaxel plus carboplatin ( TC ) in patients with advanced ovarian cancer . METHODS A total of 798 patients with International Federation of Gynecology and Obstetrics stage IIB-IV were r and omly assigned to receive six courses of either PT or TC at 3-week intervals . The primary endpoint was the proportion of patients without progression at 2 years . Secondary endpoints included toxicity , response to treatment , quality of life , and overall and progression-free survival time . Quality of life was evaluated using the European Organization for Research and Treatment of Cancer quality -of-life question naire (QLQ)-C30 , version 2.0 . Survival curves were calculated using the Kaplan-Meier method , and hazard ratios were estimated using the Cox proportional hazards model . RESULTS The proportion of patients without progression at 2 years was not statistically significantly different between the two treatment arms ( 40.0 % for PT versus 37.5 % for TC , difference = 2.5 % , one-sided 95 % confidence interval [ CI ] = - infinity to 8.2 % ) . Median progression-free survival time in the TC arm ( 17.2 months , 95 % CI = 15.2 to 19.3 months ) and the PT arm ( 19.1 months , 95 % CI = 16.7 to 21.5 months ) were also not statistically significantly different ; the same was true of median overall survival time ( 43.3 months , 95 % CI = 37.2 to 47.8 months versus 44.1 months , 95 % CI = 40.2 to 49.4 months , for the TC and PT arms , respectively ) . The TC regimen was associated with a higher frequency of hematologic toxicity , but a lower frequency of gastrointestinal and neurologic toxicity , than the PT regimen . Mean global quality -of-life scores at the end of treatment were statistically significantly better in the TC arm than in the PT arm ( 65.25 versus 51.97 , respectively ; difference = -13.28 , 95 % CI = -18.88 to -7.68 ) . CONCLUSION The TC regimen achieved comparable efficacy to the PT regimen but was associated with better tolerability and quality of life , and should , therefore , be considered as an important alternative for st and ard first-line chemotherapy in patients with advanced ovarian cancer See accompanying article on page 91 . The most significant characteristic feature of ovarian cancer is the intraperitoneal spread in its early occurrence . Therefore , it is reasonable to consider the intraperitoneal ( IP ) chemotherapy for this disease entity . The primary concept of IP chemotherapy is to expose the tumor tissue directly to an extremely high concentration of anticancer agents by perfusing inside the peritoneal cavity [ 1 ] . IP chemotherapy has been investigated for a long time , and there have actually been three large-scale r and omized trials conducted in the US , all of which showed overall and /or progression-free survival benefit [ 2 - 4 ] . Based on these results , the National Cancer Institute ( NCI ) and the Gynecologic Oncology Group ( GOG ) performed a meta- analysis on the results of these three US trials and other phase III trials of IP versus intravenous ( IV ) chemotherapy , and significant improvement of survival was shown with IP therapy . Based on this meta- analysis , the NCI has released a clinical announcement encouraging the gynecological oncology community to consider IP chemotherapy using cisplatin as the st and ard treatment for advanced ovarian cancer patients in whom the residual disease were debulked to 1 cm or less [ 5 ] . Unfortunately , however , IP chemotherapy has not been adopted as a st and ard care because there are several controversial issues to be solved . One of the major issues to be resolved is the chemotherapy-related toxicity . Another concern is the catheter-related problems such as port infection or occlusion [ 4,6 ] . In the GOG 172 trial , the completion rate of  IP chemotherapy for 6 cycles was only 42 % . Twenty-seven percent of them received either no IP chemotherapy ( 8 % ) or only one cycle ( 19 % ) . Despite the fact that the majority of patients in the IP arm of the GOG 172 trial did not complete the IP chemotherapy , overall survival was significantly better than the IV chemotherapy arm . This raised the question of how many cycles of IP chemotherapy is needed to obtain survival advantage ? In this issue of the Journal , Kim et al. [ 7 ] reported the preliminary results of IP administration of cisplatin at the time of primary surgery followed by IV chemotherapy . The toxicities were acceptable as predicted , and the authors concluded that further prospect i ve trials are warranted based on this study . The most advantageous benefit of this approach is that there is no need to place the access device for repeating IP chemotherapy . Also , as the authors described , the use of IP chemotherapy at the time of surgery and /or in the immediate postoperative period facilitates uniform drug delivery and may avoid some of the complications of prolonged peritoneal access . However , it seems to be too early to test this approach in a large scale comparative trial , because we do not know how many cycles of IP chemotherapy is minimally needed to obtain survival advantage . In other words , only one cycle may loose the survival benefit of IP chemotherapy . In fact , it has not been eluci date d why the GOG 172 trial demonstrated a strikingly better survival in the IP arm compared to the IV arm , despite the fact that many of the patients in the IP arm did not receive the complete IP regimen of chemotherapy [ 4 ] . Until we find some clues as to the background mechanisms involved in IP chemotherapy , we should try providing IP chemotherapy as many times as IV chemotherapy using IP access devices . The major drawback of IP chemotherapy is that the IP chemotherapy agent is cisplatin , which is more toxic and more difficult to manage compared to carboplatin , the current st and ard IV chemotherapy agent . Therefore , it is important to explore whether carboplatin may replace cisplatin in IP chemotherapy . Several studies have demonstrated that the use of carboplatin as IP chemotherapy would be feasible [ 8 - 10 ] . Currently , three large-scale r and omized trials are ongoing to examine the efficacy of  carboplatin-based IP chemotherapy . The simplest study is the iPocc Trial ( GOTIC-001/JGOG-3019 ) [ 11 ] . In this trial , dose-dense weekly paclitaxel at 80 mg/m2 will be administered in combination with carboplatin at area under the curve ( AUC ) 6 every three-week either by IV or IP . In this study , eligible patients are those with epithelial ovarian cancer stages II to IV , thus , this study will explore the potential of IP chemotherapy in suboptimally treated advanced ovarian cancer , and not only for optimally debulked cases . The classical concept of IP chemotherapy is local therapy , which is the direct contact of cancer cells with anticancer drugs , and it is believed that direct penetration of agents is limited to a few millimeters from the tumor surface [ 1 ] . However , it has been hypothesized the carboplatin administered into the IP cavity is absorbed from the peritoneal surface within 24 hours and serum the AUC is exactly the same as serum platinum AUC after IV administration , although platinum AUC in the IP cavity was 17 times greater when carboplatin was given by the IP than the IV route [ 12 ] . It has been demonstrated that IP carboplatin for suboptimal residual cases was also feasible as a phase II trial [ 13 ] , and therefore , the iPocc Trial is also challenging this important scientific question . The iPocc Trial has just been opened to international study groups such as the Korean Gynecologic Oncology Group ( KGOG ) or the Arbeitsgemeinschaft Gynaekologische Onkologie ( AGO ) of Austria . The contracts also have been under process with individual hospitals in Singapore , Australia , and Spain . The target accrual is 746 , and at the present time approximately 100 patients have been enrolled , and the international community is encouraged to participate in this important trial . Another trial is the GOG 252 study . In this trial , the control arm and one of the experimental arms are exactly the same as the iPocc Trial , except that there is a combination and maintenance administration of bevacizumab . The GOG incorporated this strategy based on the GOG 218 trial results . The GOG 252 trial has a third arm , which is the modified GOG 172 winner regimen . In this arm IV paclitaxel at 135 mg/m2 on day 1 followed by IP cisplatin at 75 mg/m2 on day 2 , and then IP paclitaxel is administered on day 8 . This arm also incorporates the combination and maintenance of bevacizumab . The GOG 252 trial has completed accrual and awaits for the results . The third trial is the OV-21/GCIG study lead by the Canadian National Cancer Institute . This trial has a unique approach to the IP chemotherapy . All patients with stages III patients will receive neoadjuvant chemotherapy . Those patients who respond to the neoadjuvant chemotherapy will receive interval debulking surgery ( IDS ) , and if the residual disease after IDS becomes the optimal < 1 cm , the patient will be r and omized to one of the three arms . The control arm is the combination of IV paclitaxel at 135 mg/m2 followed by IV carboplatin at AUC 5 on day 1 , and then IV paclitaxel at 60 mg/m2 will be given on day 8 . The second arm is same as the control arm but carboplatin will be given by the IP route . The third arm is the modified GOG 172 winner arm , which is the same as the third arm of GOG 252 trial but in which bevacizumab is not given . One of these two IP arms ( arm 2 or arm 3 ) will be chosen , as a r and omized phase II manner , and the winner arm will be compared with the control arm as phase the III trial . These three trials have different patient population s and different treatment regimens , but will answer important questions when compared between trials . It is encouraged for gynecologic oncologists to participate in one of these trials to resolve the important IP chemotherapy questions for the future PURPOSE In r and omized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer . Although in nonr and omized trials , carboplatin and paclitaxel was a less toxic and highly active combination regimen , there remained concern regarding its efficacy in patients with small-volume , resected , stage III disease . Thus , we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population . PATIENTS AND METHODS Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were r and omly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 ( arm I ) , or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours ( arm II ) . RESULTS Seven hundred ninety-two eligible patients were enrolled onto the study . Prognostic factors were similar in the two treatment groups . Gastrointestinal , renal , and metabolic toxicity , as well as grade 4 leukopenia , were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II . Neurologic toxicity was similar in both regimens . Median progression-free survival and overall survival were 19.4 and 48.7 months , respectively , for arm I compared with 20.7 and 57.4 months , respectively , for arm II . The relative risk ( RR ) of progression for the carboplatin plus paclitaxel group was 0.88 ( 95 % confidence interval [ CI ] , 0.75 to 1.03 ) and the RR of death was 0.84 ( 95 % CI , 0.70 to 1.02 ) . CONCLUSION In patients with advanced ovarian cancer , a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity , is easier to administer , and is not inferior , when compared with cisplatin plus paclitaxel PURPOSE A Gynecologic Oncology Group ( GOG ) r and omized phase III trial ( GOG 172 ) in optimal stage III epithelial ovarian cancer showed that intravenous ( IV ) paclitaxel plus intraperitoneal ( IP ) cisplatin and paclitaxel significantly lengthened progression-free survival and overall survival compared with IV paclitaxel and cisplatin . The purpose of this report is to comprehensively evaluate the patient-reported outcomes associated with IP versus IV therapy . PATIENTS AND METHODS Four hundred fifteen eligible women were enrolled onto GOG 172 at member institutions . The Functional Assessment of Cancer Therapy-Trial Outcome Index ( FACT-TOI ; which includes physical , functional , and ovarian subscales ) and neurotoxicity ( Ntx ) and abdominal discomfort ( AD ) subscales were used to assess patient-reported outcomes . Assessment s were completed before r and om assignment , before cycle 4 , and 3 to 6 weeks and 12 months after treatment . RESULTS Physical and functional well-being and ovarian cancer symptoms were significantly worse in the IP arm before cycle 4 ( P < .001 ) and 3 to 6 weeks after treatment ( P = .001 for FACT-TOI ) . Patients in the IP arm also reported significantly worse AD before cycle 4 ( P < .001 ) and significantly worse Ntx 3 to 6 weeks ( P = .001 ) and 12 months ( P = .003 ) after completing IP treatment . In general , however , the quality of life of both groups improved over time . CONCLUSION During active treatment , patients on the IP arm experienced more health-related quality -of-life disruption , AD , and Ntx compared with patients receiving conventional IV therapy . However , only Ntx remained significantly greater for IP patients 12 months after treatment . This trade-off should be included when discussing treatment options with patients . Future studies to mitigate the added burden associated with IP therapy are planned BACKGROUND Paclitaxel and carboplatin given every 3 weeks is st and ard treatment for advanced ovarian carcinoma . Attempts to improve patient survival by including other drugs have yielded disappointing results . We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer . METHODS Patients with stage II to IV epithelial ovarian cancer , fallopian tube cancer , or primary peritoneal cancer were eligible for enrolment in this phase 3 , open-label , r and omised controlled trial at 85 centres in Japan . Patients were r and omly assigned by computer-generated r and omisation sequence to receive six cycles of either paclitaxel ( 180 mg/m(2 ) ; 3-h intravenous infusion ) plus carboplatin ( area under the curve [ AUC ] 6 mg/mL per min ) , given on day 1 of a 21-day cycle ( conventional regimen ; n=320 ) , or dose-dense paclitaxel ( 80 mg/m(2 ) ; 1-h intravenous infusion ) given on days 1 , 8 , and 15 plus carboplatin given on day 1 of a 21-day cycle ( dose-dense regimen ; n=317 ) . The primary endpoint was progression-free survival . Analysis was by intention to treat ( ITT ) . This trial is registered with Clinical Trials.gov , number NCT00226915 . FINDINGS 631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population ( dose-dense regimen , n=312 ; conventional regimen , n=319 ) . Median progression-free survival was longer in the dose-dense treatment group ( 28.0 months , 95 % CI 22.3 - 35.4 ) than in the conventional treatment group ( 17.2 months , 15.7 - 21.1 ; hazard ratio [ HR ] 0.71 ; 95 % CI 0.58 - 0.88 ; p=0.0015 ) . Overall survival at 3 years was higher in the dose-dense regimen group ( 72.1 % ) than in the conventional treatment group ( 65.1 % ; HR 0.75 , 0.57 - 0.98 ; p=0.03 ) . 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early . Reasons for participant dropout were balanced between the groups , apart from withdrawal because of toxicity , which was higher in the dose-dense regimen group than in the conventional regimen group ( n=113 vs n=69 ) . The most common adverse event was neutropenia ( dose-dense regimen , 286 [ 92 % ] of 312 ; conventional regimen , 276 [ 88 % ] of 314 ) . The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group ( 214 [ 69 % ] ) than in the conventional treatment group ( 137 [ 44 % ] ; p<0.0001 ) . The frequencies of other toxic effects were similar between groups . INTERPRETATION Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer . FUNDING Bristol-Myers Squibb PURPOSE To develop a tolerable , dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma . PATIENTS AND METHODS Patients underwent initial surgical assessment and tumor debulking . Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle . Carboplatin dose was calculated based on projected area under the curve ( AUC ) for concentration over time ( mg . mL-1.min ) and escalated to determine the maximum-tolerated dose ( MTD ) . Paclitaxel dose was also escalated as a 3- , 24- , or 96-hour infusion . Granulocyte colony-stimulating factors ( G-CSFs ) were required at selected dose levels or could be added based on hematologic toxicity . RESULTS Thirty-nine patients were enrolled and assessable for toxicity and response . Dose-limiting toxicity ( DLT ) was hematologic , primarily neutropenia . Less than 2 % of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia . The carboplatin MTD was AUC 7.5 ( equivalent to a median dose of 471 mg/m2 ) . The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF . A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression , and was not further evaluated . Measured carboplatin  AUC agreed well with the calculated AUC . The overall complete ( n = 16 ) and partial ( n = 2 ) response rate among 24 patients with measurable disease was 75 % , with a median progression-free survival time of 15 months . CONCLUSION Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance . The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF . This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area BACKGROUND There is no clear data on the optimum number of courses of platinum chemotherapy required for treating advanced ovarian cancer . A prospect i ve r and omised trial was performed to compare five with eight courses of either carboplatin 400 mg/m2 or cisplatin 75 mg/m2 given four-weekly to patients with stage IC-IV ovarian cancer . PATIENTS AND METHODS 225 patients were entered into the study and 233 were eligible for r and omisation : 118 to five courses and 115 to eight courses . In each r and omisation , half the patients received carboplatin and half received cisplatin . RESULTS The mean number of courses received on the five arm was 4.74 and on the eight arm , 6.42 , an increase of 35 % . The median survival for all patients was 24 months with the median survival for the 156 patients with stage 3 disease being 21 months . No difference was detected in survival ( P = 0.53 ) or time to progression from initial surgery ( P = 0.29 ) between the two arms of the trial . False-negative calculations based on a multivariate analysis show that the trial currently has 95 % power for excluding a difference of 10 % in favour of the eight course arm at three years . CONCLUSION There is insufficient evidence at the present time to justify more than five courses of first-line single agent platinum chemotherapy in the management of advanced ovarian cancer BACKGROUND Intravenous platinum-based chemotherapy is the st and ard primary therapy for advanced ovarian cancer . We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated , stage III , epithelial ovarian cancer . METHODS The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm . Within four weeks after surgery , six courses of intravenous cyclophosphamide ( 600 mg per square meter of body-surface area per course ) plus either intraperitoneal cisplatin ( 100 mg per square meter ) or intravenous cisplatin ( 100 mg per square meter ) were administered at three-week intervals . RESULTS Of 654 r and omized patients , 546 were eligible for the study . The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin ( 49 months ; 95 percent confidence interval , 42 to 56 ) than in the group receiving intravenous cisplatin ( 41 months ; 95 percent confidence interval , 34 to 47 ) . The risk of death was lower in the intraperitoneal group than in the intravenous group ( hazard ratio , 0.76 ; 95 percent confidence interval , 0.61 to 0.96 ; P = 0.02 ) . Moderate-to-severe tinnitus , clinical hearing loss , and neuromuscular toxic effects were significantly more frequent in the intravenous group . CONCLUSIONS As compared with intravenous cisplatin , intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less Three large r and omized clinical trials have shown a survival benefit in women with stage iii epithelial ovarian cancer ( eoc ) who receive intraperitoneal ( IP ) chemotherapy after optimal primary debulking surgery . The most recent Gynecologic Oncology Group study , gog 172 , showed an improvement in median overall survival of approximately 17 months . That result led to a U.S. National Cancer Institute ( nci ) clinical announcement recommending that IP chemotherapy be considered for this group of women with eoc . However , IP chemotherapy is associated with increased toxicity , and rates for completion of treatment are low ( 42 % in gog 172 ) . The optimal IP regimen and duration of treatment has yet to be defined . Women undergoing chemotherapy before optimal debulking surgery were not included in the studies or in the nci clinical announcement . The National Cancer Institute of Canada Clinical Trials Group has developed a protocol for a r and omized phase ii/iii study which will examine whether IP platinum-taxane-based chemotherapy benefits women who have received neoadjuvant chemotherapy before optimal surgical debulking . To address whether the less systemically toxic  carboplatin can be substituted for cisplatin IP , the first phase of the study will have 3 arms : 1 intravenous-only , and 2 IP-containing regimens . At the end of the first stage , and provided that IP therapy is feasible to administer in this patient population , one of the IP regimens , either IP carboplatin or IP cisplatin , will proceed into a phase iii comparison with the intravenous arm . This exciting new study has gathered international support OBJECTIVES To evaluate reasons for discontinuing intraperitoneal ( IP ) chemotherapy , and to compare characteristics of patients who did versus did not successfully complete six cycles of IP chemotherapy .  METHODS In a phase III trial , women with optimal stage III ovarian or peritoneal carcinoma were r and omly allocated to receive IP therapy ( paclitaxel 135 mg/m(2 ) intravenously ( IV ) over 24 h , cisplatin 100 mg/m(2 ) IP day 2 , paclitaxel 60 mg/m(2 ) IP day 8) every 21 days for six cycles . Patients unable to receive IP therapy were treated with the alternate ( IV ) regimen . Variables compared included surgical procedures prior to enrollment , timing of IP catheter insertion , and primary and contributing reasons for discontinuing IP therapy . RESULTS Among 205 eligible patients r and omly allocated to the IP arm , 119 ( 58 % ) did not complete six cycles of IP therapy . Forty ( 34 % ) patients discontinued IP therapy primarily due to catheter complications and 34 ( 29 % ) discontinued for unrelated reasons . Hysterectomy , appendectomy , small bowel resection , and ileocecal resection were not associated with failure to complete six cycles . IP therapy  was not initiated in 16 % of patients who did versus 5 % of those who did not have a left colon or rectosigmoid colon resection ( P = 0.015 ) . There was no association between timing of catheter insertion and failure to complete IP therapy . CONCLUSIONS In this multi-institutional setting , it was difficult to deliver six cycles of IP therapy without complications . There appears to be an association between rectosigmoid colon resection and the inability to initiate IP therapy . Catheter choice , timing of insertion , and how surgical treatment of ovarian cancer influences the successful completion of intraperitoneal chemotherapy  require further study OBJECTIVE Currently , no long-term follow-up data are available on intraperitoneal ( IP ) carboplatin-based chemotherapy for ovarian carcinoma . In this study we evaluated retrospectively the survival and recurrence of a retrospective cohort of patients with epithelial ovarian cancer treated with first-line IP carboplatin-based therapy .  METHODS Records were review ed of 174 patients with epithelial ovarian cancer who received IP carboplatin-based therapy between 1990 and 2000 . All patients underwent surgical staging , and implantable port systems were placed regardless of residual tumor size . The pathological slides were su bmi tted and review ed , and then nine patients were excluded because of borderline malignancies ( n = 8) , and wrong histology ( n = 1 ) . Therefore , the records of 165 patients were analyzed for survival . Tumor grade was determined by the Universal grading system . Statistical analysis included tests for association between potential prognostic factors , and between prognostic factors and survival . Survival probabilities were estimated by Kaplan-Meier methods , and prognostic factors for survival were evaluated by a Cox regression model . RESULTS The mean age of the patients was 53.7 years ( range 21 - 83 ) . The median follow-up was 41 months . The distribution by stage and histology was as follows : high risk ( grade 2/3 , clear cell , capsule rupture ) stage I , 54 ; II , 21 ; III , 72 ; IV , 18 ; and serous , 75 ; clear cell , 30 ; mucinous , 27 ; endometrioid , 20 ; others , 13 . The chemotherapy regimen was either carboplatin alone ( n = 22 ) or in combination with cyclophosphamide ( n = 116 ) or paclitaxel ( n = 27 ) . Catheter-related complications occurred in 16 ( 9.7 % ) cases . The chemotherapeutic response in 54 patients with measurable disease was 66.4 % . The 5-year survival was 94.4 % for stage I , and 87.9 % for stage II . The median survival for optimal and suboptimal stage III/IV patients was 51 months and 34 months , respectively . The median survival of patients with stage III/IV disease was 51 months with carboplatin doses of 400 mg/m(2 ) or more , but it was only 25 months with carboplatin doses smaller than 400 mg/m(2 ) . Poor prognostic factors , determined by Cox regression multivariate analysis , were clear cell histology ( P < 0.001 ) and a carboplatin dose smaller than 400 mg/m(2 ) ( P = 0.002 ) . CONCLUSIONS Survival of patients who underwent carboplatin-based IP chemotherapy was excellent when the dose of carboplatin was higher than 400 mg/m(2 ) . A prospect i ve evaluation of IP carboplatin therapy with modern combination is warranted Cisplatin ( C ) or carboplatin ( CBP ) plus cyclophosphamide ( CTX ) was until recently considered st and ard chemotherapy for advanced ovarian cancer ( OC ) . Attempts to maximize platinum and its analog activity against OC include its administration directly into the peritoneal cavity . In the past we have shown that intraperitoneal ( IP ) CBP administration is a safe and effective treatment for OC [ Polyzos et al : Proc Am Assoc Cancer Res 1990;31 : 1120 ] . In the present study we aim ed to compare the effectiveness and toxicity of CBP administration either intravenously ( IV ) or IP plus CTX IV . Since 1990 , 90 evaluable patients with stage III OC were prospect ively r and omized to receive CBP 350 mg/m2 IV or IP plus CTX 600 mg/m2 IV ( in both groups ) every 3–4 weeks for six courses . The r and omization incorporated stratification according to performance status and the amount of residual tumor ( maximum diameter ≤2 or > 2 cm ) . Clinical assessment was performed with abdominal CT and serum CA-125 . Responses were observed in 33/46 = 72 % ( 95/CI 56.5–84.0 ) of the IV group and in 33/44 = 75 % ( 95/CI 59.7–86.8 ) of the IP group with 48 and 45 % clinical complete responses , respectively . Times to progression were 19 months ( 8–62 + ) for the IV group and 18 ( 6–72 + ) for the IP group . Median survivals were : 25 months ( 6–80 + ) and 26 months ( 6–72 + ) , respectively . Significantly more patients in the IV group than in the IP group had grade 3 or higher leukopenia ( p < 0.01 ) and grade 3 thrombocytopenia ( p < 0.09 ) . Morbidity due to infectious complications in the IP group was minimal . It seems that  IP CBP  is equally effective to IV administration in terms of response and survival with less myelotoxicity . The favorable results on survival demonstrated in studies with IP C administration in patients with small volume disease [ Alberts et al : N Engl J Med 1996;335:1950–1965 ] could not be repeated in the present study applying CBP in patients with variable tumor size and a relatively small number of patients . The likelihood that patients with large volume disease would benefit from a regional approach compared to systemic administration is small and this explains the inability to detect a difference between the two arms First-line intravenous chemotherapy ( CT ) following debulking surgery is associated with prolonged survival , in particular in patients who achieve a pathological complete remission ( pCR ) at second-look surgery but in whom a high rate of relapses still occurs . Between 1988 and 1997 , 153 patients in pCR following platinum-based intravenous CT were r and omized between four courses of intraperitoneal cisplatin ( P ) ( 90 mg/m2 every 3 weeks ) or observation .  Overall survival ( OS ) was the primary endpoint , while progression-free survival ( PFS ) was a secondary endpoint . This intent-to-treat analysis includes 16 patients who were not eligible and 17 patients who had protocol violations . The two groups were well balanced in terms of age ( median = 55 years ) , performance status ( 78 % P.S. O ) , FIGO stage ( 96 % stage III ) , histology ( serous in 66 % ) , grade ( 2 or 3 in 80 % ) , and residuum before intravenous CT ( > 1 cm in 40 % ) . Intraperitoneal CT was delivered mainly through intraperitoneal catheters ( Port-a-Cath 61 % and Tenckhoff 25 % ) . Side effects of intraperitoneal cisplatin  included vomiting [ ≥ grade 2 ( 82 % ) ] , rise in serum creatinine [ ≥ grade 2 ( 14 % ) ] , abdominal pain [ grade 1–2 ( 38 % ) ] , and neurotoxicity [ grade 2–3 (15%)].After a median follow-up of 8 years , 80 patients ( 52 % ) have progressed with no difference in the pattern of relapse between the two groups and 75 patients ( 49 % ) have died ; the respective hazard ratios for PFS and OS with 95 % CI are 0.89 ( 0.59–1.33 ) and 0.82 ( 0.52–1.29 ) . These results are suggestive of a treatment benefit but do not support a change in clinical practice . Other r and omized clinical trials of intraperitoneal CT are review ed and briefly discussed 20 patients with F.I.G.O. stages III ovarian cancer were entered into a r and omised trial between January 1980 and March 1984 . After a surgical resection as complete as possible , 10 of these patients received an intravenous chemotherapy with Adriamycin , Vincaleucoblastin Bleomycin , Fluorouracil and Ifosfamid monthly for 10 months . The other 10 patients received the same combined chemotherapy but by a double route : Intravenously and intraperitoneally . The results were judged at " second look surgery " . 1 Of the 10 patients who were treated intravenously , 2 who had had a complete surgical resection had no recurrence . Of the remaining 8 patients who had had an incomplete resection , 4 still had residual lesions that could not be removed completely Intraperitoneal chemotherapy has a strong biological and pharmacological rationale in the treatment of ovarian cancer . From 1989 to 1996 the present study included 113 patients with FIGO stage II-IV ovarian cancer with residual disease less than 2 cm who were r and omly allocated to receive 50 mg/m(2 )  intraperitoneal cisplatin ( CDDP ) plus 60 mg/m(2 ) intravenous epidoxorubicin ( EPIDOX ) and 600 mg/m(2 ) intravenous cyclophosphamide ( CTX ) ( ipPEC arm ) or 50 mg/m(2 ) intravenous CDDP plus 60 mg/m(2 ) intravenous EPIDOX and 600 mg/m(2 ) intravenous CTX ( ivPEC arm ) . Chemotherapy was repeated every 4 weeks for six cycles . Treatment protocol was changed in 22 patients , 2 from the iv arm ( who received single-agent carboplatin ) and 20 from the ip arm ( who were crossed to systemic chemotherapy , ivPEC , or single-agent carboplatin ) . At the end of chemotherapy , a second-look was performed in 33 of the 54 patients from the ip arm and in 34 of the 57 patients from the systemic arm . The pathologic complete response rate was 41 % of all entered patients and 69 % of patients su bmi tted to second-look . No significant difference in pathologic response rate as well as in hematologic and nonhematologic toxicities was seen between the two arms . Up to September 1998 , 72 patients showed a disease recurrence ( 33 treated with ipPEC and 39 treated with ivPEC ) , 55 died ( 22 ipPEC and 30 ivPEC ) , and 10 were lost to follow-up ( 6 ipPEC and 4 ivPEC ) . Median progression-free survival was 42 and 25 months for ipPEC and ivPEC , respectively ( p = 0.13 ) . Median overall survival was 67 and 51 months for ipPEC and ivPEC , respectively ( p = 0.14 ) . In conclusion , besides confirming that intraperitoneal chemotherapy is feasible with acceptable toxicity but with poor compliance in community hospitals , this trial showed that intraperitoneal CDDP compared with intravenous CDDP in combination with EPIDOX and CTX obtained a slight ( not significant ) improvement in progression-free survival and overall survival of optimally cytoreduced advanced ovarian cancer patients OBJECTIVE The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery ( CRS ) and hyperthermic intraperitoneal chemotherapy ( HIPEC ) in treatment-naive epithelial ovarian cancer ( EOC ) with advanced peritoneal involvement . Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy ( TTC ) . METHODS Twenty-six women with stage III-IV EOC were prospect ively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin . Then they received systemic chemotherapy with carboplatin ( AUC 6 ) and paclitaxel ( 175 mg/m(2 ) ) for 6 cycles . RESULTS Macroscopically complete cytoreduction was achieved in 15 patients ; only minimal residual disease ( ≤2.5 mm ) remained in 11 . Major complications occurred in four patients and postoperative death in one . After a median follow-up of 25 months , 5-year overall survival was 60.7 % and 5-year progression-free survival 15.2 % ( median 30 months ) . Excluding operative death , all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment ( range : 29 - 75 ) . The median number of cycles per patient was 6 ( range : 1 - 8 ) . The time to chemotherapy did not affect the OS or PFS . CONCLUSIONS In selected patients with advanced stage EOC , upfront CRS and HIPEC provided promising results in terms of outcome . Morbidity was comparable to aggressive cytoreduction without HIPEC  . Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival . These data warrant further evaluation in a r and omized clinical trial PURPOSE To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous ( IV ) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin . PATIENTS AND METHODS Patients were r and omized to receive either IV paclitaxel 135 mg/m(2 ) over 24 hours followed by IV cisplatin 75 mg/m(2 ) every 3 weeks for six courses or IV carboplatin ( area under curve 9 ) every 28 days for two courses , then IV paclitaxel 135 mg/m(2 ) over 24 hours followed by intraperitoneal ( IP ) cisplatin 100 mg/m(2 ) every 3 weeks for six courses . RESULTS Of the 523 patients who entered this trial , 462 were determined to be assessable , with prognostic factors well balanced between the treatments . Neutropenia , thrombocytopenia , and gastrointestinal and metabolic toxicities were greater in the experimental arm . As a result , 18 % of the patients received < or = two courses of IP therapy . Progression-free survival was superior for patients r and omized to the experimental treatment arm ( median , 28 v 22 months ; relative risk , 0.78 ; log-rank P = .01 , one-tail ) . There was a borderline improvement in overall survival associated with this regimen ( median , 63 v 52 months ; relative risk , 0.81 ; P = .05 , one-tail ) . CONCLUSION An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a st and ard regimen of IV cisplatin and paclitaxel . Because the improvement in overall survival was of borderline statistical significance and toxicity was greater , the experimental arm is not recommended for routine use . However , the results provide direction for further clinical investigation in small-volume ovarian cancer
BACKGROUND Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history .
These features have made it an obvious target for intraperitoneal ( IP ) chemotherapy .
Chemotherapy for ovarian cancer is usually given as an intravenous ( IV ) infusion repeatedly over five to eight cycles .
Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity .
There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy .
OBJECTIVES To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival , progression-free survival , quality of life ( QOL ) and toxicity in the primary treatment of epithelial ovarian cancer .